In the first study to ever assess the prognostic value of a change
in heart rate (HR) over a number of years, French doctors have found
that there is a relation between this variable and mortality. Dr
Xavier Jouven (Hôpital Européen Georges Pompidou, Paris, France) and
colleagues report their findings in a study published online
November 7, 2008 in the American Journal of Cardiology [1].

They found that in a cohort of healthy policemen, HR at rest and its
change over 5 years were both predictors of death, independent of
the standard cardiovascular risk factors. Those whose HR rose by
more than 3 beats per minute (bpm) over this time period had an
almost 20% increased mortality risk compared with men whose HR
remained unchanged.

Jouven told heartwire that this is "an important paper and the
second step" in a jigsaw. "We knew before that if a person has a
high heart rate, they have a high mortality. Now this article shows
we are advancing in the research concerning the potential
association between HR and mortality."

Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York) commented
to heartwire: "The present study is unique in that it shows that
patients whose heart rate increased during a 5-year period had
an . . . increased mortality risk. Of note, the policemen who did
best were the ones who had a low heart rate at the beginning of the
PARIS prospective study and whose heart rate remained unchanged."

Reduced HR Associated With 14% Lower Risk of Death

The observational, although prospective, study followed 5139
asymptomatic men (aged 42 to 53 years) who were recruited from 1967
to 1972 and had their HRs measured at rest in standardized
conditions every year for 5 consecutive years. HR change was defined
as the difference between HR at examination 5 and HR at inclusion.
Subjects were divided into the following tertiles: decrease >4 bpm;
unchanged (from -4 to +3 bpm); or increase >3 bpm.

After adjustments were made for confounding factors, including
baseline HR at rest, and compared with subjects with unchanged HRs,
those with decreased HRs during the 5 years had a 14% decreased
mortality risk (RR, 0.86; 95% CI, 0.74 to 1.00; p=0.05), whereas men
with increased HRs during the 5 years had a 19% increased mortality
risk (RR, 1.19; 95% CI, 1.04 to 1.37; p<0.012).

Because the study was performed in relatively young French
policemen, the generalizability of the findings to women or a more
unselected or recent population cohort is unclear, the researchers
point out.

They say that the association between high HR at rest and mortality
is consistent with data already published in a number of
epidemiologic studies, and that high HR at rest could reflect
underlying abnormalities, possibly via increased mechanical stress
on the arterial wall and heart.

"We found that change in HR over a 5-year period conferred
additional information beyond HR at rest and the usual risk factors,
[and] was an independent predictor of mortality in middle-aged men,"
they observe.

Exercise Keeps Heart Rate Low

Messerli told heartwire that "the most common reason for a slow
heart rate in young to middle-aged subjects, such as in the present
study, is regular conditioning. Conceivably therefore, subjects in
this group were the ones who exercised regularly and continued to
exercise regularly throughout the 5-year period, thereby keeping
heart rate slow. As expected, BMI was lowest in this group."

"It is of little surprise, then, that these slow heart rate
policemen had a drastically lower mortality than those who started
out with an increased heart rate [that] accelerated . . . even more
during the 5-year period," he added.

Jouven told heartwire that the next step to prove an association
will be with some kind of interventional trial aimed at
investigating whether an induced HR decrease--with, for example
regular exercise--is associated with a decrease in mortality
risk. "If we change HR, do we change mortality?" he wondered.


Jouven X, Empana JP, Escolano S et al. Relation of heart rate at
rest and long-term (>20 years) death rate in initially healthy
middle-aged men. Am J Cardiol. Published online before print
November 7, 2008. DOI:10.1016/j.amjcard.2008.08.071.

In the largest study to date looking at the issue, researchers
report that survival in heart-transplant recipients is significantly
reduced if recipients receive a heart from a donor of the opposite
sex.

According to Dr Eric Weiss (Johns Hopkins Medical Institutions,
Baltimore, MD), who presented the analysis during the American Heart
Association 2008 Scientific Sessions, the findings should help
transplant programs choose the best recipient for a heart transplant
when a donor organ becomes available.

In an interview with heartwire, Weiss explained that gender matching
has been explored in other solid-organ transplants and even in the
setting of heart transplantation, but in small numbers, typically at
single-center institutions. For his study, Weiss and colleagues used
the United Network for Organ Sharing, containing information on more
than 18 000 heart-transplant recipients who underwent
transplantation between 1998 and 2007.

They found that 77% of men and 51% of women had actually been
matched by gender to their donor and that gender-matching was
associated with a 15% reduction in adjusted, all-cause, cumulative
mortality. Patients at greatest risk of dying over the study follow-
up were women who had received hearts from male donors, a
statistically significant 23% increased risk as compared with men
who received hearts from male donors, followed by males who received
hearts from female donors, a 15% increased risk. By far, male
recipients of male hearts had the lowest mortality out to nine years-
-61%, as compared with 54% in women who'd received a heart from a
male donor, a statistically significant difference (p<0.001 by log
rank test).

In secondary analyses, the authors also looked at gender mismatch
and transplant rejection and found that gender mismatch was
associated with organ rejection only in men who'd received hearts
from female donors. In fact, female recipient gender in itself was a
risk factor for rejection, regardless of the sex of the donor.

According to Weiss, gender is already taken into account during
donor-recipient selection, in part due to the size of the chest
cavity. Many women, for example, cannot physically accommodate a
larger (male) heart due to the constraints placed by the chest wall.
Physiologically, he added, sex matters in terms of functional
capacity. "The heart needs to have the functional reserve, the
beating power, to pump to a large body," Weiss explained.

Other factors include the minor histocompatibility antigen on the Y
chromosome, believed to be an important cause of transplant
rejection, and what Weiss called the "hormonal milieu," which
appears to confer benefit when the donor and recipient are of the
same gender. But overall, he said, the reasons underpinning gender-
matching are incompletely understood and were not something that
could be probed in any depth in the current study.

"With these multi-institutional databases, it's a little hard,
because we are at the mercy of the variables that individual
institutions have collected," Weiss said. "So this study would have
been designed a bit differently if we had been collecting the
variables ourselves."

According to Weiss, the current study is part of an ongoing effort
to create a risk score for predicting patient outcomes. "Our focus
is on understanding factors that lead to improved outcomes after
heart transplantation. This is one factor, and clearly there are
other factors--as we learn more about this we can improve our
ability to match donors and recipients."

He emphasized that patients who have received a heart from someone
of the opposite sex or physicians with patients whose hearts
are "gender mismatched" should not be overly concerned. "We don't
want people to think that this somehow means they're going to have a
poor outcome. It still is much better to receive a transplant than
to live with end-stage heart failure, even if you have a mismatched
organ, especially if the organ is matched in a lot of other ways,
from a [human leukocyte antigen] standpoint or an age standpoint--
that kind of thing."

But he also emphasized that the information could help guide
decision-making, particularly since the number of patients needing
heart transplantation far exceeds the number of donor organs. "If
all else is equal and you're trying to decide which recipient should
get a heart, it would probably be better to take a donor of the same
sex," he said.

Custom-compounded plant-derived hormone cream may not only improve
menopausal symptoms, including depression, anxiety, and pain, it may
also provide an anti-inflammatory effect without increasing blood-
clot formation, a small study suggests.

Researchers at the University of Texas Health Science Center, in
Tyler, found promising 1-year safety and efficacy results in 75 peri-
  and postmenopausal women who received individually formulated
hormone-replacement therapy applied as a cream to the skin.

"The 1-year findings are pretty encouraging," lead author Kenna
Stephenson, MD, told Medscape Psychiatry. "We thought compounded
transdermal hormones would relieve menopausal symptoms, but we
didn't anticipate that they would also have a favorable effect on
inflammatory, hemostatic, and cardiometabolic pathways."

The study was presented here at the American Heart Association 2008
Scientific Sessions.

Unproven Safety and Efficacy

In the United States, about 15 million women are currently peri- or
postmenopausal and, as such, have an increased risk for
cardiovascular disease, said Dr. Stephenson.

Since the Women's Health Initiative study showed an increased risk
for breast cancer, stroke, and dementia with conventional hormone
therapy, more women have been seeking alternative treatments for
menopausal symptoms, such as hot flashes, night sweats, disrupted
sleep, and irritability.

"We've seen an increase in the use of compounded transdermal hormone
therapies among this population, but the safety and efficacy of
these formulations have not been studied," she said.

To evaluate the hemostatic and anti-inflammatory effects of a
compounded transdermal hormone-replacement therapy, the researchers
recruited 150 peri- and postmenopausal women, aged 30 to 70 years.

Half were assigned to usual care and the rest were assigned to the
compounded cream. Usual care was defined as conventional hormone
therapy of conjugated equine estrogens and medroxyprogesterone.

The transdermal hormonal therapy consisted of plant-derived
estrogen, progesterone, and sometimes testosterone and
dehydroepiandrostenedione (DHEA).

Subjects in the transdermal-cream group were prescribed
individualized therapy on the basis of their hormone levels. The
women applied the cream to the skin once or twice daily to receive
the target dose.

Although progesterone and DHEA are available over the counter in the
United States, the doses of prescribed therapy, such as those used
in the study, are much higher.

Encouraging Findings

At 12 months, the subjects who received the study treatment had:

Significant decreases in depression and anxiety, as assessed by the
Hamilton Depression Scale and the Hamilton Anxiety Scale
Significant improvements in quality of life and menopausal symptoms,
such as hot flashes and night sweats, as assessed by the Greene
Climacteric Scale
No harmful hemostatic effects, as indicated by significant decreases
in fibrinogen and factor VII, and no significant changes in factor
VIII or plasminogen activator inhibitor type I.
No harmful anti-inflammatory effects, as shown by significant
decreases in C-reactive protein (CRP), and no significant changes in
interleukin-6
Beneficial cardiometabolic effects, as shown by significant
decreases in systolic blood pressure, pulse pressure, fasting
glucose, and fasting triglycerides.

Still Early Days

"All hormones are not equal, and all hormone preparations are not
equal," said Dr. Stephenson. "There are distinctly different risks
and effects on inflammatory and thrombotic factors and
cardiovascular biomarkers."

In this study, CRP and triglycerides decreased in women who received
transdermal plant-derived compound hormones, whereas other studies
have shown increased CRP and triglycerides in women receiving
conventional equine and synthetic hormone therapy, she added.

However, "larger clinical trials are needed to determine whether
this therapy is a good alternative to conventional hormone-
replacement therapy," she said.

"Patients Like It"

"Many perimenopausal and postmenopausal women with mood symptoms may
be given antidepressant therapy or anti-anxiety therapy, but by
treating the underlying cause ¡X hormonal changes ¡X we see a
statistically significant improvement in dysphoria," said Dr.
Stephenson.

She added that patients in her clinical practice who receive
compounded transdermal hormone-replacement therapy like it because
it is easy, there are few adverse effects, it is very well
tolerated, and it is effective for mood symptoms and hormone-related
symptoms, such as vaginal dryness and night sweats."

It is important, she added, that a trained compounding pharmacist
prepare transdermal hormone-replacement therapy. The International
Academy of Compounding Pharmacists, which helped fund the study,
lists such pharmacists on their Web site. Other information is
available from the Professional Compounding Centers of America
(PCCA) and the PCCA Canada Web sites.

The study was partly funded by the Progesterone Foundation and the
International Academy of Compounding Pharmacists. The study authors
have disclosed no relevant financial relationships.

American Heart Association (AHA) 2008 Scientific Sessions: Abstract
5071. Presented November 11, 2008.

Patients with atrial fibrillation (AF) who received dronedarone
(Multaq, Sanofi-Aventis) were less often hospitalized for
cardiovascular reasons regardless of whether the cause of hospital
admission was AF or something else, in a large placebo-controlled
trial that--researchers say--offered those hints and others that
some of the drug's clinical benefits may derive from
nonantiarrhythmic effects [1].

Moreover, as an antiarrhythmic agent, dronedarone displayed both
rate- and rhythm-controlling properties in the trial, called ATHENA,
which randomized >4500 "moderate- to high-risk" patients with AF
[2].

Those secondary findings were reported here last week at the
American Heart Association 2008 Scientific Sessions. In
presentations earlier this year, as reported by heartwire, the trial
had shown a 24% drop in the primary end point of CV hospitalization
or death and a 34% decline in risk of stroke in the dronedarone
group compared with placebo over its mean 21-month follow-up.

"The amazing thing about this data set is the consistency of the
findings," Dr Richard L Page (University of Washington, Seattle),
told heartwire, pointing to independent dronedarone-related declines
in hospitalization rate of 37% when the cause of admission was AF
and 14% when it wasn't AF (both significant), 30% when it was acute
coronary syndromes (perhaps significant), and 14% (nonsignificant)
when the cause was heart failure. The "intriguing but not
definitive" risk decreases that fell short of significance, he
said, "at least all go in the right direction."

The results of ATHENA can be interpreted only so far, as the drug
has not been directly compared with the likeliest drug AF patients
might now receive, amiodarone; a comparator trial called DIONYSUS is
ongoing, observed Page, who reported ATHENA's secondary results at
the meeting. But if the drug's benefits vs placebo seen in ATHENA
are borne out in further studies, he noted, some AF patients who
might not respond to or tolerate amiodarone could become candidates
for dronedarone.

Observers of ATHENA agree that dronedarone has so far shown a fairly
benign safety profile, with rates of clinically important adverse
events similar to those seen with placebo. That contrasts it with
its chemical cousin amiodarone, which is notorious for its potential
end-organ toxicities.

But observers also note that dronedarone's ability to suppress AF
doesn't seem quite as strong as that of amiodarone. Moreover, many
have reservations about using the drug in patients with heart
failure; the two conditions commonly coexist. As previously reported
by heartwire, a trial called ANDROMEDA had been terminated early
after an apparent mortality increase with the drug among the
trial's "high-risk" patients with systolic heart failure. ATHENA
excluded patients with NYHA class 4 heart failure.

The trial randomized patients with paroxysmal or persistent AF or
atrial flutter to receive dronedarone (400 mg twice daily, n=2301)
or placebo (n=2327); beta blockers, calcium-channel blockers, and
digoxin were used as frequently in one group as the other.
Participants were required to be older than 75 years or, in the
presence of at least one other risk factor, older than 70 years; the
other risk factors could be diabetes, hypertension, a history of
stroke, reduced LVEF, or atrial enlargement.

There was no significant difference in rate of non-CV
hospitalizations.

Among patients in sinus rhythm at baseline, the median time to first
recurrence of AF or atrial flutter was significantly improved in the
active-therapy group: 737 days vs 498 days on placebo (hazard ratio
0.75, 95% CI 0.68¡V0.82; p<0.001).

At least one electrical cardioversion occurred in 14.7% and 20.7% of
the patients, respectively (HR 0.68, 95% CI 0.60¡V0.79; p<0.001).

Associated with the significant observed dronedarone-related
reductions in morbidity was significantly reduced hospitalization
time for patients taking the drug, observed Page. Actively treated
patients spent about 28% fewer days in the hospital and about 35%
fewer when hospitalized for CV reasons (both differences p<0.001).

"That reduction of almost 4000 hospital days translates to a
decrease of 1.26 hospitalization days per patient per year,"
according to Page. "Almost 500 of those days were in the CCU or ICU,
and a good number were in medium care." That, he said, "would
translate into significant savings."

Interestingly, heart rate during AF or atrial flutter also decreased
significantly in the dronedarone group compared with placebo; the
median and mean both fell by 9 bpm (p<0.001 for both). That and
other observations, according to Page, suggest that dronedarone,
like amiodarone, has cardiovascular effects that aren't directly
antiarrhythmic but may contribute to clinical benefits.

For example, Page observed that systolic blood pressure dropped
among ATHENA's actively treated patients compared with controls. "A
little bit, by about 2 mm Hg, which may play a role when it's spread
over this many patients." Also, as heartwire previously reported,
dronedarone appeared to reduce the risk of stroke.

Moreover, according to Page, there were 473 patients in the trial,
178 on dronedarone and 295 in the placebo group (p<0.001), who never
produced an ECG showing sinus rhythm and so were classified as
having permanent AF--yet as a group showed a trend of a 26% drop in
risk of CV hospitalization or death (p<0.10). "They had a hazard
ratio [for the primary end point] almost identical to the overall
study population," he said. "They did not reach a 0.05 p value
because they were in the minority, but it suggests that there could
be something going on here over and above the antiarrhythmic effect."

ATHENA was sponsored by Sanofi-Aventis. Page has disclosed being an
advisor or consultant for Sanofi-Aventis and Astellas. At least two
ATHENA coauthors are employees of Sanofi-Aventis.


Torp-Pedersen C, Page RL, Connolly SJ, et al. The effect of
dronedarone on hospitalizations in patients with atrial
fibrillation. Results from the ATHENA study. American Heart
Association 2008 Scientific Sessions; November 8-12, 2008; New
Orleans, LA. Abstract 4101.
Page RL, Connolly SJ; Crijns HJ, et al. Rhythm- and rate-controlling
effects of dronedarone in patients with atrial fibrillation:
Insights from the ATHENA trial. American Heart Association 2008
Scientific Sessions; November 8-12, 2008; New Orleans, LA. Abstract
4097.

An international genomewide association study has identified 6
genetic loci associated with serum lipid levels in European
populations. This brings to 22 the total number of genomic regions
affecting serum lipid levels, a major risk factor in cardiovascular
disease. The study, presented here at the American Society of Human
Genetics 58th Annual Meeting, is part of the ENGAGE Consortium, an
extensive research project funded by the European Union.

Presenter Samuli Ripatti, PhD, from the Karolinska Institute, Solna,
Stockholm, Sweden, and the University of Helsinki, Finland, reported
that the study combined genomewide association data from 16 European
cohorts of nonselected population-based samples. A total of 22,562
samples were collected. "We also extended the definition of Europe a
bit to be inclusive," he added, noting that there were 424 samples
from Australia.

The threshold for genomewide significance was <5 x 10¡V8. Analysis
for loci associated with total cholesterol levels found 3 loci not
previously identified in genomewide association studies: TMEM57 (P =
5.4 x 10¡V10), ABCG5 (P = 1.5 x 10¡V11), and FADS3/FADS2 (P = 1.5 x
10-10), on chromosomes 1, 2, and 11 respectively. An additional
locus on chromosome 7 was associated with low-density lipoprotein
(LDL) cholesterol levels (DNAH11; P = 6.1 x 10¡V9), and 2 additional
loci were associated with serum high-density lipoprotein (HDL)
cholesterol levels: the CTCF-PRMT8 region (P = 8.3 x 10¡V16) on
chromosome 16 and the MADD-FOLH1 region (P = 6 x 10¡V11) on
chromosome 11. The large HDL-related region on chromosome 11 merits
further functional studies.

The 22 genomic regions associated with serum lipid levels account
for as much as 5.6% of the variation in serum lipid levels at the
population level. Three of these loci have differential effects in
men and women. "The females, in total, have more than 2 times the
effect size than the males," said Dr. Ripatti in his presentation.

Senior author Cornelia M. van Duijn, PhD, head of the Genetic
Epidemiology Unit, Erasmus University Medical Center, Rotterdam, the
Netherlands, commented to Medscape Pathology & Lab Medicine by
email: "Although we know a lot about the difference in the blood
distribution of lipids between men and women, in particular
concerning HDL and triglycerides, we know very little about
differences in the impact of genes in humans. The reason is
statistical," said Dr. van Duijn.

"To show differences between subgroups (in this case, men vs women),
we needed roughly 4 times the sample size than that needed to
discover the gene.... With 20,000 to 30,000, we are beginning to
find genes with small effects. We need to study more than 100,000
persons to find genes that act only in men or women," Dr. van Duijn
observed. "We are trying to achieve this number by merging consortia
into a large one: global lipids."

To calculate genetic-risk scores, the investigators not only looked
at the risk alleles per person, but also weighted risk alleles by
their effect sizes, as estimated in the complement cohorts. They
calculated genetic risk for subjects in the Rotterdam study, a large
longitudinal study, focused on subjects older than 55 years.

Dr. van Duijn added: "If you are interested in the effect of lipids
[over a] lifetime, you do not want to study a young population, in
which there will be many persons who still have not developed
pathology yet, but who will in the future.... In women in
particular, the lipid levels change drastically after menopause (¡Ó50
years). This is one of the 'forgotten' side effects. We tend to
think of osteoporosis as the major problem, but lipids change as
dramatically postmenopausally. In the Rotterdam study, we can be
fairly sure that we can see the lipid problems."

The investigators looked at the predictive power of the genetic-risk
scores for future cases of hypercholesterolemia, intima-media
thickness, and coronary heart disease. "The bottom line," said Dr.
Ripatti, "was when we looked separately at the risk scores based on
the HDL genes, the LDL genes, and the total-cholesterol genes. One
of the findings was that the total-cholesterol genes had the most
predictive power for all of these." Total-cholesterol scores were
significantly associated with risk for hypercholesterolemia (P
< .001), intima-media thickness (P = .001), and coronary heart
disease (P = .042).

Medscape Pathology & Lab Medicine also spoke with comoderator Ruth
McPherson, MD, PhD, FRCPC, director of the Lipid Clinic, Lipid
Research Laboratory, University of Ottawa Heart Institute, in
Ontario. "We're now having the opportunity to go beyond SNPs [single-
nucleotide polymorphisms] that confer effects on [coronary heart
disease] risk factors, like proteins that are associated with risk,
to actually look at SNPs that may have gender-specificity," Dr.
McPherson said.

"We've known in genetics for many years, in many areas, that genetic
variants may interact with other factors...so that should be pointed
out as something that we have to do in the consortiums that are
sharing their data from various genomewide association studies,"
said Dr. McPherson. "We're now able to look at things like gender
effects and effects of other lifestyle factors, looking at gene-
environment interactions. And I think that's going to be pretty
exciting."

Atherosclerosis progression as gauged by intravascular ultrasound
(IVUS) was unaffected by a year and a half of treatment with
rosiglitazone (Avandia, GlaxoSmithKline), compared with more
conventional treatment with the sulfonylurea glipizide (Glucotrol,
Pfizer) in diabetics with CV disease, reported investigators at the
American Heart Association 2008 Scientific Sessions [1].

In their international trial, called Assessment on the Prevention of
Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes
Patients with Cardiovascular History (APPROACH), there were no
suggestions of any of a host of potential clinical hazards and
adverse effects that have been attributed to rosiglitazone over the
past 18 months, as covered extensively by heartwire. In particular,
the trial, with fewer than 700 patients, showed no significant
differences between the two antidiabetic therapies with respect to
risk of CV death, new MI, heart failure, peripheral edema, or bone
fracture.

Despite the trial being negative for its primary end point, its
investigators pointed to secondary suggestions that the controversial
thiazolidinedione (TZD) may have had an antiatherosclerotic effect
among the trial's CV patients with more established diabetes.

"I do think it's reassuring as far as the effect of the drug on the
coronary arteries," APPROACH principal investigator Dr Richard W
Nesto (Lahey Clinic Medical Center, Burlington, MA), who presented
the trial at the meeting, said at a press conference. The data
suggest that rosiglitazone is not proatherosclerotic, at least, "and
I think the data suggest it could be antiatherosclerotic."

Also at the press briefing, Dr Beatriz Rodriguez (Pacific Health
Research Institute, Honolulu, HI), the assigned discussant for
Nesto's formal presentation, acknowledged the recent controversies
about rosiglitazone, including suggestions in a controversial meta-
analysis from 2007 that suggested the drug increases the risk of MI
and CV death. APPROACH, on the other hand, "suggests that
rosiglitazone may be associated with a reduction in the total
atheroma volume," she said, referring to another secondary
observation. "But we need to be cautious with this interpretation."

APPROACH randomized 672 patients with type 2 diabetes and indications
for coronary angiography or PCI, at least one clinically significant
coronary lesion, and 10% to 50% narrowing of at least one untreated
coronary artery. They could be on up to three antidiabetic agents and
had to have an LVEF of at least 40% and be free of heart failure.

Among the 339 patients who received glipizide at 15 mg/day and the
333 who took rosiglitazone at up to 8 mg/day, 54% were on one and 28%
were on two other antidiabetic agents. Other medication use by the
end of the trial included aspirin in about 84%, beta blockers in 67%,
ACE inhibitors or angiotensin-receptor blockers in about 74%, statins
in about 80%, and metformin in about 66% of patients.

When atherosclerosis progression over 18 months was measured in terms
of "percent atheroma volume" (PAV) in the study's primary analysis,
there was no significant difference between the treatment groups.

There were no significant differences in a composite clinical end
point that included death from any cause, nonfatal MI, or stroke,
revascularization, or hospitalization for ischemia; a composite end
point including CV death or nonfatal MI or stroke; death from any
cause; or new congestive heart failure, Nesto reported.

Prespecified subgroup analyses suggested that any rosiglitazone
antiatherosclerotic effect may be stronger in patients with longer-
established diabetes, and there was a favorable trend in older
patients.

Neither APPROACH nor another study that used IVUS to assess disease
progression in TZD-treated diabetics with CV disease, called
PERISCOPE, were large enough to say much conclusively about the
drugs' safety or efficacy in that population, Dr Mark A Creager
(Brigham and Women's Hospital, Boston, MA), who wasn't part of either
trial, told heartwire. Creager has been a member of the writing
committees for a range of guidelines from the North American
cardiology societies on the use of coronary interventions and the
treatment of acute coronary syndromes and arrhythmic and valvular
diseases.

As reported by heartwire, PERISCOPE tracked the same IVUS metric used
in APPROACH in 543 patients treated with either pioglitazone (Actos,
Takeda Pharmaceuticals) or the sulfonylurea glimepiride (Amaryl,
Sanofi-Aventis). But unlike APPROACH, the trial showed a significant
slowing of atherosclerosis progression compared to the more
traditional drug.

Nesto RW. Assessment on the Prevention of Progression by
Rosiglitazone on Atherosclerosis in Type 2 Diabetes patients with
Cardiovascular History (APPROACH). American Heart Association 2008
Scientific Sessions; November 12, 2008; New Orleans, LA. Late
Breaking Clinical Trials Session 4.

In the largest and reportedly most clinically detailed population-
based study of carotid endarterectomy to date, researchers outline 11
risk factors for poor outcomes. The results appear online October 23
in Stroke and are expected to influence guideline updates.

"Carotid revascularization is very much a time trade-off," lead
investigator Ethan Halm, MD, from the University of Texas
Southwestern Medical Center, in Dallas, told Medscape Neurology &
Neurosurgery. "We don't want to cause a stroke to prevent a stroke,"
he said.

New endovascular procedures for treating internal carotid artery
stenosis with angioplasty and stenting techniques are growing in
popularity but are controversial.

Researchers point out that although the results of randomized
controlled trials comparing stenting with carotid surgery are mixed
and the appropriate role for stenting is uncertain, it is largely
promoted as an option for patients who are considered high risk or
too old or too sick to safely undergo carotid endarterectomy.

This underscores the need for empirically validated data on risk
factors for perioperative death or stroke after surgery," they write.

Known as the New York Carotid Artery Surgery Study, this new
initiative includes more than 9300 patients. Carotid endarterectomies
were performed by 482 surgeons in 167 hospitals.

Investigators obtained clinical data from medical charts to assess
sociodemographic, neurological, and comorbidity risk factors. Dr.
Halm and his team developed a multivariable model predicting the risk
for death or stroke within 30 days of carotid endarterectomy.

Asymptomatic Patients Not Necessarily Low Risk

Most previous studies focused on differences in complications between
patients operated for symptomatic vs asymptomatic carotid disease.
These new results confirm the well-documented finding that
symptomatic patients have twice the risk for perioperative death or
stroke. But it raises important new issues as well.

These studies and current national guidelines largely consider
asymptomatic patients a homogenous low-risk group. This new finding
suggests otherwise.

"Asymptomatic patients with a history of distant cerebrovascular
disease have one-third higher risk-adjusted complication rates
compared with patients with no history of stroke or [transient
ischemic attack] TIA," Dr. Halm said during an interview. "This is
important because three-quarters of carotid endarterectomies in the
United States are performed in asymptomatic patients, and these
patients have less to gain from surgery."

The presence of a deep carotid ulcer was of borderline significance,
with an odds ratio of 2.08 (95% CI, 0.93 ¡V 4.68).

The investigators point to several limitations to their work,
including the study's observational cohort design. As a result,
researchers relied on information on risk factors and complications
documented in medical records. There was no standard approach to pre-
or postsurgical assessment as could have been done in a prospective
trial.

"These results have several practical implications," Dr. Halm
said. "From a clinical standpoint, information about risk factors
should help referring physicians, neurologists, surgeons, and
anesthesiologists better weigh the risks and benefits of carotid
endarterectomy for an individual patient."

He explained, "This prognostic information may also help identify
those who might be considered potential candidates for carotid
stenting because they are too high risk for carotid endarterectomy."

Researchers who fitted study subjects with "air-pollution vests" to
continuously monitor exposure to both indoor and outdoor air
pollutants say that people are probably exposed to much higher levels
of pollutants than community monitoring stations typically indicate
and that this exposure affects both endothelial function and systolic
blood pressure.

Dr Robert Brook (University of Michigan, Ann Arbor) and colleagues
presented a poster with the results of their Detroit Exposure and
Aerosol Research Study (DEARS) during the American Heart Association
(AHA) 2008 Scientific Sessions. In an interview with heartwire, study
coauthor Robert Bard said that the results should serve as a reminder
to cardiologists, who tend to forget the extent to which air
pollution can harm the heart.

"Cardiologists are really not aware of this as a risk factor," Bard
said, despite a 2004 AHA scientific statement warning about the
cardiovascular risks of air pollution. What's needed, Bard said,
is "a greater awareness that air pollution is contributing to CVD."

Something in the Air

Brook, Bard, and colleagues enlisted 65 people--most of them women--
between the ages of 19 and 80 living in three areas of Detroit. All
subjects wore pollution-monitoring vests for 24 hours over five
consecutive days in the summer and five consecutive days in the
winter, only taking the vests off to shower or sleep, in which case
they were instructed to keep the vests close to them, in the same
room. As a result, Bard explained, the vests picked up not only
communitywide pollutants but exposures in the home, as well as short-
term exposures, when subjects walked past someone smoking or a bus
pulling away from a curb and emitting a burst of exhaust.

Investigators found that mean personal exposure to fine particulate
matter <2.5 µm (PM2.5), combining both indoor and outdoor exposures,
was 21.9 µg/m3 but ranged up to 225.4 µg/m3--much higher than that
being measured at community monitoring stations, which was a mean of
15.4 µg/m3 and a maximum of 41 µg/m3. Strikingly, a 10-µg/m3 increase
in personal exposure in the study was associated with brachial blood
vessel diameter narrowing within two days of the exposure and
increased systolic blood pressure (by 1.6 mm Hg) after one day of
exposure.

According to Bard, the main types of air pollutants detected by the
vests were "by-products of combustion," namely motor-vehicle exhaust
and second-hand cigarette smoke, despite the fact that all study
participants were nonsmokers living in nonsmoking households. Smoking
is still permitted, for example, in restaurants in Michigan, Bard
noted.

"Air pollution is actually noted as the 13th leading cause of death
worldwide," Bard reminded heartwire. "We already knew that air
pollution is associated with adverse cardiovascular events, including
increases in blood pressure, but the novel aspect here is that we
were measuring pollution that people were directly exposed to and
evaluating cardiovascular function. We found that the average person
in our study had increased blood pressure and reduced endothelial
function from the air they were exposed to in the previous 24 hours.
And importantly, these results were shown despite levels of ambient
air pollution that were at or below those recommended in the current
EPA guidelines."

He continued: "Patients shouldn't panic, because these levels are
still relatively low. But people need to be more aware of air
pollution as a CVD contributor and to support clean-air initiatives.
And if you have cardiovascular disease, you may need to try to avoid
exposure to air pollution at peak times."

Heart-failure patients participating in a highly structured exercise
program in the HF-ACTION trial, reported here at the American Heart
Association (AHA) 2008 Scientific Sessions, saw no significant
reductions in all-cause mortality or all-cause hospitalization as
compared with patients getting "usual care," including
recommendations for daily exercise.

But in secondary analyses, where investigators adjusted for what
they called the "strongest prognostic factors," the structured-
exercise group did show significant reductions in the combined
primary end point, as well as in the secondary end point of
cardiovascular mortality and heart-failure hospitalization.

On these grounds, co-principal investigator for the study, Dr
Christopher O'Connor (Duke University Medical Center, Durham, NC),
concluded: "The HF-ACTION study results support a structured
exercise training program for patients with reduced LV function and
HF symptoms in addition to evidence-based therapy."

HF-ACTION randomized 2331 heart-failure patients (NYHA class 2-4,
ejection fraction <35%) to either an exercise program focused on
increasing workout intensity and duration or to usual care, in which
exercise was simply encouraged, but without specific advice. The
structured-exercise group began with 36 supervised training sessions
for 30 minutes of exercise three times per week. Halfway through
this period, patients were given a treadmill or stationary bicycle
to use at home along with a heart-rate monitor and were advised to
work out five times per week at moderate intensity for 40 minutes.
The usual-care group, by contrast, was told at the study outset to
try to exercise at moderate intensity, 30 minutes per day, as
recommended by the ACC/AHA, but were not supervised or encouraged
along the way

Taking Action

After a mean of 2.5 years, rates of all-cause mortality and all-
cause hospitalizations combined were not significantly different
between the two groups. In secondary analyses, however,
investigators used what they termed prespecified major prognostic
factors identified at the outset of the trial--heart-failure
etiology, exercise duration, left ventricular ejection fraction,
Beck depression inventory, and history of atrial
fibrillation/flutter. When the analysis was adjusted for these
prognostic factors, the composite primary end point was
significantly reduced by 11%, and a composite of cardiovascular
mortality/heart-failure hospitalization was reduced by 15%.

In a comparison of safety outcomes--such as rates of cardiovascular
events, ICD firing, hospitalization for physical activity, or
fracture of the hip/pelvis--event rates were very similar between
the two groups. "One of the most important findings was that
exercise at this level was safe," O'Connor said.

Despite missing its primary end point, said O'Connor, "The HF-ACTION
study results support a structured exercise training program for
patients with reduced LV function and HF symptoms in addition to
evidence-based therapy."

Compelling Results

Discussing the results following their presentation, Dr Philip Poole-
Wilson (Imperial College London, UK) also took the view that HF-
ACTION provides support for a more intense and structured exercise
programs.

"Some people would say, well, they missed their primary end point,
let's all go home. I think that would be very wrong," he said.

Instead, he said, the adjusted outcomes are "very compelling" and
consistent with the findings from exercise tests in the two
groups. "I think this trial does support the use of exercise, and it
will strengthen the guidelines," he said.

The problem with HF-ACTION, as with every other exercise trial, is
that convincing patients to adopt and stick with an intensive
exercise program is very difficult. O'Connor told the media that at
three years, the median minutes of exercise per week for people in
the intensive arm of the study was approximately 50 minutes and the
proportion of patients adhering to the recommended 120 minutes per
week was just 30%.

"The one thing this trial does not show is what type of exercise to
advocate, and I think we're going to see a lot of other studies in
that area," Poole-Wilson said. "Not just what sort of exercise, but
how do you persuade people with heart failure to exercise and to
continue to exercise, so that the effect does not fade simply
because the person ceases to exercise?"

Not the Old Silk Purse/Sow's Ear

Challenged during the press conference to explain how a trial that
missed its primary end point could be interpreted so positively,
O'Connor took pains to distinguish the HF-ACTION results from those
of a negative drug trial, where overemphasis on secondary end points
is roundly viewed as a no-no.

"This is not a drug, it's a lifestyle intervention, and we know that
lifestyle intervention trials are very, very difficult," O'Connor
said. "At the end of 2.5 years of a drug trial, you'd have 85% to
95% of the patients still on the drug. In a trial like this, the
amount of exercise that people were doing in the exercise-training
group after three years was in the order of 50 to 60 minutes; we
wanted them at 120 minutes. So adherence is extremely difficult."

Having said that, he continued, the hazard ratios for the primary
end point and cardiovascular mortality/heart-failure
hospitalizations were very similar for the main results and the
adjusted analysis. "In the context of this type of trial, and
because it was prespecified, it was a fair analysis," O'Connor
said. "It's probably closer to the truth when you compared patients
who were alike in risk and low risk and alike in risk and high risk."

A phase 2 trial has shown that interferon beta-1b (IFNB-1b)
(Betaferon/Betaseron, Bayer Healthcare)--a drug currently used to
treat multiple sclerosis (MS)--may be effective in chronic viral
cardiomyopathy (CVC). Dr Heinz Peter Schultheiss (Charité-Univ
Medizin, Berlin, Germany) presented the results at a late-breaking
trial session here today at the American Heart Association 2008
Scientific Sessions.

The study showed that IFNB-1b treatment led to a significant
reduction of viral load, with some evidence of clinical improvement
in those with CVC, and indicates for the first time that a biopsy-
based specific and causal therapy is possible for this condition,
Schultheiss noted. But he stressed that a phase 3 trial is needed
for definitive proof of concept and that he is currently in
discussions about this with Bayer. A final decision has not yet been
made on the phase 3 study, he told heartwire, but added that the
company "is much more positive than we thought."

Discussant of the study, Dr Michael Felker (Duke University, Durham,
NC), said that although this was only a phase 2 study, it is
nevertheless the largest randomized controlled trial conducted to
date in CVC. "Now, instead of just treating these patients with
heart-failure therapies," there may be the option of a specific
treatment, he said. However, he also stressed that a phase 3 trial
is needed to help understand the relative benefits and risks of IFNB-
1b in this patient population.

And Dr Clyde Yancy (Baylor University Medical Center, Dallas, TX)
told heartwire he has some concerns about this study: "This is
provocative but not definitive."

Differential Effect of IFNB-1b Depending on Causative Virus

Idiopathic, or unexplained, dilated cardiomyopathy (IDCM) is a
common cause of heart failure that disproportionately affects
younger patients and is the most frequent indication for heart
transplantation. Findings of viral persistence in the myocardium
have been found in around 50% of IDCM patients, leading to the
concept of a new clinical entity of CVC. Such patients have a poor
prognosis, Schultheiss noted.

In their placebo-controlled, randomized, double-blind, Europe-wide
multicenter study, 143 patients with CVC were randomized to one of
two doses of IFNB-1--4 MIU per injection or 8 MIU per injection--or
placebo every other day. This is a much lower dose than is used in
MS, Schultheiss said, "because we expected cardiovascular side
effects, but we didn't get them." Patients were treated for 24 weeks
followed by a 24-week follow-up phase and had to undergo serial
endomyocardial biopsies, as this is the only way to make a clear
diagnosis of CVC, the German doctor explained.

The primary end point was virus load reduction/elimination, which
was reduced overall in both groups taking IFNB-1b compared with
those on placebo (p=0.048). There was a significant effect of the
treatment on quality of life in the interferon group compared with
placebo (p=0.032), and there was also some indication of reduction
in NYHA class in those taking the interferon, he noted. However,
this lost significance by the end of the study due to an improvement
in this parameter in the control group.

There also appeared to be a differential effect of the therapy on
viral load reduction, depending on the type of virus causing the
CVC, Schultheiss noted, with the effect being greater in those with
CVC caused by enteroviruses or adenoviruses and less in those in
whom the CVC is caused by a parvovirus.

Many Hurdles, With Biopsies Perhaps the Biggest One

Discussant Felker told a press conference that the aim of this phase
2 trial "was not to prove definitively that something has a clinical
effect, but to look for a signal worth pursuing in phase 3."
Although this was a positive trial in many regards, there were a
variety of clinical events that did not reach significance with the
treatment, such as the six-minute walk, he noted.

And there remain many unanswered questions, he said, noting, "What
is the optimal timing in the disease course for interferon therapy?
Is interferon more effective against some viruses than others?

"IFNB-1b is an expensive therapy--around $10 000 a year, requiring
every-other-day injections," he pointed out. "A phase 3 trial will
help us better understand the benefits and risks."
Another important point, he stressed, is whether the low
complication rate of endomyocardial biopsy seen in expert centers in
this study can be replicated in broader clinical practice. "Although
biopsying the heart sounds barbaric, in the right hands it is safe,
but it's not something your average cardiologist is accustomed to
doing," he commented

One doctor on the press conference panel said the risks of
endomyocardial biopsy are similar to that of coronary procedures,
but Yancy told heartwire this is only true of patients who have
already had a heart transplant. In patients who have not had a
transplant--which was the patient population in this study--the risk
is higher, he explained.

"We need to pause for long enough to look for biomarkers so we can
forgo the issue of having to specify biopsy," Yancy said.

"I would have hesitancy moving ahead with this: it's costly, the
study has demonstrated only a reduction in viral load, and it's not
clear that this would improve clinical outcomes. The risks are
unrealized, and the patient cohort has not been defined in a precise
way," Yancy concluded.

Results of a small randomized trial show that 3 cups of hibiscus tea
daily for 6 weeks reduced systolic blood pressure (SBP) by about 7
mm Hg in prehypertensive and mildly hypertensive subjects.

Among those with SBP over the median of 129 mm Hg, the reduction was
double that, almost 14 mm Hg after 6 weeks, and produced significant
reductions in diastolic and mean arterial pressures.

The finding "suggests that regularly incorporating hibiscus tea into
the diet may actually help control blood pressure in people who are
at risk for developing hypertension," said lead author Diane L.
McKay, PhD, from the Jean Mayer USDA Nutrition Research Center on
Aging at Tufts University, in Boston, Massachusetts, at a press
conference here.

On a population basis, even small changes such as those seen in this
study would be expected to reduce stroke, coronary artery disease,
and all-cause mortality, Dr. McKay added.

The findings of this trial, which was supported by the Agricultural
Research Service of the United States Department of Agriculture
(USDA) and by Hain Celestial Group, makers of the Celestial
Seasonings brand of herbal teas, were presented here at the American
Heart Association 2008 Scientific Sessions.

Bioactive Phytochemicals

Hibiscus is among the most common ingredients found in herbal tea
blends sold in the United States, Dr. McKay said. The principal
components of hibiscus include anthocyanins and other flavanoids, as
well as polyphenolic compounds and phenolic acids.

A variety of bioactivities have been attributed to these compounds,
she noted, including the ability to act as an angiotensin-
converting¡Venzyme (ACE) inhibitor. Earlier short-term trials in
humans used black tea as a control, which also has an effect on
vascular reactivity, making it not a proper control to look at the
effects of hibiscus tea, she pointed out. "It is also interesting to
note that a study comparing hibiscus tea with captopril, an ACE
inhibitor, found no difference in blood pressure¡Vlowering effects."

The aim of their study, she said, was to determine whether hibiscus
tea, "in an amount that can be readily incorporated into the diet,"
will lower blood pressure in prehypertensive and mildly hypertensive
adults compared with a placebo beverage.

The study was a randomized, double-blind, placebo-controlled trial
of 65 generally healthy men and women aged 30 to 70 years who had
SBP readings of 120 to 150 mm Hg and a diastolic blood pressure
(DBP) of < 95 mm Hg.

Subjects were not taking antihypertensive medications or other
supplements or medications that could affect their blood pressure
level. They were not excluded on the basis of body-mass index (BMI),
and BMIs in the study ranged from 18.5 to 34.9.

Participants were randomized to receive either three 8-oz servings
daily of hibiscus tea for 6 weeks or a placebo beverage. The
hibiscus tea was prepared by brewing 1 tea bag containing 1.25 g of
dried hibiscus calyces in 8 oz of boiled water for 6 minutes, after
which the tea bag was removed. The placebo beverage was prepared by
adding a small amount of hibiscus-flavored concentrate to 8 oz of
water.

The beverage had to be consumed within 12 hours of preparation and
could be served hot or cold and with or without milk and a sweetener
of the subjects' choice, she noted. The placebo beverage had no
anthocyanins, which they believe is the active component, Dr. McKay
pointed out.

Outcomes of interest were the change from baseline in SBP, DBP, and
mean arterial pressure (MAP).

"After 6 weeks, we found that subjects who consumed hibiscus tea had
a significantly lower systolic blood pressure level compared with
people in the placebo group," said Dr. McKay. A drop in DBP and MAP
was also seen, but these changes were not significantly different
from placebo.

However, in a subgroup analysis of subjects with systolic pressures
higher than 129 mm Hg, the magnitude of the change found with
hibiscus tea was almost double that seen in the overall group, and
differences with placebo with regard to systolic, diastolic and mean
arterial pressure were all statistically significant, Dr. McKay
said.

Dr. McKay put their findings into the context of previously
published work suggesting that, on a population basis, a reduction
of 3 mm Hg in systolic blood pressure would be expected to translate
into a reduction in stroke mortality of 8%, of 5% in coronary heart
disease mortality, and of 4% in all-cause mortality (Whelton PK et
al. JAMA. 2002;288:1882-1888).

During her presentation, she was asked by an audience member about
any potential adverse events from this amount of hibiscus tea.

No adverse effects were reported, she responded. "There are some
data from Nigeria, where we know that the average per capita
consumption of a hibiscus-containing beverage is about the
equivalent to 25 cups of our hibiscus tea every day, and no adverse
effects have been demonstrated."

The study was funded by the Agricultural Research Service of the
USDA and by Hain Celestial Group. The authors report no disclosures.


American Heart Association 2008 Scientific Sessions: Abstract 3278.
Presented November 10, 2008.

Music may speak to the heart, but it should do so via the ears:
that's the message from a new analysis showing that while iPod MP3
players do not interfere with pacemakers or implantable cardioverter-
defibrillators (ICDs), their headphones can. Physicians who tested
eight popular brands of headphones used with iPod devices say that
while the potential for interference differed among the headphones,
the message is the same.

"Because exposure of a pacemaker or defibrillator to portable
headphones can result in interaction between the two, we recommend
that pacemaker or defibrillator patients not allow portable
headphones to be near their device," senior author Dr William Maisel
(Beth Israel Deaconess Medical Center, Boston, MA), told
heartwire. "Enough headphones have enough magnetic field strength
that we believe that our recommendations apply to all portable
headphones; they do not apply to one particular brand or one
particular model."

But authors of the study, who spoke with heartwire during the
American Heart Association 2008 Scientific Sessions, say that the
problems arise only if people place the headphones directly over
their devices, less than 3 cm away.

"So patients shouldn't place them in a front shirt pocket or in a
front jacket pocket, and they shouldn't allow someone wearing
headphones to rest their head on their chest," Maisel
commented. "But if the headphones are kept a reasonable distance
away, we found no interaction. . . . It's fine for patients; in fact
we encourage patients to enjoy their music and listen to it in their
ears, but they shouldn't take off their headphones and drape them
around their necks so that the earbuds dangle over the chest."

Maisel, with first investigator Dr Sinjin Lee (Beth Israel Deaconess
Medical Center) said they were motivated to look at iPod headphones
in the wake of stories in 2007 addressing the potential interference
caused by iPods and other MP3 players. "We were skeptical that there
would be an interaction between MP3 players and defibrillators, but
we also know that portable headphones contain magnets--magnets are
used in speakers to vibrate and make noise that we listen to," and
magnets are a known cause of device interference," Maisel said.

When Music Speaks to the Heart

What they found is that while two iPod brands (the Shuffle and the
Nano) caused no interference with either pacemakers or ICDs, 14 out
of 60 patients (23%) experienced device interference from close
contact with headphones. Types of interference ranged from
inappropriate (asynchronous) pacing in four out of 27 pacemaker
patients to inhibition of ICD detection in 10 out of 33 ICD
patients. Close contact with headphones actually caused device
reprogramming in one patient.

Of note, measured magnetic field strength varied considerably
between headphone brands and was highest with clip-on type
headphones such as the Sony MDR Q22 LP and Phillips SBC HS430. For
the Sony clip-on headphones, the magnetic field strength at 2 cm was
20 G and over 300 G at 0 cm; a magnetic field strength of just 10 G
can interact with a pacemaker or defibrillator, Maisel noted.

The key, said Maisel, is that magnetic field strength falls off very
rapidly with distances, although physicians and patients should be
aware that headphone magnetic field strength is "on" whether the MP3
player is on or off and whether the headphones are attached to the
MP3 player or not.

But he also emphasized that as long as patients are aware that
headphones contain magnets, the risk is minimal. "Pacemaker and
defibrillator patients are told when they get their device and they
are repeatedly reminded not to expose their device to magnets. So
they're used to that message. The real message here is that portable
headphones have magnets in them, and if that message got out,
patients and doctors would know what to do from there. So I don't
think patients are particularly alarmed, nor do I think they should
be," Maisel said. "The other thing to remember is that as soon as
the headphones are removed from the device, the device function
returns to normal."

First author Lee also added that just because patients with these
types of devices tend to be older, physicians shouldn't assume
they're not hip enough to have an iPod or other MP3 player. "We
became interested in this because a lot of patients do ask us about
these things. A lot of our patients are older, but a lot of people
do have [digital music players] or they have family members and
grandchildren who use them a lot."

Commenting on the study for heartwire, Dr Kenneth A Ellenbogen
(Medical College of Virginia, Richmond) also urged an appropriate
reaction from patients with cardiac devices. "It's not a real issue,
clinically speaking. Yes, the magnetic field that headphones make--
some brands from some manufacturers--can be significant, but you
have to take your headphones off your ears and put them right over
your device. If somebody falls asleep and happens to have one of
these earphones and puts them over their device and then sleeps for
a couple of hours, this could potentially be a problem. But the take-
home message is, wear your headphones on your head, and don't put
them in your breast pocket."

For patients with end-stage renal disease (ESRD) on dialysis who
also must be treated for coronary artery disease, stents provide the
best 1-year survival, compared with other revascularization
treatments, but bypass surgery provides the best long-term survival,
according to a retrospective study conducted by Charles Herzog, MD,
and Craig Solid, MS, from the Cardiovascular Special Studies Center
at the US Renal Data System in Minneapolis, Minnesota. Dr. Herzog
presented the study here at Renal Week 2008, the American Society of
Nephrology Annual Meeting.

Cardiovascular disease, such as coronary artery disease, is the
single largest cause of death in patients on dialysis. Dr. Herzog
and his team searched the US Renal Data System records and
identified 13,066 dialysis patients who received coronary artery
bypass graft (CABG) surgery, drug-eluting stents (DES), or stents
that were not drug eluting (non-DES) between 2003 and 2005. In the
study, 3665 patients (28%) underwent CABG surgery, 6164 (47%)
received DES; and 3237 (25%) received non-DES. These patients were
undergoing their first coronary revascularization procedure after
developing ESRD. The study estimated the long-term survival of the
subjects using the Kaplan¡VMeier method, and independent predictors
of death were examined in a comorbidity-adjusted Cox model. All
patients received standard antiplatelet therapy after all procedures.

"The use of surgical bypass in long-term dialysis patients has
increased over time [compared with] percutaneous coronary
revascularization," Dr. Herzog said during his presentation, noting
that recent reports have questioned the long-term safety of DES
because of the threat of stent thrombosis.

The study revealed that DES was associated with the best 1-year
survival, but long-term survival was best in patients receiving CABG
surgery. Of the patients receiving CABG surgery, mortality decreased
when 4 or more arteries were bypassed (compared with 1 artery;
hazard ratio [HR], 0.77; P = .0028) and with the use of internal
mammary artery grafting (HR, 0.87; P = .0081).

Dr. Herzog discussed how these results might apply to physician¡V
patient communication regarding revascularization decisions. "Even
the Kaplan¡VMeier survival curves in this abstract show that you can
choose to go for a short-term or a long-term result. When I present
this information to a patient, I basically tell them there might be
a long-term result ¡X that their postsurgical anatomy is going to be
better with coronary bypass ¡X but their short-term death risk is
higher," Dr. Herzog told Medscape Nephrology.

"A patient might choose to go with a surgical approach that has a
better short-term survival result if you are concerned about adverse
in-hospital events. The risk of stroke is going to be higher with
surgery, and risk of infection, too. Return to work or return to
home is going to be longer after surgical procedures. There is
really minimal incapacitation after percutaneous revascularization,
so there might be some quality-of-life issues to be considered," Dr.
Herzog continued.

"The physician's job is to give the patient the most accurate
information to help them make the best decision for them. And most
of the patients I've dealt with have chosen to go with the long-term
option, as long as they are confident about the surgeon who is
treating them."

David C. Wheeler, MD, one of the moderators of the session, pointed
out that "clinicians have not known how best to manage coronary
artery disease in the context of chronic kidney disease [because of]
a lack of data," Dr. Wheeler told Medscape Nephrology. In this
study, "although at 1 year those receiving stents appeared to be
doing better, those treated with bypass surgery had a survival
advantage in the longer term.

"The major limitation of this study is that it is observational and
other factors, such as patient selection, might well have influenced
the results. The results need to be confirmed in a randomized
controlled trial, but may encourage clinicians to offer patients
bypass surgery rather than stent placement." Dr. Wheeler is a reader
in nephrology at University College London Medical School and a
member of the advisory board of the US Kidney Disease Outcomes
Quality Initiative.

The study did not receive commercial support. Dr. Herzog is a
consultant for Amgen, has received honoraria from Genzyme, is a
member of an advisory board or board of directors of Cormedix, and
has a relationship with the Roche Foundation for Anemia Research.
Dr. Wheeler has disclosed no relevant financial relationships.

Renal Week 2008: American Society of Nephrology (ASN) Annual
Meeting: Abstract TH-FC045. Presented November 6, 2008.

African Americans with hypertensive nephrosclerosis (chronic kidney
disease [CKD] caused by high blood pressure [BP]) have a higher risk
of progressing to end-stage renal disease (ESRD) than of dying from
a cardiovascular event. This was the conclusion of a study presented
here at Renal Week 2008, the American Society of Nephrology Annual
Meeting.

The study looked at participants from the original African American
Study of Kidney Disease (AASK) Trial (1996¡V2001), which had a
randomized 3¡Ñ2 factorial design and 2 BP groups, and the subsequent
prospective AASK Cohort Study (2002¡V2007), in which the BP goal was
less than 130/80 mm Hg. Of the 1094 eligible patients from the
original AASK trial, 691 (63.1%) were enrolled in the subsequent
AASK Cohort Study. The patients received intensive follow-up to keep
their BP at the target level.

"In the cohort study, we used a number of medications to control
BP," lead investigator Tahira Alves, MD, from Vanderbilt University
in Nashville, Tennessee, told Medscape Nephrology. "Our first tier
of medications [was angiotensin-converting-enzyme inhibitors] or
[angiotensin-receptor blockers], then beta blockers or diuretics. We
only used calcium-channel blockers as a third tier when the first 2
groups of medications failed to achieve target BP. We know that half
of the people with CKD require 3 to 5 medications to control BP; the
average number in the AASK trial was 2.5."

At the start of the original trial, average age was 54.6 years, mean
baseline BP was 150/96 mm Hg, mean serum creatinine level was 1.8
mg/dL, and mean glomerular filtration rate was 46.4 mg/mL/1.73 m2.
Mean BP was 136/82 mm Hg at the start of the cohort study period and
129/74 mm Hg at the end of the cohort study period.

During 11 years of follow-up, patients had a higher risk of
progressing to ESRD than of experiencing cardiovascular events, such
as myocardial infarction. For each 100 patient-years of follow-up,
there were 4 cases of ESRD. By comparison, the rate of
cardiovascular events during the same period was 3.2 per 100 patient-
years.

In addition, the risk for death from cardiovascular disease in the
study was 0.8 per 100 patient-years. Of the 74 deaths that occurred
during the cohort period, more than 60% were from causes other than
cardiovascular disease.

"When you look at the variance in outcomes, compared with the
variance in protocols, we're still writing the results of [the
cohort] study," Dr. Alves told Medscape Nephrology. "The first phase
of the study was specifically targeted to find differences in renal
outcomes; cardiovascular outcomes were secondary. But when we
stratified the groups looking at cardiovascular outcomes by
different BP groups and different BP medications, there was no
significant difference in outcomes."

"In virtually all previous studies of patients with CKD (where the
population was multiracial and primarily Caucasian), all-cause
mortality rates were substantially higher than ESRD rates," Dr.
Alves said in her presentation. "The AASK trial and the subsequent
cohort study allow the medical community to gain a broader
understanding of incident cardiovascular disease and mortality
during long-term follow-up in an entirely African American
population with nondiabetic hypertensive nephrosclerosis."

David C. Wheeler, MD, one of the moderators of the session,
commented that "in most population studies, patients with early
(stage 3 or 4) chronic kidney disease are more likely to die than to
reach end-stage kidney failure. This study of African Americans
showed the opposite," Dr. Wheeler told Medscape Nephrology.

"The study is based on a cohort of selected patients involved in a
randomized controlled trial, which may not be representative of the
population as a whole. The results are unlikely to change practice,
since most clinicians would offer patients with CKD (whatever their
ethnicity) treatments that both slow the progression of kidney
damage and reduce the risk of cardiovascular disease, the major
cause of premature death," Dr. Wheeler explained. He is a reader in
nephrology at University College London Medical School and a member
of the advisory board of the US Kidney Disease Outcomes Quality
Initiative.

However, the results may provide additional insights into the
relation between high BP and kidney disease in African Americans, as
well as some of the reported racial differences in the rates and
outcomes of ESRD, Dr. Alves said.

The AASK studies were supported by the National Institute of
Diabetes and Kidney Diseases, and the National Institutes of Health.
Dr. Alves and Dr. Wheeler have disclosed no relevant financial
relationships.

Renal Week 2008: American Society of Nephrology (ASN) Annual
Meeting: Abstract TH-FC051. Presented November 6, 2008.

A new medical technology company--this time in France--has announced
it is joining the sparse ranks of innovators hoping to develop the
first total artificial heart to be used as a permanent implant, not
just as a "bridge" to heart transplantation. Carmat SAS made news
headlines in Europe earlier this week when it announced that it had
landed £á7M in start-up funding, plus £á33M in grants-in-aid and loans
from the French innovation and funding agency, OSEO--the largest
amount ever awarded by the agency to a start-up company.

But in addition to dollars, Carmat may already have a leg-up on
competing companies because of the star physician at the helm:
renowned cardiac surgeon and inventor Dr Alain Carpentier (Pierre &
Marie Curie University, Paris, France). In interviews with the
press, Carpentier has said that the Carmat device is based on 15
years of research, and he predicted it could be used for the first
time in humans within two and a half years.

According to a press release issued by the capital group behind the
Carmat venture, the Carmat artificial heart has already been used in
animals and undergone strenuous bench testing. The device itself
combines animal tissue, titanium, and technology borrowed from the
missile-defense industry; in fact, the European Aeronautic Defense
and Space Company (EADS) is one of the other funders of the project.
A unique feature of the design is the sensor technology used in
guided missiles, which senses the body's activity level and adjusts
accordingly.

The Heart Hunt

A total artificial heart is the holy grail of cardiovascular
medicine, with development efforts dating back more than half a
century. The most recent FDA-approved addition to the field is the
AbioCor fully implantable total artificial heart, made by Abiomed,
which was cleared in 2006 for end-stage heart failure patients who
are not eligible for a heart transplant. It has an internal battery
that lasts for just 30 minutes and a wearable external battery pack
that lasts four hours. Patients treated with the AbioCor heart have
lived on average about five months but, because of its size, only a
minority of patients can even accommodate the device. The company
has developed a smaller version, the AbioCor II, that it hopes to
get approved in the near future.

Another FDA-approved device, the CardioWest, is the modern-day
descendent of the Jarvik 7, the total artificial heart developed by
Dr Robert Jarvik in the early 1980s. The CardioWest is now
manufactured by SynCardia Systems and can only be used in end-stage
heart failure patients, in hospital, as a bridge to transplantation.
The FDA granted marketing clearance to the CardioWest heart in 2004.

Disappointing results or, more often, lack of funding has deterred
other groups and companies trying to develop a total artificial
heart. Even Jarvik Heart, the company founded by an artificial-heart
pioneer, focuses solely on the development of left ventricular
assist devices--a decidedly more crowded field of research--rather
than total artificial hearts.

Groups in Korea and Japan are reputedly working on total artificial
hearts, but any efforts in the US are either being done in secret or
seem to be withering on the vine. Innovators at the Cleveland Clinic
have been involved for years in the development of a device dubbed
the "MagScrew" total artificial heart. A Clinic spokesperson told
heartwire that, although one of the MagScrew prototypes has
been "cranking away" on a bench endurance test for two and a half
years, developers have not managed to drum up corporate funding to
do the necessary preclinical studies, despite publishing a steady
trickle of papers on the invention. According to the Clinic
spokesperson, the MagScrew is actually smaller and lighter than the
Carmat device, and requires no anticoagulation.

People with diabetes and hypertension are less likely to comply with
nutritional recommendations for lowering blood pressure than people
with hypertension alone, Sundar Natarajan, MD, MS, reported here at
the American Public Health Association 136th Annual Meeting.

The findings suggest that these patients may require more intensive
intervention to ensure they achieve nutritional goals, Dr.
Natarajan, an assistant professor of medicine at New York University
School of Medicine, said during his oral presentation.

He and his colleagues analyzed data from 177 hypertensive patients
enrolled in a trial to improve antihypertensive treatment. Patients
were eligible for inclusion in the study if they had uncontrolled
hypertension and had been taking antihypertensive medication for at
least 6 months. Of the 177 patients, 89 had diabetes as well as
hypertension. The study was conducted at a Veterans Affairs
hospital, so 86 of those in the diabetes group and all of those in
the hypertension-only group were male. The mean age for all subjects
was 65 years, and their mean body mass index was 31 kg/m2.

The investigators assessed diet in 2 ways. To get an idea of overall
nutrient intake, they had patients fill out the 61-item self-
administered Willett Food Frequency Questionnaire. The subjects also
completed the Healthy Eating Index (HEI), an instrument created in
1995, by the Center for Nutrition Policy and Promotion at the United
States Department of Agriculture, to evaluate the overall quality of
a person's diet. It was revised in 2006 to reflect the 2005 Dietary
Guideline for Americans. The HEI rates an individual's compliance
with the guidelines for 12 food groups or nutrients, such as fruits,
vegetables, whole grains, and sodium. The maximum score is 100;
scores over 80 are considered good, scores between 51 and 80 are
considered fair, and scores below 51 are considered poor.

People with diabetes and hypertension had a mean HEI score of 65.8,
compared with a mean of 69.1 for people with hypertension only (P
< .05). Their diets contained significantly less calcium, magnesium,
and potassium. On a more positive note, they consumed a mean of 1607
calories per day, compared with 1837 for people with hypertension
alone. The mean dietary glycemic load was 102 units and 120 units,
respectively (P < .01 for both groups).

These findings suggest that overall dietary quality is worse for
people with diabetes and hypertension than it is for people with
hypertension alone, Dr. Natarajan told Medscape Public Health &
Prevention. "I was surprised. I would have thought patients with
both diagnoses would get more education." However, he added,
nondietary factors could have come into play. "When people have
diabetes they often have other issues, such as depression. Also,
they were veterans, so they may have had other mental-health issues
that may have affected their eating behavior." It is also possible
that rather than too little education, they received too much. "They
may have been overwhelmed with information," he explained. "As
clinicians, sometimes we assume people remember everything we tell
them, but that isn't always the case."

At least 1 independent observer also expressed surprise at these
findings. "It seems we have to make different recommendations to
these patients," said Adelia Bothell-Benjamin, PhD, research
associate professor of food and nutritional sciences at Tuskegee
University in Alabama. "If this is not just a 1-time finding, it
suggests we have to do more for patients when the 2 conditions
coexist."

American Public Health Association (APHA) 136th Annual Meeting:
Abstract 183326. Presented October 29, 2008.

A large meta-analysis of radial-access PCI has shown that the novel
approach translates into a significant reduction in major bleeding.
There were also trends toward a reduction in clinical end points,
although these did not reach statistical significance, report
investigators.

"We can say with certainty that PCI with radial access compared with
femoral access reduces bleeding," lead investigator Dr Sanjit Jolly
(McMaster University, Hamilton, ON) told heartwire. "In this study
there was more than a 70% reduction in major bleeding. The question
about whether the radial approach reduces ischemic outcomes is an
interesting hypothesis but still needs to be proven. I think that's
what it might take to change practice worldwide."

Presenting the results here at the Canadian Cardiovascular Congress
2008, the investigators analyzed data from existing randomized
trials comparing radial vs femoral access PCI to assess major
bleeding, as well as ischemic events, such as MI, stroke, and death.
Other clinical trials, such as OASIS 5 and HORIZONS, have shown that
therapies that reduce bleeding also reduce mortality and ischemic
outcomes, and with that in mind, the investigators wanted to
determine whether there was an ischemic benefit with the radial
approach.

In total, 21 studies with more than 5600 patients were included in
the analysis. Major bleeding, defined as fatal bleeding,
intracranial hemorrhage, or bleeding associated with hemoglobin
reductions or requiring transfusion or surgery, was significantly
reduced with the radial approach. There were trends toward
reductions in ischemic end points, but none of these achieved
statistical significance.

A large meta-analysis of radial-access PCI has shown that the novel
approach translates into a significant reduction in major bleeding.
There were also trends toward a reduction in clinical end points,
although these did not reach statistical significance, report
investigators.

"We can say with certainty that PCI with radial access compared with
femoral access reduces bleeding," lead investigator Dr Sanjit Jolly
(McMaster University, Hamilton, ON) told heartwire. "In this study
there was more than a 70% reduction in major bleeding. The question
about whether the radial approach reduces ischemic outcomes is an
interesting hypothesis but still needs to be proven. I think that's
what it might take to change practice worldwide."

Presenting the results here at the Canadian Cardiovascular Congress
2008, the investigators analyzed data from existing randomized
trials comparing radial vs femoral access PCI to assess major
bleeding, as well as ischemic events, such as MI, stroke, and death.
Other clinical trials, such as OASIS 5 and HORIZONS, have shown that
therapies that reduce bleeding also reduce mortality and ischemic
outcomes, and with that in mind, the investigators wanted to
determine whether there was an ischemic benefit with the radial
approach.

In total, 21 studies with more than 5600 patients were included in
the analysis. Major bleeding, defined as fatal bleeding,
intracranial hemorrhage, or bleeding associated with hemoglobin
reductions or requiring transfusion or surgery, was significantly
reduced with the radial approach. There were trends toward
reductions in ischemic end points, but none of these achieved
statistical significance.

The diagnosis of rheumatoid arthritis is the most influential factor
in the increased incidence of myocardial infarction (MI) seen in RA
patients, according two population-based studies presented here at
the American College of Rheumatology 2008 Annual Meeting.

Yet traditional risk factors such as age, sex, hypertension,
diabetes, and smoking are also important in determining risk for MI,
and of these, modifiable risk factors should be aggressively
treated, said Christopher Edwards, MD, consultant rheumatologist and
honorary senior lecturer in the department of rheumatology at
Southampton General Hospital in Southhampton, UK and lead
investigator on both studies.

While medications such as DMARDs have previously been linked to MI
risk, the studies presented here found no such correlation. However,
the researchers did find that treatment with lipid-lowering drugs
produced a significant reduction in MI incidence, although
antihypertensives had no effect.

¡§As a clinician I want to know what¡¦s driving the increase in MI
incidence in RA patients. Not only do RA patients have an increased
rate of MI, but the MIs are silent with an increased case fatality,
and [occur] earlier in life. Not only do RA patients suffer from MI,
but it¡¦s bad MI,¡¨ Dr. Edwards told meeting attendees.

¡§Previous studies have looked at traditional risk factors in RA as
causative factors for heart attack, but they are not the whole
story,¡¨ he added.

To assess the incidence of MI, as well as the factors contributing
to it, the UK researchers analyzed the United Kingdom General
Practice Research Database (GPRD), which contains the medical
records of over seven million individuals. The investigators were
able to identify 34,364 adults with RA and 103,089 age and sex-
matched controls, studied between 1987 and 2002. They found that RA
patients suffered MI at a rate of 6.49 per 1000 people per year
versus 2.96 in the control group.

Although the database contained data from 600 medical practices and
5% of the UK population, it also had its limitations, the
researchers acknowledged. Some diagnostic information on patients ¡X
such as lipid levels, hypertension, and smoking status ¡X was
missing from the GPRD, and other information such as exposure to
DMARDs and hypertension and lipid-lowering medications was not
complete.

Yet in their analysis, the researchers found that having a diagnosis
of RA was the strongest influence on MI risk. A diagnosis of RA
increased the incident rate ratio (IRR) for MI (2.23; 95% confidence
interval [CI], 2.07 - 2.41; P < .001), and this effect remained even
when the researchers controlled for traditional risk factors,
antihypertensive drugs, lipid-lowering drugs, and
DMARDs/prednisolone use. Of the traditional risk factors, body mass
index (BMI) alone did not produce a significant effect on MI. The
researchers also found that treatment with lipid-lowering drugs
produced a significant decrease in MI incidence (IRR, 0.75; 95% CI,
0.62 - 0.90; P = .003), although antihypertensives had no effect
(IRR, 0.92; 95% CI, 0.84 - 1.00; P = .062).

In a related study by the same researchers, they analyzed the effect
of DMARDs and prednisolone use on MI incidence. In the patients who
had suffered an MI, 73% had taken a DMARD or prednisolone prior to
the study, and in 56% of cases, patients had taken these drugs in
the 2 months prior to the MI. The researchers¡¦ data analysis showed
that DMARDs were protective against MI, but prednisolone increased
MI risk. However, when adjusted for confounders (such as BMI,
hypertension, diabetes, and smoking), the effects of these drugs
were no longer significant.

¡§This study shows us just one piece of the jigsaw puzzle unfolding,
and helps us decide how much investment we should make in treating
RA and traditional risk factors,¡¨ Dr. Edwards told the attendees.

¡§In my opinion it¡¦s important to treat RA because it¡¦s the
biggest risk factor for MI, but we can¡¦t forget the traditional
risk factors either,¡¨ he told Medscape Rheumatology. ¡§We need to
give these approaches equal weight.¡¨

Deborah Symmons, MD, professor of rheumatology at Manchester
University in the United Kingdom and the moderator of the session,
agreed. ¡§The implications of these studies are that we have to
target traditional risk factors as aggressively as we can and at the
same time we have to manage the disease activity of RA,¡¨ she said.

The studies did not receive commercial support. Dr. Edwards and Dr.
Symmons have disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2008 Annual Scientific
Meeting: Abstract 688. Presented October 26, 2008.

Systemic hypothermia prior to catheterization does not decrease the
risk of acute kidney damage caused by iodinated contrast agents, a
new study has shown. Researchers report the investigational
endovascular cooling device tested is safe, but it failed to reduce
the incidence of radiocontrast nephropathy.

Speaking with the media here at TCT 2008, lead investigator Dr Gregg
Stone (Columbia University, New York) said there are data to suggest
that systemic hypothermia could reduce or prevent the radiocontrast
nephropathy after PCI.

"There was a lot of interest in this," said Stone. "There have been
a lot of preclinical and pilot studies suggesting that if we mildly
cool patients about 3¢XC or 4¢XC before injecting iodine-based
contrast, we could significantly reduce contrast nephropathy, which
is a major cause of morbidity and mortality after interventional
cardiology procedures."

In this study, known as Cooling to Prevent Radio Contrast
Nephropathy in Patients Undergoing Diagnostic or Interventional
Catheterization (COOL-RCN), 63 patients were randomized to systemic
hypothermia and 73 patients to routine management. All patients were
considered high risk for radiocontrast nephropathy, with a
creatinine clearance (CrCL) ranging from 20 to 50 mL/min.

The COOL-RCN investigators used the Reprieve Endovascular System,
initially made by Radiant Medical, which acts as an "intravenous
refrigerator," said Stone, cooling the body from the inside out. The
catheter contains a cool saline circulating within it and is
positioned in the inferior vena cava. Blood flowing past the
catheter is cooled, which reduces body temperature. The goal of
treatment with the device was to cool patients to a core temperature
of 33¢XC or 34¢XC, a temperature that was achieved in approximately 30
minutes. Patients were hydrated with normal saline and sodium
bicarbonate.

Despite successfully cooling patients, there was no difference in
the incidence of contrast-induced nephropathy between the systemic
hypothermic and control patients. In addition, there was no
difference in serum creatinine levels between the two arms at 24
hours, 48 hours, or 72 to 96 hours.

There were no statistically significant differences in adverse
events at 30 days, although all-cause mortality in the hypothermia-
treatment arm was numerically higher compared with patients treated
conventionally (5.2% vs 1.4%, p=0.22).

"We achieved hypothermia very easily in almost all patients and
without complications," said Stone. "There are no safety concerns
with the device, but as it turns out, there was no efficacy."

Financial problems have plagued the study, however, and as a result
of Radiant Medical going bankrupt in August 2007, just 136 of the
planned 400 patients were enrolled in COOL-RCN. Based on data from
these enrolled patients, ZOLL Circulation completed the study after
it purchased the assets of Radiant Medical.

Stone said that systemic hypothermia is still being tested as a
possible adjunctive treatment option for reducing infarct size in
patients with MI. Radiant Medical had just begun enrolling patients
in the COOL-MI II study before it went bankrupt, he noted. The first
COOL-MI study, presented at TCT in 2003, showed that mild systemic
hypothermia as an adjunctive therapy in acute MI patients failed to
reduce infarct size. Hypothermia has been previously shown to be
beneficial in coma patients or in those with severe neurologic
damage.

With three beta blockers currently recommended for heart failure and
entrenched in clinical practice, the FDA has agreed to consider
approval of yet another. But this time there's a novel, potentially
revolutionary twist: the contender, bucindolol (ARCA Biopharma,
Broomfield, CO), would be marketed with a "companion genetic test"
that may identify heart-failure patients who are predisposed to an
especially good treatment response.

That response would manifest as longer survival and fewer heart-
failure hospitalizations, according to a recent analysis of outcomes
by beta-receptor genotyping of patients with systolic heart failure
in a randomized, placebo-controlled bucindolol trial [1].

In clinical practice, the genetic test could theoretically be used
to target the beta blocker to patients it's likely to help and avoid
its use in those who probably wouldn't benefit.


Dr Alan B Miller
In other words, an FDA approval of bucindolol and its companion
genetic test would propel cardiology, somewhat unsteadily, into the
long-anticipated era of pharmacogenomics as a matter of actual
therapeutic practice rather than just a research goal.

The idea that beta-receptor polymorphisms could be the basis for
such a test has been around awhile, observed Dr Alan B Miller
(University of Florida, Jacksonville) for heartwire. But "if
bucindolol is marketed, it will be the first time that we'll
actually use it in practice," he said. "It's a huge breakthrough,
and probably the way all of us are going to receive medication in
the future."

Miller is a coauthor of the analysis, which is based on the genetic
substudy of the Beta-Blocker Evaluation of Survival Trial (BEST) and
was presented here last month at the Heart Failure Society of
America (HFSA) 2008 Scientific Meeting by Dr Christopher M O'Connor
(Duke University, Durham, NC). BEST's primary analysis of bucindolol
efficacy in heart failure was published in 2001 [2].

"What really excites me, in particular, is that it does have the
potential to usher in a new era of personalized medicine," Dr
William T Abraham (Ohio State University, Columbus), an original
BEST investigator but not a coauthor of the current analysis, told
heartwire. He described the analysis as a part of larger efforts to
identify physiologic criteria, biomarkers, or genotypes that
will "help us get the right therapy to the right patients."

ARCA Biopharma hopes to market bucindolol as Gencaro; the FDA has
yet to approve the trade name, according to the company [3]. ARCA is
working with Laboratory Corporation of America (Burlington, NC) to
develop the genetic test that would be "packaged" with the drug,
assuming both are approved.

Questions remain, however, about the strength and nature of
bucindolol's case for approval as well as other challenges.

"It would be the first drug in cardiology to be coupled with DNA
testing, which we're using not only to guide therapy but to sort out
safety issues," O'Connor noted for heartwire. But the test
represents one of the major challenges the FDA and its physician
advisory panel will face when they review bucindolol. "With
carvedilol out there, which you can get benefit from without the
test, where would it fit in?"

If clinicians are comfortable using current beta blockers and then
are presented with another and told to use it only in patients with
a particular genotype, "then you've got to convince them that that's
better than what they're already doing," Dr Dennis M McNamara
(University of Pittsburgh, PA) said when interviewed. "And that, to
be honest, is the hard sell about genetic targeting in general with
beta blockers, because the agents themselves are pretty well
tolerated."

McNamara, who led the genetic substudy of the African-American Heart
Failure Trial (A-HeFT) trial, is listed in the BEST primary report
as a participating investigator but isn't a coauthor of the genotype
analysis.

He said he frames the bucindolol genotyping research as applying to
beta blockers in general. "But it strikes me that ARCA, for a
marketing strategy, would have to approach it as more than that,
they'd have to approach it as genetic targeting of their beta
blocker. As a practitioner, I'm still waiting to hear why that
should be. Does that mean that for a subset of the population,
bucindolol is better than carvedilol? I'm not sure."

He added, "I do think this is where the field is going, I just think
there will be a few bumps in the road getting there."

In the 1040-patient BEST genetic substudy, nearly half of patients
with systolic heart failure carried certain variants of genes for
the ß1-codon 389 Arg/Gly and £\2c 322-325 "wild-type" (WT) or
deletion (DEL)-carrying adrenergic receptors that were associated
with the best clinical responses to the beta blocker.

BEST overall had randomized 2708 patients with NYHA class 3-4 heart
failure and an LVEF <35% to receive bucindolol or placebo on top of
ACE inhibitors and diuretics; DNA was collected prospectively from
the substudy participants.

Bucindolol had no significant effect on the primary end point, all-
cause mortality. On the other hand, it showed significant benefits
for the secondary end points of CV mortality, HF hospitalization,
and death or transplantation.

In the genetic substudy, patients who carried an arginine-homozygous
beta-receptor polymorphism (&szlig;1 389 Arg/Arg) and who also had either
of two variants of the alpha-receptor gene (£\2c 322-325 WT/WT or DEL
carrier) and received bucindolol showed significant risk reductions
for all-cause mortality, CV mortality, and heart-failure
hospitalization. Carriers of that genotype would presumably show the
most robust responses to bucindolol, according to BEST investigators.

Patients with an intermediate genotype for the two receptors showed
a 40% reduction in CV mortality risk only.

The remaining 13% of the population had a third genetic pattern
associated with no bucindolol effects on the end points.

O'Connor noted that heart-failure management has changed a lot since
the BEST patients were enrolled. None, for example, received
spironolactone or implantable defibrillators. "Are we going to be
able to achieve these event-rate reductions in the modern era? I
think we'll get some advantage, but I don't know if we're going to
get these large advantages."

The bucindolol experience, however, poses some challenges for the
FDA. For starters, the only major randomized trial to test
bucindolol for clinical outcomes in heart failure, BEST, was
conducted years ago and was negative for its primary end point
independent of any genotyping considerations. There may also be
questions about whether there is enough prospectively collected data
on the genotype-outcomes association to justify a bucindolol-
specific screening role for the test.

Abraham notes that the BEST patients were entered prospectively into
the DNA database, "and the hypothesis underlying the role of
adrenergic-receptor polymorphisms was prospectively stated. So one
can make a strong argument that, in fact, the prospective
[genotyping] study has already been done." But some might argue that
since the genotype-outcomes relationships were derived from the BEST
cohort, they still need to be prospectively validated in a separate
population--and that, he said, is likely to be a major focus of
debate at the FDA.

Dr JoAnn Lindenfeld (University of Colorado Health Sciences Center,
Denver), a coauthor of the genotyping analysis who was on the BEST
steering committee, confirmed that use of the &szlig;1- and £\2c-receptor
genotyping test to identify or rule out likely bucindolol responders
has not been prospectively tested. But, she noted for heartwire, the
strategy is based on more than just BEST. "It's also based on a lot
of animal data and other data with these polymorphisms. So there's a
fairly strong basic rationale" [4].

McNamara agreed that "there's very good in vitro data on the impact
of these variants on receptor efficacy, and there's also, at least
for the &szlig;1 389, good in vivo data from animal models. So they really
do have good proof of function, there's no doubt about that."

The lack of prospective validation, he observed, "is a common
complaint. Most pharmacogenetic effects that have been published are
for the most part awaiting validation--not all, but most."

That caveat was echoed by Dr Julie A Johnson (University of Florida
College of Medicine, Gainesville), not a BEST investigator, who
directs her institution's Center for Pharmacogenomics. "In genetics,
there have been a fair amount of positive associations in one study
that are never replicated again. But personally I believe these
[BEST] data, not because of this study alone but because of all the
other literature that surrounds it."

There is a good deal of clinical research, she told heartwire,
relating to the &szlig;1 389 polymorphisms in heart failure and in
hypertension, "and the data really are amazingly consistent,
basically, that the Arg/Arg genotype responds best to beta
blockers." That includes improvements in heart-failure outcomes,
gains in LVEF, blood-pressure lowering in hypertensives, and
reductions in intraocular pressure in patients with glaucoma, she
said.

"So I think that part [of the BEST genetic substudy] is really
solid," Johnson said. "Where they don't have any replication, and
where I think [their results] are unique to bucindolol, is in the £\
2c receptor. In that case, they have told a story that makes sense,
but there's no other literature to really corroborate it."

According to McNamara, "I do think that ARCA is onto something here.
I don't think any one genotype is going to be the sole deciding
factor for a therapy. I think there will be combinations of alleles
and genomic scores that will use genetic information to target
therapy."

What isn't clear, he said, is whether a bucindolol-only claim can be
made for the genetic test coming out of BEST. "I think there clearly
is a genomic signal that will help us target beta blockers. Whether
the genomic signal is going to be that different for different
classes of beta blockers remains to be determined. It's kind of a
brave new world we're entering, and I think it remains an open
question."

BEST was funded by the National Heart, Lung, and Blood Institute and
the Department of Veterans Affairs; active drug and placebo were
provided by Incara Pharmaceuticals. Abraham discloses being a
consultant to Amgen, AstraZeneca, Impulse Dynamics, Medtronic,
Novartis, Pfizer, Respironics, and St Jude Medical; serving on an
advisory board for Arrow International, BioEnergy, Biotronik,
CardioKine, CardioKinetix, CardioMEMS, Edwards Lifesciences,
Inovise, Medtronic, Paracor, St Jude Medical, and Sunshine Heart;
receiving grant support from Impulse Dynamics, Medtronic, Paracor,
and St Jude Medical and honoraria from AstraZeneca, GlaxoSmithKline,
Medtronic, Novartis, Pfizer, Respironics, and St Jude Medical; and
being on the speakers' bureau for Amgen, AstraZeneca, Medtronic,
Novartis, Pfizer, Respironics, and St Jude Medical. Johnson said she
conducts pharmacogenomic research with beta blockers and had
participated in advisory-board meetings for ARCA Biopharma.
Lindenfeld reports being a consultant to Amgen and Sanofi-Aventis;
receiving grant support from Cogenesis, Merck, and SomaLogic;
receiving honoraria from Takeda; and being an employee of CV
Therapeutics. McNamara reported that has received research grants
from and participated in the speakers' bureau for NitroMed. Miller
discloses grant support from Amgen, CV Therapeutics, Medtronic, and
Merck and honoraria from AstraZeneca, Bristol-Myers Squibb, CV
Therapeutics, GlaxoSmithKline, Novartis, and Sanofi-Aventis.
O'Connor reports being a consultant to ARCA Biopharma,
GlaxoSmithKline, Medtronic, and Pfizer.


O'Connor CM, Anand I, Fiuzat M, et al. Additive effects of beta-1
389 Arg/Gly and alpha-2c 322-325 wild-type/del genotype combinations
on adjudicated hospitalizations and death in the Beta Blocker
Evaluation of Survival Trial (BEST). Heart Failure Society of
America 2008 Scientific Meeting; September 22, 2008; Toronto, ON.
Abstract 216.
BEST investigators. A trial of the beta-blocker bucindolol in
patients with advanced chronic heart failure. N Engl J Med
2001:344:1659¡V1667. Abstract
ARCA Biopharma. FDA accepts new drug application for bucindolol, a
genetically targeted treatment for heart failure from ARCA Biopharma
[press release]. September 23, 2008. Available at:
http://www.arcabiopharma.com/assets/File/NDA_Accepted_Press_Release_F
INAL_FINAL_092308.pdf.
Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al. A polymorphism
within a conserved beta1-adrenergic receptor motif alters cardiac
function and beta-blocker response in human heart failure. Proc Natl
Acad Sci 2006; 103:11288-11293. Abstract

Once again, the Centers for Medicare and Medicaid Services (CMS) has
opted not to expand Medicare coverage of carotid stenting to a
broader range of high-risk patients. Physicians who spoke with
heartwire say the CMS is ignoring new data that clearly support a
broader role for carotid stenting in patients at high-risk of
adverse events if sent for carotid endarterectomy. Others, however,
believe the CMS was right to wait for more published data before
expanding current coverage.

Additional impressive results for carotid stenting, presented at the
TCT 2008 meeting, also suggest that the CMS Medicare coverage
decision is far too narrow, some experts say.

According to Dr Bonnie Weiner (Worcester Medical Center, MA), the
Society for Cardiovascular Angiography and Interventions (SCAI) had
asked CMS in December 2007 to review its May 2007 decision not to
expand coverage for carotid stenting. In particular, SCAI and others
had argued that a "limited expansion" of CMS coverage was warranted
in patients who are at high-risk for carotid endarterectomy due to
defined anatomic factors--such as previous radiation to the neck or
location of the target lesion. They had also asked that patients
with symptomatic carotid artery stenosis of 50% to 60% or greater or
asymptomatic carotid artery stenosis of 80% or more also be
considered for Medicare coverage.

Under the current policy, only patients at high risk for carotid
endarterectomy with symptomatic carotid artery stenosis of 70% or
greater are covered for carotid stenting procedures.

Speaking with heartwire, Dr Bill Gray (Columbia University, New
York, NY) explained that the CMS, from the outset, opted to cover
only a very narrow subgroup of patients who appeared to demonstrate
a benefit from carotid stenting in the premarket and postmarketing
studies. "We've asked for the CMS to consider the population that's
supported by the data," he said. "We don't understand why the
original decision was parsed in the first place."

But Dr Anthony Furlan (University Hospitals Case Medical Center,
Cleveland, OH), speaking at the behest of the American Academy of
Neurology (AAN), told heartwire that the AAN does not feel there is
sufficient new evidence to change current coverage. "There has been
a fairly broad consensus, set out by the AHA, that what would be
acceptable is a stroke and death rate of 3% or less in asymptomatic
patients. . . . There's been no study published that has met that
yardstick."

Early Decision Turns a Blind Eye to Pending Publications

The CMS had earlier stated that it would announce its decision on
October 29, allowing time to review results from the SAPPHIRE
Worldwide (WW) postmarketing registry, published online October 15,
2008, as well as results from the CAPTURE 2 and EXACT registries,
still under expedited review by a prominent cardiology journal,
Weiner said.

But instead, the CMS announced October 14, during last week's TCT
meeting, that it would not be reopening its coverage decision. "The
CMS has decided to make no changes to the national coverage
determination (NCD) for percutaneous transluminal angioplasty (PTA)
of the carotid artery concurrent with stenting," the announcement
reads. "We are aware of other data that have yet to be published and
strongly urge publication at the soonest possible time. We will work
with any requestor as soon as those data are published to determine
the need for an expedited review and reconsideration."

Asked by heartwire why it had bumped up its decision when it was
aware of data that were going to be published imminently, a CMS
spokesperson clarified the CMS can consider only published reports
in its decision-making. "During and after the comment period on this
proposed decision, we did receive a number of unpublished articles
from authors and other interested parties and have been in
communication with them about publication dates. These publication
dates are controlled by medical journal editors and not by the
authors or CMS. The CMS reviewed all the evidence and made a
judgment that issuing the final decision memorandum was justified on
the date of issue and would not be changed during the subsequent few
days before our due date."

Weiner says SCAI is still weighing its options as to if, when, and
how to petition the CMS about this issue once again.

Furlan, likewise, said the AAN would be willing to support expansion
of Medicare coverage if there were sufficient published evidence
supporting the safety of carotid stenting in specific patient groups
that met the AHA benchmarks. The AAN has also called for a national
multispecialty accreditation program that would require operators to
first prove that their facility can produce patient outcomes that
meet the AHA benchmarks before performing the procedure.

Furlan also said that he was aware of many of the studies presented
in the past year and said it "behooves investigators to get that
data published, so it can be considered by the CMS."

SAPPHIRE Worldwide Results

The SAPPHIRE WW results in particular, published online in
Catheterization and Cardiovascular Interventions last week, support
a role for carotid stenting in patients who, for anatomic reasons,
are poor candidates for surgery [1]. SAPPHIRE WW is ongoing, but the
paper includes results for the first 2001 patients treated with the
Precise Nitinol Stent and Angioguard XP/RX emboli capture guidewire
(Cordis) since October 2006. As Dr Douglas Massop (Iowa Clinic, Des
Moines) et al report, 30-day major adverse events (MAE) in these
patients was 4.4% overall (including a death rate of 1.1%, a stroke
rate of 3.2%, and an MI rate of 0.7%). But results differed
according to whether surgical risk was "anatomic" (postradiation
treatment, previous carotid endarterectomy, or very high or low
lesions, anatomically) or "physiological" (coexisting heart failure,
previous open heart surgery, recent MI, unstable angina, or other
severe cardiac or pulmonary disease). Overall MAE were significantly
lower in anatomic vs physiologic risk patients (2.8% vs 4.9%;
p=0.03). "The SAPPHIRE Worldwide Registry supports the use of
carotid artery stenting as an alternative to carotid endarterectomy
in patients who are at high risk for surgery due to anatomic risk
factors," Massop et al conclude.

-SW

Weiner said she and other SCAI members were "taken by surprise" when
the CMS announced its decision two weeks early. "That was
disappointing to us, knowing that the data were imminent and quite
robust to show that carotid stenting is as good as if not better in
this [anatomic-risk] population than endarterectomy, which is a
procedure that patients have access to without restriction," she
noted.

Gray, likewise, told heartwire: "Needless to say, it was
disappointing that there was no consideration of those data, which
they knew about. . . . I don't quite understand it."

Weiner estimated that patients in the anatomic high-risk group make
up just 10% to 20% of carotid stenting patients, but that this was a
group that all professional groups were expected to agree upon as a
reasonable extension of current Medicare coverage rules.

Weiner says SCAI is currently discussing next steps, but in the
meantime she believes the CMS discussion has important implications
for physicians and patients.

"Many of us are concerned about the disconnect between the approval
process and the reimbursement process for some of these new
technologies, because without continued reimbursement or the ability
to gain reimbursement, we're still dealing with first-generation
devices," she said. "There's no incentive for continued improvement
and development of devices, because the market just isn't there to
support it. Patients are continuing to be subjected to what may
ultimately prove to be inferior technologies, because we can't
develop the next generation of products that would be even better."

There is also the important issue of operator proficiency, which is
jeopardized when limited numbers of patients can afford the
procedure. "There are very few centers that are doing sufficient
numbers to remain highly skillful," Weiner acknowledged. "The
CAPTURE-2 data certainly suggest that carotid stenting can be done
by a wide range of operators, but there's no question, like most of
these procedures, the more you do, the better you are at them. And
some of that is that you get technically better, and some of it is
because you select your patients better."

Gray points out that patients who are excellent candidates for
carotid stenting, who indeed might do better with stenting than
surgery or medical therapy, are "artificially" being selected out,
simply because they rely on Medicare for 100% of their medical
costs. "So someone who depends on Medicare insurance has no option
to get a therapy that is FDA-approved that the guy next to him can
get by paying for out of pocket," Gray said.

And ironically, Gray notes, carotid stenting and endarterectomy
actually cost roughly the same, at least out to one year. "Nobody
knows beyond one year, but since there are no excess strokes in one
or the other arms, you would expect that after the initial outlay of
money that CMS pays, there shouldn't be a whole lot of differences
down the road."

Neuroprotection Studies at TCT Point to Very Low Rates of Stroke,
Death, MI

Lack of coverage decisions for carotid stenting may be slowing the
pace of innovation in the field, but not halting it altogether.
During TCT 2008, investigators for the PROTECT, EPIC and EMPIRE
trials, testing different neuroprotection devices during carotid
stenting, showed that innovation in this field, combined with
improved operator experience, is driving adverse-event rates to new
lows. The protection devices are critical to the safety of the
procedure; indeed, the CMS mandates that embolic devices are used
during carotid stenting in order for the minority of currently
applicable patients to be eligible for Medicare coverage.

Gray presented 30-day results in 274 patients who underwent carotid
stenting with the Emboshield Pro Rapid Exchange Embolic Protection
filter-based device and the Xact stent in the PROTECT trial. Overall
major adverse event rates (death, stroke, MI) were 1.8%, Gray
reported--lower than any other carotid-stenting study to date.

Dr L Nelson Hopkins (Millard Fillmore Gates Hospital, Buffalo, NY)
reported a 30-day death, stroke, MI, or transient ischemic attack
(TIA) rate of 4.5% among 245 patients who underwent carotid stenting
protected using the Gore Flow Reversal device in the EMPIRE trial.
The non¡Vfilter-based device provides embolic protection by
reversing the flow of blood through the internal carotid artery,
directing particles away from the brain.

Dr Subbarao Myla (Hoag Memorial Hospital, Newport Beach, CA)
presented the results of the EPIC trial using the FiberNet embolic-
protection system during carotid artery stenting--the device
combines a filter, occlusion balloon, and aspiration. At 30 days,
risk of death, stroke, or MI was 3% for the entire cohort, 4.2% for
symptomatic patients, and 2.7% for asymptomatic patients.

Dr Eugenio Stabile (Clinica Montevergine, Mercogliano, Italy)
presented results from a large European registry of carotid artery
stenting patients during the TCT 2008 meeting showing 30-day rates
of stroke and death to be less than 1.2%--as reported previously by
heartwire.

Gray and Weiner both emphasized that the emerging body of evidence,
starting with major premarket trials and continuing through the
latest pre- and postmarketing studies, shows that adverse event
rates for carotid stenting are steadily declining.

Massop D, Dave R, Metzger C, et al. Stenting and angioplasty with
protection in patients at high-risk for endarterectomy: SAPPHIRE
Worldwide Registry first 2,001 patients. Catheter Cardiovasc
Intervent 2008; DOI: 10.1002/ccd.21844. Available at:
http://www3.interscience.wiley.com/journal/117934745/grouphome/home.h
tml. Abstract

A decision on whether or not to approve the investigational
antiplatelet agent prasugrel (Eli Lilly/Daiichi Sankyo) in the US
will not be made until the early part of next year [1]. The FDA is
apparently planning a February 2009 meeting of its Cardiovascular
and Renal Drugs Advisory Committee to discuss the drug, according to
a posting on a widely respected pharmaceutical industry blog. This
means any approval decision would come no sooner than March 2009.

Last month, the FDA let the review deadline for approval of
prasugrel pass, saying it had not completed its review, but
crucially gave no indication of when it might decide. That
announcement came after the agency, in June, extended its original
review of the drug--which is awaiting approval for the treatment of
ACS patients who are managed with PCI--by three months.

According to the In Vivo blog, members of the FDA's Cardiovascular
and Renal Drugs Advisory Committee have been contacted about their
availability for a February panel meeting specifically on prasugrel,
and the agency's Drug Safety and Risk Management Advisory Committee
may also be convened.

FDA spokesperson Heidi Rebello told In Vivo that she could not
comment on whether an advisory committee meeting was being
considered for prasugrel. If one is planned, it will be announced on
the FDA's website, she said. However, the agency has not yet
released its draft schedule of advisory committee meetings for 2009.

Panel Discord Over Prasugrel?

And apparently, there is discord between members of the
Cardiovascular and Renal Drugs Advisory Committee about prasugrel.
The decision to grant priority review in the first place "suggests
that the top review managers are excited about the potential for the
drug," says the In Vivo report, but "another party has made a
compelling argument against approval of the application in its
current state."

Lilly and Daiichi issued a statement in response to the media
speculation, saying they have not been notified of any regulatory
action for the new drug application for prasugrel or of any decision
to have an advisory committee review the drug [2].

qThe FDA can schedule an advisory committee at any time during the
review of an application. If one is called, then we will be prepared
to participate.

"The FDA can schedule an advisory committee at any time during the
review of an application. If one is called, then we will be prepared
to participate," said Dr John Alexander (global head of research and
development, Daiichi Sankyo) in the statement.

Prasugrel, which will be sold under the brand name Effient if
approved, is expected to be the first real competitor to
clopidogrel.

Prasugrel is widely considered the most important drug in Lilly's
pipeline, and shares in the company fell by 4% on Friday on the news
of the US delay. Prasugrel is also awaiting approval in Europe, with
an application to the European Medicines Agency having being filed
in February 2008.

As widely reported by heartwire, the pivotal trial for prasugrel,
TRITON-TIMI 38, showed significantly reduced ischemic events with
the new drug compared with clopidogrel, but at the expense of an
increase in major bleeding in ACS patients scheduled for PCI.


Lilly prasugrel delay could extend well into 2009. The In Vivo Blog,
October 16, 2008. Available at:
http://invivoblog.blogspot.com/2008/10/lilly-prasugrel-delay-could-
extend-well.html
Eli Lilly. Daiichi Sankyo and Lilly respond to speculation on status
of prasugrel new drug application [press release]. October 16, 2008.
Available at: http://newsroom.lilly.com/releasedetail.cfm?
ReleaseID=341045.

The noninvasive evaluation of endothelial dysfunction using color
Doppler serves as a predictor and marker for future cardiovascular
risk, especially in patients with metabolic syndrome.

"The most striking finding in the present study was the
predictability of our covariates on the outcome of endothelial
dysfunction in a stepwise multiple regression model," lead author
Sufian Zaheer, MD, from the department of pathology at Jawaharlal
Nehru Medical College, in Aligarh, India, said in his poster
presentation.

The study findings were reported here at the American Society for
Clinical Pathology 2008 Annual Meeting.

According to the American Heart Association, when abdominal obesity,
atherogenic dyslipidemia, hypertension, insulin resistance or
glucose intolerance, a prothrombotic state (e.g., high fibrinogen or
plasminogen activator inhibitor-1 in the blood), and a
proinflammatory state (e.g., elevated C-reactive protein in the
blood) coexist, they are referred to as metabolic syndrome.

Endothelial dysfunction is generally defined as the imbalance
between growth-promoting and growth-inhibiting factors,
proatherogenic and antiatherogenic factors, vasodilators and
vasoconstrictors, and procoagulant and anticoagulant factors,
explained Dr. Zaheer.

Evaluation of endothelial dysfunction in patients at risk of
developing metabolic syndrome can predict cardiovascular morbidity
and mortality, noted Dr. Zaheer.

Clinically, endothelial dysfunction can be estimated invasively,
using coronary catheterization, or noninvasively, with ultrasound.

"This is a correlation study evaluating whether or not a noninvasive
method [i.e., brachial artery flow-mediated dilation] is actually
able to quantify a certain marker for endothelial dysfunction,
specifically with reference to the metabolic syndrome," Powers
Peterson, MD, an associate professor of pathology and laboratory
medicine at Cornell University, in New York, New York, and Weill
Cornell Medical College, in Qatar, told Medscape Pathology in an
interview. Dr. Peterson was not involved in the study.

A total of 45 patients with metabolic syndrome and 20 healthy
subjects participated in this study.

For all study participants, Dr. Zaheer and colleagues assessed the
vasodilatory response in the brachial artery using high-resolution
ultrasound images.

The multivariate correlates of endothelial dysfunction in this study
were fasting blood sugar, systolic blood pressure, levels of high-
density lipoprotein (HDL) and low-density lipoprotein (LDL), and age.

"HDL was the most significant of all the predictors in the
regression model, accounting for 66.4% predictability and 44.1 %
total variance," explained Dr. Zaheer. Only HDL was inversely
associated with endothelial dysfunction; all other variables were
directly related to endothelial dysfunction, according to the
abstract by Dr. Zaheer and colleagues.

"The authors concluded that the correlation between lipid profiles
and endothelial dysfunction does exist," commented Dr.
Peterson, "and they have reasonably solid statistical evidence to
support it. But the question I would ask is: If HDLs and LDLs and
fasting blood sugars are excellent surrogate predictors of
endothelial dysfunction, why are we doing flow-mediated dilation? Is
this really a cost-effective tool, and do we really need it?"

Dr. Zaheer's poster was selected among the best 10 AJCP Resident
Research Symposium presentations at this year's meeting.

The study did not receive commercial support. Neither Dr. Zaheer nor
Dr. Peterson have disclosed any relevant financial relationships.

American Society for Clinical Pathology (ASCP) 2008 Annual Meeting:
Poster 45. Presented October 17, 2008.

The use of an embolic-protection and aspiration device proximal to
the lesion in primary PCI results in better immediate microvascular
flow in ST-segment-elevation MI (STEMI) patients compared with
primary PCI alone, a new study has shown. There was no difference in
ST-segment resolution between the two treatments at two hours, nor
was there a difference in myocardial blush grade or clinical
outcomes at 30 days between the two arms.

"We're trying to protect the microcirculation, and by putting in a
device proximally we are trying to protect the occluded vessel prior
to crossing with stents and balloons," lead investigator Dr Karel
Koch (Academic Medical Center, Amsterdam, the Netherlands) told
heartwire. "With the device, there is a stagnation of blood flow so
that before the restoration of antegrade flow, we aspirate the
vessel, which prevents dislodged emboli from heading downstream."

The results of the study, known as the Prospective Randomized Trial
of Proximal Microcirculatory Protection in Patients with Acute
Myocardial Infarction Undergoing Primary PCI (PREPARE), were
presented here last week at TCT 2008.

Stop Blood Flow Before Inserting Stent

Presenting the results during the late-breaking clinical-trials
session, Koch said that embolization of atherothrombotic debris
plays a role in microvascular obstruction and impaired myocardial
perfusion during PCI. Thrombus-aspiration devices have been shown to
improve clinical and reperfusion outcomes compared with PCI alone,
but distal-protection devices have not fared well in STEMI patients.

In this study, investigators used a device that combines proximal
embolic protection and thrombus aspiration (Proxis, St Jude Medical,
St Paul, MN). A full-length catheter is inserted proximally to the
target lesion, and a vessel-sealing balloon is inflated to
temporarily occlude blood flow. With flow temporarily interrupted,
the interventional device is delivered to the lesion. Stagnated
blood and emboli liberated during the procedure are then removed by
aspiration before the balloon is deflated, which restores blood flow.

PREPARE was an investigator-initiated, open-label study in which 284
STEMI patients were randomized to treatment with the Proxis device
or to PCI alone. In terms of the primary end point--complete ST-
segment resolution over time--there was an immediate improvement in
microvascular flow with the proximal protection device compared with
PCI alone. The benefit was not maintained over time.

Koch said there is a "good correlation between early ST-segment
resolution and results of primary PCI in terms of myocardial salvage
and long-term outcomes" and that "based on these findings, bigger
randomized trials should be done with the device."

Asked about the technology, Dr Michael Gibson (Harvard Medical
School, Boston, MA), who moderated a press conference where the
results were first presented, told heartwire that the study is too
small to identify a clinical benefit. Other studies, however, have
shown that if one therapy is better than another at opening the
arteries early, even if there is no late difference between the two,
this can translate into better clinical outcomes.

The insertion of the proximal embolic-protection device added
approximately three minutes from the time of puncture to the
delivery of the sealing balloon, said Koch. He told heartwire that
ST-segment resolution was selected as an end point because it can be
measured independently at a core laboratory, something that is more
difficult to do with myocardial blush score.

In addition, ST-segment resolution was selected to make comparisons
with the Enhanced Myocardial Efficacy and Recovery by Aspiration of
Liberated Debris (EMERALD) trial possible. In EMERALD, distal
protection with a balloon-occlusion and aspiration device (GuardWire
Plus, Medtronic, Santa Rosa, CA) failed to improve microvascular
flow and reperfusion success, reduce infarct size, or enhance event-
free survival in acute-MI patients undergoing primary PCI.

Cardiac surgery in patients 80 years and older often yields benefits
with respect to quality of life, functional status, and life
expectancy, according to a report presented here at the American
College of Surgeons 94th Annual Clinical Congress. The study
assessed patients' living arrangements, functional status, and
leisure activities in the cognitive, social, physical, volunteer,
and creative realms as an index of well-being.

Author Rakesh K. Chaturvedi, MD, PhD, from the division of cardiac
surgery at the Royal Victoria Hospital, McGill University Health
Center, in Montreal, Quebec, noted in his presentation that
morbidity and mortality from cardiac surgery are higher in
octogenarians than in younger patients. However, "in octogenarians,
the engaged and functional life after surgery is probably more
important than the actual survival statistic," he observed. Few
outcomes have been studied for this group beyond the 30-day
mortality figures.

One impetus for the study was the fact that the fastest-growing
population group in North America is people 80 years and older.
Nearly half (40%) this population has or will develop symptoms of
cardiac disease, and improved techniques have increased cardiac
surgeries in octogenarians to 7% to 10% of all cardiac
surgeries. "Everybody's [studying] 50 years, 40 years,...and the
results are good," Dr. Chaturvedi told Medscape General
Surgery. "But what is happening with this particular age group?"

To find out, the study followed 400 octogenarians (185 women, 215
men) who had undergone ¡ª and survived ¡ª cardiac surgery during a 6-
year period (September 2000 to September 2006). This group comprised
8.7% of the patients having cardiac surgery during this interval.
Average age at surgery was 82.56 years. By the end of follow-up (7¨C
78 months), 264 patients (65.5%) were still living ¡ª 150 men and
114 women, with an average age of 85.5 years. Survival did not vary
significantly with sex.

Functional status, living arrangements, and leisure activities were
evaluated by telephone interviews. Questions were drawn from the
Karnofsky Performance Score (KPS), the Barthel Index (BI), and a
leisure activity sheet. The KPS measures a patient's ability to
perform certain ordinary tasks, and the BI assesses function in
activities of daily living in terms of disability or dependence.

Functional status was classified as autonomous (BI = 100; KPS ¡Ý 70)
or dependent (BI < 100; KPS < 70). Living arrangements were
classified as living at home without help for activities of daily
living (ADL) or instrumental activities of daily living (IADL);
living in a residence without help for ADL or IADL; or supervised,
with some help required for ADL and IADL.

Preoperative functional status was not assessed in this prospective
descriptive study. However, preoperative conditions included
congestive heart failure (46%), left ventricle ejection fraction of
less than 50% (33.3%), renal dysfunction (20%), pulmonary
hypertension (19.8%), and diabetes mellitus (16.8%). "The majority
of patients were severely symptomatic preoperatively because of
cardiac problems, and their functional level was very much
compromised for their daily living and activities," reported Dr.
Chaturvedi. More than 60% of the cardiac surgeries were "urgent,"
and 31.5% were "elective."

However, the absence of preoperative data concerned session
moderator Frank W. Sellke, MD, FACS, from the division of
cardiothoracic surgery at Beth Israel Deaconess Medical Center,
Harvard Medical School, in Boston, Massachusetts. "When you're
looking at outcomes, you really need to know where they were before
they did something, in this case surgery," he told Medscape General
Surgery. "While they all, presumably, require surgery for one reason
or another, a lot of patients get surgery for anatomy. So their
quality of life would presumably be pretty good. To make the kind of
conclusions they're trying to make, you really have to get a better
handle on what the patients were like prior to the operation," Dr.
Sellke concluded.

Greater morbidity and mortality in patients older than 80 years was
evident in the 30-day mortality of 15.7% and 1-year survival of
76.5%. However, among those who survived, 92% were
ranked "autonomous" for functional status and only 8%
were "dependent" at the end of follow-up. When categorized by years
since cardiac surgery (a maximum of 78 months), there was little
difference in the proportion of survivors designated autonomous or
dependent.

"Their [intensive-care-unit] time is a little bit more than younger
patients, but once they cross the 3-month period, they become as
normal as the general population," said Dr. Chaturvedi. Correcting
cardiac problems can also lead to improvement in factors such as
kidney function.

Living arrangements also reflected high function, with more than 72%
living at home without help for ADL or IADL, 19% in a residence
without help for ADL or IADL, and only 8% living in supervised
facilities.

The investigators explained their preference for observable leisure
activities, rather than health-related quality of life, to assess
quality of life. "Measurement scales are usually performed on fixed
points, imposing standardized models of quality of life...without
giving patients flexibility to elaborate or explain their actual
expressions," said Dr. Chaturvedi in his presentation. "A large
proportion of elderly patients are not able to quantify their
responses on scales," he added, and many patients could not complete
the questionnaire, which would bias the results.

"We see observable behavior, what the person is doing. Is he going
to sit at McDonald's or his club? Is the person going out or not?"
Dr. Chaturvedi explained to Medscape General Surgery.

Using leisure activities as an assessment tool, this study found
that 89% to 96% of patients were involved in cognitive, social, or
physical leisure activities at the end of the follow-up period. Some
(17%) were also involved in creative or volunteer work. "They are,
amazingly, doing very well, they are going on cruises, they are not
wasting their time," Dr. Chaturvedi told Medscape General Surgery.

Knowing the long-term functional outcomes and leisure activities in
these patients is helpful for octogenarians, their families, and
their physicians when weighing the risks and benefits of cardiac
surgery.

Neither Dr. Chaturvedi nor Dr. Sellke have disclosed any relevant
financial relationships.

American College of Surgeons (ACS) 94th Annual Clinical Congress:
Session GS35. Presented October 14, 2008.

Taxus and Cypher stents are no different in the treatment of high-
risk left main disease and are associated with relatively low rates
of death, MI, and revascularization at one and two years
poststenting, results from the ISAR-Left Main (ISAR-LM) study show.
Dr Julinda Mehilli (Deutsches Herzzentrum, Munich, Germany)
presented the results here at the TCT 2008 meeting.

"Treatment of unprotected left main lesions in unselected patients
with DES is feasible, safe, and effective up to two years," Mehilli
concluded. "Both Taxus and Cypher provide similar clinical and
angiographic outcomes in this form of CAD."

ISAR-LM randomized 607 high-risk patients with symptomatic left main
disease (blockage >50%) to either the Taxus paclitaxel-eluting stent
(n=302) or the Cypher sirolimus-eluting stent (n=305). The high-risk
patient profile included 40% ACS, 25% prior MI, 50% prior PCI, more
than 70% multivessel disease, 30% diabetic, 63% distal lesions, and
50% culotte stenting.

One-year poststenting, there were no differences in the combined
primary end point of death, MI, or repeat revascularization (ranging
from 13.6% to 15.8%) or in each of the end points individually. As
seen in other left main studies, the rate of definite stent
thrombosis at two years was very low with both stent types (0.3%¡V
0.7%) and not significantly different.

At two years, mortality was 10.4% for Taxus and 8.7% for Cypher, a
nonsignificant difference. Overall MACE at two years was identical
in the two groups: 21% for both stent types.

Speaking with the press, Mehilli said that event rates were actually
lower than anticipated at one year, but more or less in line with
expectations by two years and in keeping with the high-risk profile
of the patients, who had a Parsonnet score of about 8 and a
EUROSCORE of 12--both scores are preoperative risk-of-mortality
estimates. Patients normally sent to CABG typically have a lower
surgical risk, she said. In the MAIN-COMPARE registry, she noted,
the mean age of CABG-treated patients with left main was 62, as
opposed to 69 in the ISAR-LM study; the proportion of patients with
reduced ejection fraction and prior MI was also dramatically lower.

Discussing the results following the presentation, Dr Stephen
Windecker (University Hospital Bern, Switzerland) suggested that
ISAR-LM "added a very important piece of information."

"I think the trial shows very favorable short-term safety" for using
PCI to treat left main disease with either the Taxus or Cypher
stent, he concluded. "Against this background, I would like to ask
the professional societies if the class 3 indication [meaning not
indicated], as shown in the ACC/AHA 2005 guidelines, is really still
justified."

Boston Scientific's TAXUS Liberté drug-eluting coronary stent,
described as a more flexible, easier-to-deliver descendant of the
paclitaxel-based TAXUS Express, has received FDA market approval,
the company announced today [1].

Marketing of the Liberté in the US will actually begin "early next
month," according to the company's news release, "following
completion of the introduction of its TAXUS Express Atom paclitaxel-
eluting coronary stent system, which was approved by the FDA last
month," as reported by heartwire. The Liberté has been available in
Europe since 2005, was approved in Canada in April of this year, and
remains under regulatory review in Japan.

In its statement, Boston Scientific notes that the Liberté was
judged noninferior to the Express with respect to nine- and 12-month
efficacy and safety in the TAXUS ATLAS trial. "Despite using similar
inclusion and exclusion criteria, the contemporary TAXUS Liberté
cohort had more complex lesions when compared with the historic
TAXUS Express controls," it states.

TAXUS ATLAS gained unexpected notoriety in August when the Wall
Street Journal published a story questioning how the trial was
analyzed and its noninferiority judgment [2]. Reaction to the
article from physicians interviewed by heartwire included
indignation that a newspaper would assume the role of peer reviewer,
acknowledgment of an oversight role for journalism, and seeing it as
a statement on the limitations of clinical-trial analysis.


Boston Scientific announces FDA approval of second-generation TAXUS
Liberte drug-eluting stent [news release]. Oct. 10, 2008. Available
at http://bostonscientific.mediaroom.com/index.php?s=43&item=774.
Winstein KJ. Boston Scientific Stent study flawed. Wall Street
Journal, August 14, 2008. Available at http://www.wsj.com.

Delivering another blow to the theory that patent foramen ovale
(PFO) can cause migraine headaches, researchers in Florida are
reporting that in a large, multiethnic cohort the prevalence of
either condition is about 15%, but the two are only rarely present
in the same person [1]. Using data from the Northern Manhattan Study
(NOMAS), Dr Tatjana Rundek (University of Miami, FL) and colleagues
found that only 2% of subjects had both PFO and self-reported
migraine.

Their results are published in the September 30, 2008 issue of
Circulation.

In other news, heartwire has learned that another company has
quietly pulled the plug on its trial investigating PFO closure for
migraine.

Discussing the results with heartwire, Rundek pointed out that
earlier studies have tended to first identify a population of
patients with PFO and then go looking for migraine prevalence or to
first identify a population of patients with migraine and then test
them for PFO. Their study specifically started with a population in
whom neither the PFO rates nor presence/absence of migraine was
known at baseline.

In NOMAS, 1101 stroke-free subjects, mean age 69, were asked about
their history of migraine, then screened for PFO using transthoracic
echocardiography. In all, 16% of the population reported a history
of migraine (13% migraine with aura), and 15% were found to have
PFO. But strikingly, prevalence of PFO was no different in subjects
with or without migraine (14.6% vs 15%), nor was PFO associated with
increased prevalence of migraine after adjustment for possible
confounders, including diabetes, hypertension, smoking, or
dyslipidemia.

"The main message here is that both conditions are prevalent, but
having both is not that prevalent," Rundek told heartwire. "In this
population, which is a little bit older than other case-controlled
studies, we're pretty confident that this association does not
exist. However, we cannot make this conclusion for a younger
population."

But the causative-link hypothesis seems to be crumbling, along with
hopes that PFO closure might help migraineurs. As previously
reported by heartwire, the MIST I trial found no benefit of PFO
closure using NMT Medical's Starflex device, compared with a sham
procedure, in terms of migraine cure or reduction in migraine days.
AGA Medical has two studies of PFO closure for migraine using its
Amplatzer device still enrolling patients (the US PREMIUM trial and
the international PRIMA trial), but a third company, St Jude
Medical, has stopped enrollment in its ESCAPE trial, which was
testing its Premere device as a treatment for migraine. A company
spokesperson confirmed that just 56 patients out of a planned 492
subjects had been enrolled since 2006. "The company has determined
that it is not reasonable to continue the study," she said.

Rundek said she is disappointed, if unsurprised, to hear of ESCAPE's
halt. "My opinion all along was, let's finish the studies and get
some answers, as long as there are no concerns about safety."

But she also commented that the theory had always, to her, seemed
too good to be true. "Migraine either with or without aura is a very
complicated disorder in terms of the pathophysiology, and the
mechanisms are still not clearly known to the full extent. It's hard
to believe that having a PFO would be completely linked to such a
complex mechanism of migraine and that by closing PFO we would
completely eradicate migraine," she said. Earlier studies reporting
a link between PFO and migraine "speak more to maybe some underlying
genetic mechanism or some specific polymorphism that actually
predisposes people to have both conditions than actually having the
conditions linked through a certain mechanism," she speculated.

Don't Go Hunting for Pfos in Migraineurs

In an editorial accompanying the NOMAS study, Dr Tobias Kurth
(Brigham and Women's Hospital, Boston, MA) et al point to the scant
evidence linking migraine with PFO in case-control studies; linking
people with migraine with aura, who also have PFO, to an increased
risk of stroke; or linking PFO closure to effective migraine
treatment [2].

"Thus, detection of PFO or PFO closure should not be recommended to
patients who have only migraine," they conclude. "It is, however,
plausible that PFO may affect specific subgroups of patients with
migraine, and future studies identifying and targeting such
subgroups are warranted."

Indeed, an observation made by both the editorialists and the NOMAS
study authors is that these particular results are confined to an
older group of patients, in whom prevalence of migraine tends to be
lower than in younger patients.

Also commenting on the NOMAS findings for heartwire, Dr Randy Evans
(Baylor College of Medicine, Houston, TX), had similar views, saying
that the link between migraine, stroke, and PFO "is becoming more
and more tenuous."

"Despite several positive observational studies, the controversial
MIST trial showed no improvement in migraine frequency with PFO
closure," he noted. "And now, despite case-control studies showing
an association between migraine with aura and PFO, the population-
based NOMAS study shows no association."

Population-based studies generally have the least bias, Evans
pointed out, although in the case of NOMAS, there may have
been "ascertainment bias," since the authors relied on participant
self-reporting with regard to their migraine history. The older age
of the patients might also have played a role, leading to "recall
bias," he added.

"For now, the evidence does not support closing PFOs in migraineurs
with aura," Evans said. "However, several further studies are
ongoing with different closure devices; perhaps the results will be
positive and lead to even more controversy."


Rundek T, Elkind MSV, Di Tullio MR, et al. Patent foramen ovale and
migraine. A cross-sectional study from the Northern Manhattan Study
(NOMAS). Circulation 2008; 118:1419-1424. Abstract
Kurth T, Tzourio C, Bousser MG. Migraine: A matter of the heart?
Circulation 2008; 118:1405-1407. Abstract

A largely abandoned imaging test is providing some welcome new
insights about the technology it produced: researchers in California
using CT angiograms taken with electron-beam tomography (EBT)
scanners have shown than the images can predict mortality among
patients with suspected coronary artery disease (CAD) [1]. They say
the findings represent the first solid outcome data supporting a
role for CT angiography in predicting all-cause mortality.

"All the other studies that have been published have almost entirely
been on coronary calcium scanning and outcomes, but this study was
looking at whether CT angiography (CTA) predicts outcomes, and there
are virtually no data in the literature looking at this," senior
author Dr Matthew Budoff (Harbor-University of California, Los
Angeles [UCLA] Medical Center, Torrance) told heartwire. "We now
have some evidence that the plaque we see on CT angiography and the
stenosis we see on CTA actually have prognostic implications."

The study appears in the October 14, 2008 issue of the Journal of
the American College of Cardiology.

Today, most of the excitement--and controversy--over CT angiography
has centered on multislice scanners with 64 detectors or more. But
as Budoff, with first author Dr Matthew Ostrom and colleagues
(UCLA), point out in their paper, much-needed outcome data, linking
angiographic burden identified by CTA to subsequent adverse events,
are hard to come by, since the technology itself is so new and
patient follow-up is limited.

EBT Scans Date Back to Late 1990s

For their study, Ostrom et al reviewed CT angiograms for 2538
patients who underwent CTA using EBT during the late 1990s and early
2000s. All patients had no known CAD at the time of their scans;
their CAD was categorized by EBT scan as obstructive or
nonobstructive CAD in one, two, or three vessels.

After a mean follow-up of more than six years (and a maximum of 12
years) patients diagnosed with CAD by CT angiography were
significantly more likely to have died than patients with no
evidence of CAD by CT angiography at baseline, a finding that
remained significant after adjustment for CAD risk factors. Ostrom
et al further demonstrated a clear trend wherein patients with
nonobstuctive CAD in one vessel were more likely to survive than
patients with two- or three-vessel nonobstructive disease,
increasing all the way across the spectrum to patients with three-
vessel obstructive CAD, in whom survival was the lowest. Moreover,
coronary artery calcium score, added to presence or absence of CAD
by EBT angiography, increased the predictive power of the test.

The primary results of our study reveal that the burden of
angiographic disease detected by CTA positively correlates with the
incidence of all-cause mortality among patients with suspected CAD
referred for evaluation in an outpatient setting," Ostrom et al
write. "This is the first study to demonstrate that CTA is
incremental to traditional risk factors plus coronary calcium in
predicting all-cause mortality. . . . To our knowledge, this cohort
represents the largest and longest follow-up after CTA in such a
population and is one of few studies demonstrating the prognostic
value of this technology."

64-Slice Scanners Likely Better, But Outcome Data Take Time

To heartwire, Budoff emphasized that the newer, 64-slice scanners
would undoubtedly be better for visualizing plaques and defining
stenosis, but it will be some time before outcome data are available
for 64-slice CTA. "I am confident 64-slice will do better, but we
won¡¦t have 10-year data for another seven years," he predicted.

And still to be established, he notes, is how the prognostic
capacity of CTA compares with that of other imaging modalities, such
as conventional invasive angiography and nuclear imaging for hard
outcomes. Other outstanding questions include which patients are
best suited to noninvasive CTA, as opposed to other screening
modalities, and how much radiation dose can be minimized.

"Radiation exposure [from CTA] at our site has been diminishing over
the years--we've been averaging under 10 mSv for CTA over the past
three years, and we continue to find ways of reducing radiation
exposure with prospective imaging and by reducing the scan
parameters to lower radiation exposure to our patients," Budoff said.

Conventional invasive angiography, he added, is between 2 to 5 mSv,
while nuclear imaging is higher, ranging from 8 to 20 mSv.

Newer CT scanners, with 128 detectors or higher, will be a mixed
blessing, Budoff notes--something that may provide reassurances to
centers that have already invested in 64-slice scanners. "I think
the radiation dose will go up with the next-generation scanners,
because when you have more detectors, the radiation dose goes up.
The diagnostic accuracy may go up a little bit, and the number of
noninterpretable studies may go down a little bit, but you will be
paying a price both because the cost of the machines will go up and
in terms of higher radiation exposure."


Ostrom MP, Gopal A, Ahmadi N, et al. Mortality incidence and the
severity of coronary atherosclerosis assessed by computed tomography
angiography. J Am Coll Cardiol 2008; 52:1335-1343.

A new economic analysis of elective endovascular repair of abdominal
aortic aneurysms (EVAR) in high-risk patients suggests that the
minimally invasive approach is a cost-effective strategy compared
with open surgical repair [1].

The investigators, led by Dr Jean-Eric Tarride (McMaster University,
Hamilton, ON), also showed that the average one-year costs for EVAR
and open surgery were nearly identical, despite the significantly
more expensive endovascular procedural costs, which include the $10
000 endograft. Patients undergoing endovascular repair spent less
time in the hospital--7.7 days compared with 16 days for those
treated with traditional open surgery--and this translated into
lower nonprocedural costs. Despite similar baseline characteristics,
there was also less morbidity associated with the endovascular
approach.

The results of the study are published in the October 2008 issue of
the Journal of Vascular Surgery.

Data From the London Health Sciences Center

The Canadian Society for Vascular Surgery recommends EVAR for
patients with suitable anatomy at intermediate and high risk for
perioperative morbidity with open repair, while open repair is the
current standard for those at low risk. Previous economic analyses
of EVAR vs open surgery concluded that the endovascular approach was
not cost-effective, but the studies focused on all comers and not
just those at high risk. In this review, Tarride and colleagues
evaluated the cost-effectiveness of EVAR compared with open surgery
in high-risk patients only.

In this nonrandomized study, demographic, medical, healthcare-
resource utilization, and quality-of-life data were collected over a
period of one year following elective abdominal aortic aneurysm
(AAA) repair. Two effectiveness measures were used in this economic
evaluation: number of life-years gained (LYGs) and number of quality-
adjusted life-years (QALYs). QALYs, which combine duration of life
with quality of life, are a measure commonly used in economic
evaluations.

Data were collected on 192 high-risk patients undergoing surgical
repair of an abdominal aortic aneurysm >5.5 cm at the London Health
Sciences Center, in Ontario. Of these patients, 140 underwent
endovascular repair of the aneurysm while 52 had open repair
surgery. The 30-day postoperative complication rates were lower in
those undergoing EVAR, with mortality rates of 0.7% for those
undergoing endovascular repair and 9.6% for those undergoing open
surgery. Hospital lengths of stay, intensive care unit (ICU)
admissions, and ICU lengths of stay were also shortened with EVAR.

At one year, the total costs of the two treatments were similar,
although there were differences in how the money was spent. Initial
hospitalization costs were less with EVAR than with open surgery,
but follow-up medical costs were higher with the endovascular
approach. In terms of postprocedural surveillance, EVAR patients
have a computed tomography (CT) scan and are seen by the surgeon at
one, three, six, and 12 months postoperatively, while open repair
requires only a single postoperative visit at four to six weeks. At
one year, all-cause mortality was lower in EVAR patients--7.1% vs
17.3%--and there were no differences in terms of quality of life.

In terms of the cost-effectiveness analysis, point estimates at one
year showed that EVAR "dominated" open surgical repair, as EVAR was
less costly and more effective than open surgery in terms of LYGs
and QALYs. The investigators note that when bootstrap techniques
were used to deal with the sampling uncertainty associated with the
trial, there was more uncertainty regarding the QALYs and less
uncertainty regarding the life-years gained.

To summarize the uncertainty with the data, the authors used cost-
effectiveness acceptability curves to show the probability that a
treatment is cost-effective for several threshold values. "If
society were willing to pay $50 000 per life-year gained or per
quality-adjusted life-year gained, the probability of EVAR being
cost-effective was found to be 0.76 and 0.55, respectively," they
write.

Sensitivity analyses examining several different mortality scenarios
allowed investigators to extrapolate the findings out to five years,
and these data showed that EVAR was cost-effective.

The provincial Ministry of Health and Long-Term Care requested the
cost-effectiveness study in order to provide evidence to support
policy recommendations regarding the use of EVAR in Ontario and
approved funding for the procedure based on interim results of this
study and the clinical-outcomes data, which will be published soon.


Tarride JE, Blackhouse G, De Rose G, et al. Cost effectiveness
analysis of elective endovascular repair compared with open surgical
repair of abdominal aortic aneurysms for patients at a high surgical
risk: a 1-year patient-level analysis conducted in Ontario, Canada.
J Vasc Surg 2008; 48:779-787. Abstract