Familial factors influence the risk of microvascular complications
of type 1 diabetes, independent from the familial risk of diabetes
itself, according to a report in the December issue of The Journal
of Clinical Endocrinology & Metabolism.

"To the extent that glucose control is important, it may be even
more critical in those patients potentially at higher risk for
complications, those being type 1 diabetic-affected siblings of type
1 diabetes patients with complications, and also women, who appear
to be at higher risk for complications," Dr. David A. Greenberg from
Columbia University, New York told Reuters Health.

Dr. Greenberg, along with Dr. Maria C. Monti and colleagues, sought
to identify familial risk factors for diabetic microvascular
complications and to examine how these risk factors influence
retinopathy, nephropathy, and neuropathy onset. They included a
total of 8114 subjects in the study: 4935 probands with type 1
diabetes, 921 siblings, and 695 parents.

The presence of type 2 diabetes (but not type 1 diabetes) in a
parent was significantly associated with the development of all
three microvascular complications, the authors report.

Diabetic patients whose siblings had type 1 diabetes complications
faced substantially higher risks of developing microvascular
complications themselves, with odds ratios of 9.9 for retinopathy in
patients whose siblings had retinopathy, 6.18 for nephropathy in
patients whose siblings had nephropathy, and 2.2 for neuropathy in
patients whose siblings had neuropathy.

Retinopathy and neuropathy were more common in female type 1
diabetes patients than in male type 1 diabetes patients, the
researchers say, and the risk of second complications was higher in
female patients than in male patients.

The risk of complications increased with increasing duration of type
1 diabetes, and diagnosis at a very young age (under 5 years) or
past puberty (over 14 years) was associated with a lower likelihood
of developing complications.

"These new findings tell us that the explanation for what causes
complications must involve shared pathogenic mechanisms in the
family (mechanisms that may be independent of the susceptibility to
type 1 diabetes)," the authors conclude.

"Today, the emphasis is on whole-genome association studies and
SNS," Dr. Greenberg pointed out. "One of the consequences of this
emphasis is that family data, such as we used in our work, has been
denigrated, and data collection in genetic studies focuses on
subjects with the disease and their comparison with controls. Thus,
the familial aspects of genetic studies are being lost, which will
ultimately be detrimental to our overall understanding of how genes
cause disease."

J Clin Endocrin Metab 2007.

A scientific watchdog group is asking the government to cut the
amount of sodium Americans consume, while regulators consider
whether such a move would have widespread health benefits.

The group is calling on the FDA to set new standards limiting the
sodium content of food. Americans on average consume far more that
the recommended amount of sodium, a fact thought to play a key role
in high rates of hypertension and cardiovascular disease.

Most of the sodium Americans eat is from packaged food or restaurant
meals. The group, the Center for Science in the Public Interest
(CSPI), says voluntary industry efforts to curb the use of salt have
not gone far enough. The CSPI petitioned the FDA to compel more cuts.

"We have a health crisis on our hands, and history suggests that
more certain and more permanent measures are needed," Michael
Jacobson, PhD, the group's executive director, said at FDA hearings
on the petition.

Cardiovascular disease, including strokes, heart attacks, and heart
failure, is the No. 1 killer of Americans. Hypertension, or
abnormally high blood pressure, is a major risk factor for
cardiovascular disease.

Cutting Sodium Levels

The hearings mark the first time in 25 years that the FDA has
considered measures to cut sodium levels in food. The agency
concluded in 1982 that voluntary industry efforts were sufficient to
protect the public's health.

Americans' average sodium intake did not drop appreciably, while
rates of cardiovascular disease have gone up.

"I think the FDA's optimism about voluntary changes has proved
unwarranted ... and many tens of thousands of people have died
unnecessarily," Jacobson said.

Agency officials called Thursday's hearing an information-gathering
session and said they have not determined when or if they will move
to curb sodium in the food supply. The agency could enact new limits
on the amount of sodium companies can add to food or come up with
stricter labeling standards warning consumers about the dangers of
sodium.

"There is a lot of research for us to consider," Barbara Schneeman,
PhD, director of FDA's office of nutrition, labeling, and dietary
supplements, told WebMD.

Much of that research has been done since the agency last considered
salt levels in food.

Lawrence Appel, MD, a professor of medicine and epidemiology at
Johns Hopkins Medical Institutions, said three studies since 2001
have linked cutting dietary sodium to a reduction in cardiovascular
events like heart attack.

The latest, published last April in BMJ, showed that adults who cut
their dietary sodium levels reduced their changes of a heart attack
or stroke by 30%.

"This is truly a public health epidemic," Appel said of hypertension.

Appel led an Institute of Medicine panel that in 2004 urged adults
to limit sodium intake to 2,300 milligrams per day, the amount
present in one teaspoon of table salt. But most sodium intake is
from processed foods.

Voluntary Cuts in Sodium

Representatives of the food industry said companies have succeeded
in voluntarily cutting unnecessary sodium out of their products.
They warned that consumers were driven away from products when
companies previously experimented with quickly removing salt.

"Improvement in the health of Americans is best achieved through
education to modify behaviors ... rather than single policies on
individual ingredients," said Robert Earl, senior director of
nutrition policy for the Grocery Manufacturers Association -- Food
Products Association.

Jacobson said that industry efforts to cut sodium have occurred but
that they have been too gradual. The CSPI tracked 71 grocery store
products and found that they dropped about 0.5% per year between
1984 and 2004. At that rate, Jacobson said it would take 100 years
to cut average sodium intake by 50%.

Several government and private groups, including the American
Medical Association, have recommended such a cut take place over the
next decade.

"I don't think we have that long to wait," Jacobson said.

A new analysis of 61 prospective observational studies has failed to
find any association of total cholesterol (TC) with stroke mortality
[1]. The research, from the Prospective Studies Collaboration (PSC;
Clinical Trial Service Unit, University of Oxford, UK), appears in
the December 1, 2007 issue of the Lancet.

Trial coordinator Dr Sarah Lewington (Clinical Trial Service Unit)
told heartwire that while the stroke finding "was surprising, it is
actually in line with previous observational studies. There has
always been this discrepancy between the observational data and the
randomized trials." However, she stressed that, despite their
findings, "there is conclusive evidence from randomized trials that
statins reduce stroke rate to the same degree that they reduce
coronary event rates."

She adds that the most important result from the PSC study, to her
mind, is that "cholesterol is a risk factor for heart disease not
just in middle age, but also in old age. Because the risk in old age
is so much greater, the absolute relevance of cholesterol is even
greater for older people," she notes. Another key finding was
that "high-density lipoprotein cholesterol adds to the prediction.
We found the ratio of TC to HDL is more informative than HDL-C alone
and much more informative than TC. So doctors should be measuring
HDL-C as well as total cholesterol, if they can. You're much more
likely to be able to determine someone's risk if you measure their
HDL-C."

No lower threshold for cholesterol

The PSC researchers obtained information from 61 prospective
observational studies, mostly in Western Europe or North America,
although there were a few studies from China. The total trial
population was almost 900 000 adults without previous disease and
with baseline measurements of TC and blood pressure. The research
was mostly conduced during the 1980s, when TC was routinely measured
rather than LDL cholesterol, Lewington explained.

During nearly 12 million person-years at risk between the ages of 40
and 89, there were 55 000 vascular deaths (34 000 ischemic heart
disease [IHD], 12 000 stroke, 10 000 other). Information about HDL-C
was available for 150 000 participants, among whom there were 5000
vascular deaths (3000 IHD, 1000 stroke, 1000 other).

TC was positively associated with IHD mortality in both middle and
old age and at all blood-pressure levels. A 1-mmol/L-lower TC was
associated with about a half (hazard ratio 0.44), a third (HR 0.66),
and a sixth (HR 0.83) lower IHD mortality in both sexes at ages 40
to 49, 50 to 69, and 70 to 89 years, respectively, throughout the
main range of cholesterol in most developed countries, with no
apparent threshold.

This latter point is important, says Lewington. "We found no
threshold level below which lower cholesterol is not associated with
lower risk, so there is no worry about lowering cholesterol as far
as heart disease is concerned. Because we had a lot of data we could
divide the bottom group up, and even below 3.5 mmol/L there was
still an indication that lower cholesterol gave lower risk of heart
disease. This shows conclusively there is no risk [to lowering
cholesterol]."

The researchers also performed a parallel analyses of the Multiple
Risk Factor Intervention Trial (MRFIT) that involved a further 34
242 vascular deaths--the combined results showed similar findings to
the PSC study overall.

Despite lack of association of TC and stroke, treatment should be
guided by RCTs


The PSC researchers found a positive relation between cholesterol
and stroke only in middle age and only in those with below-average
BP; at older ages (70-89), and particularly for those with systolic
BP greater than 145 mm Hg, total cholesterol was negatively related
to hemorrhagic and total stroke mortality.


"The absence of any independently positive association between TC
and stroke mortality in middle age (after allowing for systolic
blood pressure [SBP]) or in those with SBP below 145 mm Hg and the
negative association of cholesterol with stroke mortality at older
ages or at higher blood pressures are unexplained and invite
research," they observe. "Further investigation of exactly how
lipoprotein particles affect stroke risks might help to explain this
striking discrepancy."

In an accompanying comment [2], Drs Pierre Amarenco (Bichat-Claude
Bernard University Hospital, Paris, France) and P Gabriel Steg
(Université Paris 7-Denis Diderot, France) note the lack of a clear
association between cholesterol and stroke in the PSC study.

But they point out, "The various causes of ischemic stroke might
have different associations with cholesterol. While myocardial
infarction almost always follows atherothrombotic disease, brain
infarction stems from conditions ranging from rheumatic heart
disease to atherosclerotic carotid stenosis. Blood cholesterol is
associated with carotid stenosis, and carotid stenosis causes
stroke, so observational studies including stroke associated with
carotid stenosis might mimic the findings with IHD."

And they note that stroke risk reduction with statins was recently
confirmed in SPARCL in the secondary prevention of stroke or
transient ischemic attack: "The lower the achieved LDL cholesterol
over the course of the trial, the greater the reduction in the risk
of recurrent stroke," they say. Amarenco was in fact the principal
investigator of SPARCL, which was published in the New England
Journal of Medicine in 2006.

However, they also observe that, as in another trial, baseline LDL
cholesterol was not predictive of stroke in SPARCL, and the
treatment effect was observed regardless of baseline LDL-C, findings
they say are "puzzling."

Nevertheless, "a link between cholesterol and stroke risk probably
exists (at least with atherothrombotic stroke), and there is good
evidence that lowering blood cholesterol with statins reduces stroke
risk and carotid atherosclerosis, independently of blood
cholesterol, blood pressure, and age," they state.

Lewington and the PSC group agree: "Treatment should be guided
principally by the definitive evidence from randomized trials, that
statins substantially reduce not only coronary-event rates but also
total stroke rates in patients with a wide range of ages and blood
pressures."

Move over LDL: TC/HDL ratio is more informative

With regard to the HDL analyses, the PSC found that the ratio of
TC/HDL-C was the strongest predictor of IHD mortality--40% more
informative than non-HDL cholesterol and more than twice as
informative as TC.

Amarenco and Steg also comment on this finding: "Interestingly,
TC/HDL cholesterol is more informative in this meta-analysis than
HDL, non-HDL, or TC. This result parallels the observation in the
INTERHEART study that the apoB/apoA-1 ratio was the most informative
variable.

"These findings argue for applying the benefits of statins to high-
risk patients, regardless of age and blood pressure, and suggest
that clinicians might need to consider the ratio of TC/HDL
cholesterol, rather than the LDL-cholesterol level to which they
have become accustomed," the French doctors conclude.

The Clinical Trial Service Unit is involved in clinical trials of
cholesterol modification therapy with funding from various companies
(Merck, Schering, Solvay) as research grants to (and administered
by) Oxford University. Amarenco and Steg report receiving honoraria,
speaker's fees, and research funding from a variety of companies,
listed in their paper.



Prospective Studies Collaboration. Blood cholesterol and vascular
mortality by age, sex and blood pressure: a meta-analysis of
individual data from 61 prospective studies with 55 000 vascular
deaths. Lancet 2007; 370:1829-1839.
Amarenco P and Steg PG. The paradox of cholesterol and stroke.
Lancet 2007; 370:1803-1804.

Osteoprotegerin appears to be an independent marker of silent
myocardial ischemia in asymptomatic diabetic patients, French
researchers report in the November issue of Diabetes Care.

"Additional markers," lead investigator Dr. Antoine Avignon told
Reuters Health, "are truly necessary for optimal management of
cardiovascular risk in diabetic patients."

To investigate the utility of osteoprotegerin, a substance involved
in atherosclerosis, and other possible markers of cardiovascular
risk, Dr. Avignon of Lapeyronie Hospital, Montpellier and colleagues
studied 465 diabetic patients and identified 92 with silent
myocardial ischemia.

Levels of other proteins including C-reactive protein and fibrinogen
had no significant value as markers, but patients with
osteoprotegerin levels above the 75th percentile were at
significantly increased relative risk (3.19) of silent myocardial
ischemia compared to those with lower levels.

This remained true after adjusting for other known silent myocardial
ischemia risk factors including age, body mass index and blood
pressure. The association remained significant in patients of both
sexes with type 1 or type 2 diabetes, with or without nephropathy.
However, it was not significant in patients with peripheral artery
disease.

Thus, concluded Dr. Avignon, "osteoprotegerin appears as a promising
marker that may help identify patients for whom non-invasive and
invasive investigations are justified."

Diabetes Care 2007;30:2934-2939.

Another multicenter study has confirmed the diagnostic accuracy of
CT angiography (CTA), as compared with standard coronary
angiography, this time in an unselected series of chest-pain
patients referred for invasive coronary angiography. Results from
the Assessment by Coronary Computed Tomographic Angiography of
Individuals Undergoing Invasive Coronary Angiography (ACCURACY)
study corroborate the results from the CORE 64 trial, presented at
the recent America Heart Association meeting in Orlando. CORE-64,
however, excluded patients with calcium scores greater than 600 and
looked only at vessels larger than 1.5 mm.

Dr James Min (Cornell University, New York, NY) presented the
ACCURACY results Monday at the Radiological Society of North America
(RSNA) 2007 meeting.

In ACCURACY, he told heartwire, investigators did not exclude
patients on the basis of body-mass index, calcium score, or vessel
size and as such more closely mimicked how Min believes CTA would be
used in the real world. "Some labs are excluding patients based on
baseline calcium score: that, to me, makes the test not so useful,"
he said. "You would have to do a test to see whether you can do
another test. If the test can't be done a priori on its own, I think
probably we should be thinking about a different way. In our study,
we evaluated all segments in all-comers because that's how people
come through a CT lab."

That said, he continued, "Our study corroborates a lot of the CORE
64 findings--namely that, in a blinded fashion, in a prospective
multicenter study, we can look at CTA as being as highly accurate in
its diagnostic performance as standard coronary angiography."

ACCURACY results

A total of 16 sites participated in the ACCURACY study, enrolling
232 patients with typical or atypical chest pain. All patients
underwent invasive quantitative coronary angiography (QCA) and 64-
slice CTA; all scans were graded on a per-patient and per-segment
basis, with all vessel segments imaged regardless of patient or
vessel calcium score. Test results for 229 patients were ultimately
analyzed in the ACCURACY study. For the purposes of the study, no
segments were deemed "nonevaluable" and were instead interpreted as
being the same as the adjacent evaluable segments.

The authors report that quantitative coronary angiography (QCA)
identified 55 patients with >50% stenoses and 34 patients with >70%
stenoses. Diagnostic accuracy for both the >50% and >70% blockages
using CTA was high for both the per-patient and per-vessel
analyses. "The cutoff of >50% is what has been historically used in
clinical trials assessing CT accuracy, but >70% is probably the more
clinically useful cutoff--ie, patients don't usually get stented for
a 55% lesion, but they do for a 75% lesion," Min told heartwire. "So
we wanted to be in line with what had historically been done in
limited single-center studies but also try to examine the accuracy
of CT when it came to a clinically useful end point--ie, >70%."

"The high negative predictive value (98%-99%) indicates that cardiac
CTA is an effective noninvasive alternative to exclude coronary
stenosis," Min concluded. The data also support earlier research
confirming the diagnostic performance and negative predictive value
of 64-slice CTA, he added.

The low positive predictive value reflects the low prevalence of CAD
in this group, Min explained, adding that the results were something
of a surprise given the high-risk patient population (roughly 70%
had a family history of CAD, hypertension, and hyperlipidemia; 55%
were smokers; and 25% were diabetic). "We had expected a high
prevalence of disease, but what we found was that prevalence of
disease was not that high," he said.

"What this underscores is that in this patient population with an
intermediate prevalence of CAD, the negative predictive value is
exceptionally high and the diagnostic accuracy is exceptionally
high. We were pleased with these results because they underscore two
points: the first is that the people who are usually getting scanned
by CTA are in that low- and intermediate-risk population with an
expected low and intermediate prevalence of obstructive CAD. And we
found that CTA was highly accurate in that patient population.
Second, what it highlights is that were we to send all these
patients to invasive coronary angiography, as we did, over 85% of
those patients didn't have obstructive CAD and didn't need to be
cathed in the first place. So CTA [would have] acted as an effective
gatekeeper for patients who would otherwise undergo an invasive
coronary angiogram."

Outcome studies will be done

As with CORE 64, however, results from ACCURACY speak to how the
test compares with standard coronary angiography and do not resolve
some of the continuing debate over whether CTA tests could
ultimately improve patient outcomes or which types of patients might
benefit the most from the scans.

"This is a proof-of-concept study to demonstrate diagnostic accuracy
in a blinded prospective multicenter fashion," Min said. "The
outcome studies--I agree--need to be done. Now that we have
solidified and definitively established a high diagnostic
performance of CTA, we can move on to the next step, which is
proving its clinical utility--its effectiveness at risk-stratifying
individuals who present with certain symptoms such as chest pain or
shortness of breath."

Next-generation CT scanners unveiled

The major manufacturers of CT scanners are unveiling their new
technology at the RSNA meeting. Toshiba launched its AquillionONe, a
320-detector scanner that can scan the heart (or other organs) in a
single rotation, reducing exam time, radiation, and contrast dose.
The device can also perform functional studies, a Toshiba press
release states. Philips, meanwhile, rolled out its 256-slice
Brilliance iCT scanner, which can capture the heart in two beats;
the new scanner can reduce radiation dose by as much as 80%, the
company claims. Taking a slightly different tack, GE has focused on
improving image quality not by increasing the number of "slices" but
by fine-tuning the detectors themselves: its new high-definition CT
scanner, dubbed the GE Gemstone, uses a 4600-karat "megagarnet" that
improves on the optical precision of standard CT-detector
technology, also carrying the potential to reduce radiation dose and
improve image quality. Finally, Siemens unveiled its Somaton
Definition-AS--available in 40-, 64-, and 128-slice options--that
the company is touting as the world's first "adaptive" scanner,
which can be adapted to the medical scenario or organ being scanned.
It also has a novel radiation dose-shield and the ability to do
perfusion imaging.

Toshiba's device has already received FDA approval, while GE's
Gemstone and Siemen's Definition-AS are not yet commercially
available.

Min disclosed serving on the speaker's bureau for GE.

Radiological Society of North America 93rd Scientific Assembly and
Annual Meeting. Presented November 26, 2007.

Examination of more than 500 consecutive stroke patients suggests
that, contrary to current thinking, paradoxical embolism related to
patent foramen ovale (PFO) is likely an important cause of stroke in
older subjects, and not just younger patients [1].

Writing in the November 29, 2007 issue of the New England Journal of
Medicine, Dr Michael Handke (University Hospital Freiburg, Germany)
and colleagues point out that most studies looking at the connection
between PFO and cryptogenic stroke have enrolled primarily younger
patients, since the incidence of other causes of stroke increases
with age. Indeed, the rationale for developing percutaneous closure
devices to close PFOs was in part the younger age of the patients
who would not want to spend a lifetime on anticoagulants or undergo
surgical closure.

"Although it seems logical that PFO does not convert from a risk
factor to an innocent bystander at the age of 55, the association
between PFO and stroke has not been proven for older patients to
date," Handke told heartwire. "A few small studies were conducted,
but the results were contradictory. To our knowledge, this is the
first study showing a significant association in a large cohort of
consecutive patients."

Handke et al looked for PFOs in 503 consecutive stroke patients
ranging in age from 18 to 85; of these, 276 had a known cause of
stroke. They report that PFOs were more common in all patients with
cryptogenic stroke than in patients with a known cause of stroke,
regardless of patient age. Of note, patients who also had atrial
septal aneurysms in addition to PFOs had the strongest association
with cryptogenic stroke.

Even after adjustment for age, blood pressure, plaque thickness, and
presence or absence of CAD, PFO was independently associated with a
three- to fourfold increased risk of cryptogenic stroke in both
older and younger patients. Of note, subjects with cryptogenic
stroke also had significantly less aortic plaque than did patients
with stroke of known cause.

"From a purely diagnostic point of view, it would be logical to also
examine older patients with cryptogenic stroke for PFO," Handke told
heartwire. "In daily routine, older patients with stroke undergo
transesophageal echocardiography, which is the standard for the
diagnosis of PFO/atrial septal aneurysm, less often than younger
patients."

No easy answers for older patients

In their paper, the authors also note that the randomized controlled
trials addressing the question of whether PFO closure can prevent
recurrent stroke are still ongoing; it is by no means universally
accepted that using a device to close a PFO can prevent stroke. But
even when these studies--namely, the RESPECT, CLOSURE-I, and PC
Trials--are complete, they may not provide answers for preventing
stroke in older subjects, since the trials have enrolled only
patients age 60 or younger.

"The results from the current analysis offer a rationale for
broadening studies of PFO closure," Handke commented to
heartwire. "From a scientific point of view, the cutoff of 60 in the
ongoing trials is reasonable, since the relation between PFO and
stroke was [initially] shown for the younger group only. In daily
practice, individual decision-making leads to device closure also in
patients >60 years in many centers. Whether or not device closure is
really an evidence-based, therapeutic option for older patients with
cryptogenic stroke could be clarified in additional randomized
trials including older patients. "

According to information included in the paper, the authors had no
relevant conflicts of interest.

Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and
cryptogenic stroke in older patients. N Engl J Med 2007; 357:2262-
2268.

Pioglitazone use is associated with an increased incidence of
serious heart failure, but still provides clinical benefits, with no
evidence that it increases subsequent mortality and morbidity,
according to a report in the November issue of Diabetes Care.

"Although there is an increased risk of CHF with pioglitazone, our
analysis of serious heart failure events in PROactive showed that
when serious heart failure does develop in pioglitazone-treated
patients with type 2 diabetes and existing macrovascular disease, it
does not increase (and may even decrease) risk of mortality or
morbidity," Dr. Erland Erdmann from Universitaet zu Koeln, Germany,
told Reuters Health.

Dr. Erdmann and colleagues studied investigator-reported heart
failure rates and the treatment effect on sequelae after serious
heart failure in more than 5200 patients with type 2 diabetes and
preexisting cardiovascular disease in the Prospective Pioglitazone
Clinical Trial in Macrovascular Events (PROactive).

Serious heart failure was reported in 41% more patients in the
pioglitazone group than in the placebo group, the investigators say.

Elevated creatinine level, diuretic use, LDL cholesterol above 3
mmol/L, previous myocardial infarction, and diabetes duration of at
least 10 years were additional significant predictors of serious
heart failure.

Serious heart failure occurred more frequently among patients
treated with insulin, the authors report, but the use of
pioglitazone did not further elevate the risk among insulin-treated
patients.

Fatal heart failure events were no more common among pioglitazone
patients than among placebo patients, the researchers note, and
pioglitazone patients had lower rates of all-cause mortality,
nonfatal myocardial infarction, and stroke than did placebo patients.

Pioglitazone-treated patients were also more likely to develop non-
serious heart failure and edema than were placebo-treated patients.

"Because the rates for the composite endpoint subsequent to a report
of serious heart failure were similar between pioglitazone and
placebo," the authors write, "the cardiovascular benefits observed
in PROactive with pioglitazone were not diminished by the increased
incidence of heart failure."

"The mechanisms of action behind the fluid retention with
thiazolidinediones remain unclear," the investigators
continue, "although it has been suggested that peroxisome
proliferator-activated receptor-gamma may regulate sodium
reabsorption in the cortical collecting ducts via stimulation of
epithelial sodium channel activity."

"The long-term study of pioglitazone use and heart failure, funded
by the American Diabetes Association, argues against the possibility
that thiazolidinediones cause heart failure," the researchers add.

"PROactive demonstrated the macrovascular ischemic safety profile of
pioglitazone in patients with type 2 diabetes who are at high risk
for cardiovascular events," Dr. Erdmann said.

"As a cardiologist, I have no reservations in its use in this
condition when correctly and appropriately prescribed....When
considering the appropriate therapeutic strategy for patients, the
potential benefits and risks should be fully considered based on the
evidence for both efficacy and safety," he concluded.

Diabetes Care 2007;30:2773-2778.

Children born prematurely exhibit subtle abnormalities of blood
pressure regulation in childhood, indicated by a selective increase
of nocturnal systolic blood pressure. These abnormalities are most
prominent in those with intrauterine growth restriction.

"Blood pressure (BP) regulation is affected by numerous physiologic,
biochemical, genetic, and environmental factors," write Dr. Umut
Selda Bayrakci, of Hacettepe University in Ankara, Turkey, and
colleagues. "Conditions affecting intrauterine growth and
development may program individuals for hypertension, metabolic
abnormalities, and cardiovascular morbidity in later life."

The researchers used 24-hour ambulatory BP monitoring to evaluate BP
abnormalities in 41 children between the ages of 5 and 17 years who
were born prematurely and 27 matched term-born children who had
appropriate birth weights for gestational age. Eleven of the
children born preterm had intrauterine growth restriction.

The results of the study are published in the October issue of the
Journal of Pediatrics.

The mean 24-hour BP did not differ between the two groups, but the
children born preterm had significantly higher mean nighttime
systolic BP than controls (100.2 versus 96.3 mm Hg). The lack of a
nocturnal decrease was more prevalent in the preterm children (73%
versus 42%, respectively).

The mean standardized nighttime systolic BP was significantly higher
in the light-for-date children. However, the preterm children born
at appropriate weights were similar to the controls.

"Our analysis suggests that intrauterine growth restriction, rather
than prematurity per se, is the major effector of the early
cardiovascular abnormalities observed in preterm children."

"Nocturnal systolic BP was closely linked to heart rate, pointing to
a possible role of sympathetic hyperactivation," Dr. Bayrakci and
colleagues suggest.

J Pediatr 2007;151:399-403.

Significantly changing normal sleep patterns ¡X either getting much
more or much less sleep ¡X increases the risk for mortality,
according to a new study appearing in the December 1 issue of Sleep.

The study found that decreasing nightly sleep from 6, 7, or 8 hours
doubles the risk for cardiovascular death, while increasing sleep
from 7 or 8 hours doubles the risk for noncardiovascular death.

¡§If you have a regular pattern ¡X 6, 7, or 8 hours ¡X and you
maintain that over time, that¡¦s protective against premature
mortality,¡¨ said Jane E. Ferrie, PhD, a senior research fellow in
department of epidemiology and public health at University College,
London, in the United Kingdom, and lead author of the study. ¡§If
you move out of that to the 9-hours-or-more category, that seems to
increase all-cause mortality and the group of deaths that increases
is the noncardiovascular deaths. If you go to the short end of the
spectrum, you increase your risk for cardiovascular mortality.¡¨

Changing Sleep Patterns

While other studies have looked at associations of sleep and
mortality, this is the first to look at the health effects of
significant changes in sleep patterns over time, Dr. Ferrie told
Medscape Psychiatry.

The Whitehall II study of London-based civil servants aged 35 to 55
years began enrolling participants in 1985 with baseline (phase 1)
screening continuing until early 1988. Data collection for phase 3
took place in 1992¡V1993. Both phases involved a clinical
evaluation, including measurement of cardiovascular risk factors
(body-mass index, systolic and diastolic blood pressure, total
cholesterol), and self-administered questionnaires that included
questions about duration of sleep. Participants in phase 1 selected
from these sleep categories; 5 hours or less; 6 hours; 7 hours; 8
hours; and 9 hours or more. For phase 3, the response categories of
1 to 12 hours of sleep were collapsed to form categories identical
to the initial phase.

Researchers collected data on 9781 participants at phase 1 and on
7729 in phase 3. Mortality data were available from the National
Health Services central registry until September 2004, a mean of
17.1 years from phase 1 and 11.8 years from phase 3.

Double Mortality Risk

The study found a U-shaped association in both phases between sleep
and subsequent all-cause mortality. It also showed that decreasing
sleep from 6, 7, or 8 hours doubled the cardiovascular mortality
risk (fully adjusted hazard ratio for cardiovascular disease of
2.04) and that increasing sleep from 7 or 8 hours also doubled the
risk for death, but for noncardiovascular mortality (fully adjusted
hazard ratio for noncardiovascular deaths of 2.06).

(¡§Normal¡¨ sleep categories of 6, 7, and 8 hours had to be pooled
because researchers did not have enough data to look at the
categories separately, they note.)

The link between decreased hours of sleep and higher cardiovascular
mortality risk seems to make some sense: Short sleep duration is a
risk factor for weight gain, insulin resistance, and type 2
diabetes, the authors write. Short sleep is also accompanied by
increased cortisol levels and abnormal growth hormone secretion and
has been associated with hypertension and some cardiovascular
diseases, they said. ¡§It¡¦s fairly obvious what¡¦s going on
there,¡¨ Dr. Ferrie added.

Link Between Deaths and Long Sleep Unclear

However, the link between deaths and longer sleep patterns is not as
clear. ¡§At the other end of the spectrum, until we have sufficient
deaths where we can see what is making up that noncardiovascular
group of deaths, we can¡¦t explore that any further,¡¨ said Dr.
Ferrie. ¡§We really don¡¦t know what¡¦s driving that.¡¨ She did say,
though, that long sleep is associated with depression and that
researchers may want to take a look at the role of increased cancer
deaths or trauma deaths among patients changing to a long sleep
pattern.

This new research is bound to generate a lot of interest among sleep
researchers, she added. ¡§I think lot of people will look at
this . . . and hopefully they will be able to elucidate what¡¦s
making up those noncardiovascular deaths,¡¨ said Dr. Ferrie.

A significant change in sleep patterns may be a red flag for some
underlying disease, she said. ¡§If somebody comes to you and they¡¦
re now reporting having moved from a normal sleep pattern either to
the very short end of the sleep spectrum or the long end of the
sleep spectrum and that appears to be a pattern that¡¦s continuing
over time and is not their regular pattern, then that is probably a
marker of something.¡¨

Sleep experts are even discussing the merits of restricting sleep of
people who regularly sleep 9 or more hours per night, she said.

Patients with venous thromboembolism (VTE) have a substantially
increased long-term risk of subsequent arterial cardiovascular (CV)
events, such as myocardial infarction (MI) and stroke, according to
the results of a new Danish study [1]. Dr Henrik Toft Sorensen
(Aarhus University Hospital, Denmark) and colleagues report their
findings in the Lancet.

They explain that they undertook the research because previous
studies examining associations between VTE and arterial CV events
have yielded conflicting results. Sorensen told heartwire that "we
have shown there is an association between two very common diseases.
Now we need to find out whether there is a direct link between them,
or whether they share risk factors. Future studies are needed to
clarify the association and to evaluate its implications for
clinical practice."

In an accompanying commentary [2], Dr Gordon DO Lowe (University of
Glasgow, UK) says: "This large study substantially extends the
evidence for an association between VTE and risk of subsequent
arterial thromboembolism that precipitates MI or ischemic stroke."

Risk highest in the first year after VTE

The Danish researchers and Lowe explain that VTE and arterial
thrombosis have traditionally been viewed as separate diseases with
different risk factors, pathogenesis, and treatments. VTE disorders
are generally considered to be distinct from thrombotic
atherosclerotic disorders because arterial thrombi consist mainly of
platelets, in contrast to venous thrombi, which consist mainly of
red blood cells and fibrin.

But in 2003, two case-control studies suggested an association
between the two. However, further research failed to find a link and
these inconsistent findings mean that it is not clear whether VTE is
associated with arterial CV morbidity.

Sorensen et al thus undertook a large 20-year population-based
assessment of the risk of hospitalization for acute MI or stroke
after a diagnosis of VTE, using data from Danish medical databases.
After excluding those with known CV disease, they assessed the risk
of MI and stroke in 25 199 patients with deep vein thrombosis (DVT),
16 925 patients with pulmonary embolism (PE), and 163 566 population
controls.

For patients with DVT, the relative risk of MI was 1.60 and of
stroke was 2.19 in the first year after the thrombotic event. For
patients with PE, relative risks were 2.60 for MI and 2.93 for
stroke in the first year.

The relative risks were also raised, although less markedly, during
the subsequent 20 years of follow-up, with 20% to 40% increases in
risk for arterial CV events, say Sorensen et al. The relative risks
were similar for those with unprovoked and provoked (eg, due to
pregnancy, surgery, or other factors) DVT and PE.

Lowe says that the fact that the increased risk of MI and stroke was
highest in the first year after diagnosis of VTE "is perhaps
surprising because the standard treatment (oral anticoagulant drugs
for 3-6 months) should lower the risk of MI and ischemic stroke."

Link explained by shared risk factors?

Sorensen et al say the mechanism underlying the association between
VTE and atherosclerotic disease is not known, and that it might even
be different for MI than for stroke. However, it is likely that the
link is due to shared risk factors, etiologic pathways, or both,
they suggest.

In his comment, Lowe says "the association is probably because of
shared risk factors." He cites others studies that have shown that
smoking, hypertension, and diabetes (but not cholesterol) are
significantly associated with VTE.

Hypertension was an exclusion criterion in the study by Sorensen et
al, but "the shared risk-factor profile of obesity, smoking, and
diabetes might account for much of the increased risk of arterial
thrombotic events in patients with VTE," Lowe notes. He adds that
shared thrombotic tendency might also play a part.

Sorensen agrees that shared risk factors are a likely culprit. "I
think Lowe is right. I believe obesity is at least a part of the
explanation," he told heartwire. He added that in their study, they
did not adjust for obesity or smoking, and they did not have data on
cholesterol. "However, diabetes did not explain the association we
found," he said, noting that although this analysis with regard to
diabetes was performed, it is not included in the final Lancet
paper.

"Further epidemiologic studies (especially prospective studies) and
systematic reviews are needed to establish the magnitude, duration,
and possible causes of increased risk of MI and stroke after a
diagnosis of VTE," says Lowe.

What are the Implications? Will Aspirin or Statins Reduce Risk?

In the meantime, we need to know what the implications for
management are, says Lowe. Sorensen et al agree: "Our findings could
have clinical implications," they observe, "however, the value of
preventive measures against MI and stroke in patients with VTE is
uncertain."

Two ongoing studies are evaluating the effect of aspirin on the long-
term treatment of VTE and a few observational studies have shown
that statins might reduce the risk of VTE, "but the role of these
drugs specifically for prevention of MI and stroke in patients with
VTE has not yet been explored," the Danish researchers say.

In fact, Sorensen told heartwire that his team is doing work on
statins and aspirin to see if they can prevent an increased risk of
atherosclerosis in patients with VTE, and vice versa (i.e., whether
they can prevent VTE in patients with atherosclerosis). They are
using a low dose of aspirin (75 mg/day) or a prescribed daily dose
of a statin. Patients will likely stay on the medications for life,
Sorensen noted. He says there is preliminary evidence that statins
might prevent VTE in patients with atherosclerotic disease, but the
full findings will be reported at a later date.

Sorensen HT, Horvath-Puho E, Pedersen L, et al. Venous
thromboembolism and subsequent hospitalization due to acute
cardiovascular events: a 20-year cohort study. Lancet 2007; 370:1773-
1779.

Lowe GDO. Is venous thromboembolism a risk factor for arterial
thrombosis? Lancet 2007; 370:1742-1744.

There have been concerns raised in multiple press reports this week
about delays in reporting the results of the first key study with
the cholesterol drug ezetimibe.

The results of the carotid ultrasound trial, ENHANCE, are indeed
late, which has led to much speculation that the results are
negative and the companies are therefore delaying their release, but
lead investigator of the study, Dr John Kastelein (Academic Medical
Center, Amsterdam, the Netherlands), says this is not the case. He
commented to heartwire: "Yes, there have been delays with this
trial, but that does not mean the results are negative. In fact, the
data are still blinded so we do not know the outcome yet. This whole
media interest has been a lot of excitement about not much."

Ezetimibe has a complementary action to the statins, preventing the
intestinal absorption of cholesterol, and generally adds an extra
20% LDL reduction to that seen with statins alone. It is available
as a stand-alone treatment under the name Zetia, and as a
combination tablet with simvastatin under the name Vytorin, and is
marketed by Merck and Schering-Plough. Ezetimibe is a relative
newcomer to the cholesterol market, but is already generating
blockbuster sales, said to be in the region of $5 billion. That is
despite the fact there are no outcome data available on the drug.

High Stakes Riding on ENHANCE

The ENHANCE trial is the first major study to be conducted with
ezetimibe, which is why the results are so eagerly anticipated.
Although it is not a clinical outcome study, carotid ultrasound
studies monitoring the effects of drug therapy on atherosclerotic
plaque are seen as a reliable surrogate and normally predict whether
a drug will be effective in lowering cardiac events. ENHANCE, which
was started in 2002, randomized almost 800 patients with familial
hypercholesterolemia to treatment with simvastatin alone or
simvastatin plus ezetimibe. It was hoped that results, focusing on
the progression of atherosclerosis in the carotid artery, would be
available this year, but they have not been presented yet.

Kastelein explained that the study was late in reporting because of
technical difficulties with the large amount of data generated. He
commented to heartwire: "This is the largest study of carotid IMT
that we have conducted, involving 19 different centers, and this is
also the first trial in which all the IMT data have been recorded
digitally rather than on videotape. We have assessed atherosclerosis
at three different sites in each of the two carotid arteries and in
two femoral arteries. And we have to assess each image with two
different ultrasound waves--B mode to assess the size of the plaque
and M mode to assess the elasticity of the artery. We have almost 40
000 images to process. That is an incredible amount of data to deal
with. Maybe we were a little ambitious on the timeframe required to
process so much data. That is why there has been some delay. The
suggestion that the results are being suppressed because they are
negative is simply wrong. People are assuming that anyone can take a
peak at the data, but how can they do that if it hasn't even been
unblinded and there are 40 000 images to analyze?"

Primary End Point Changed

Kastelein said the current bout of media reports were generated by a
press release issued last week by Schering Plough announcing that
the primary end point of the study was being changed. This was the
result of a meeting of an outside expert panel, convened by the
company, to discuss how to proceed with the analysis of the data.
Kastelein explained: "The company was insecure about a few things--
the fact that there were some images missing and some outliers
(patients who have odd results). But these things are completely
normal in this type of trial. I told them that, but they wanted to
consult some other experts on this. And they all said the same thing-
-that it was normal and they should just get on with the analysis."

One other thing that was discussed at that meeting was which site in
the carotid artery would be the best for the primary end point.
Kastelein said that when the study began it was believed that a
combination of three different measurements from different sites in
the carotid artery was the best indication of atherosclerosis
progression, and that is what the primary end point was set as. But
since then, several other studies have suggested that the one
measurement in the common carotid artery was the most sensitive to
lipid changes, and is easier to measure so would be subject to less
variation, giving greater statistical power. "Slowly a picture is
emerging that this one measurement in the common carotid artery may
be better, and this was discussed at the expert panel meeting. It
was then agreed to switch the primary end point to this measurement,
which was a secondary end point before, and the original three-site
measurements will now be a secondary end point."

Asked why an independent panel was brought in to make these
decisions, which is a rather unusual occurrence, Kastelein said it
was because the company was nervous, given the high stakes riding on
this study. "These are very important data for the company. The drug
has huge sales, and this study will be the first real indication as
to whether it is working. Everybody is understandably nervous. My
opinion was that everything was fine the way it was and we should
just continue, but they wanted some additional reassurance from
outside experts and they got it. I didn't like it very much, but it
was necessary to settle their minds," he said.

Results at ACC

Kastelein says the results will now likely be presented at the
American College of Cardiology (ACC) meeting next March. He says the
current media attention will probably mean that the data will be
scrutinized more closely than ever. "You can be sure that when I'm
standing up there at the ACC announcing the results, one of my first
slides will show data to convince people that this trial is not
different from other IMT trials."

He says the whole debacle has highlighted the tensions that exist
between the lead investigator of a study and the sponsor. "The other
experts supported me, but maybe we have had more difficulties with
this study because the sponsor has control over the database. If the
investigators have control, then we get to do the analysis our way.
In future, I will try very hard to get this," he added.

Three Clinical Outcome Trials Underway

Although ENHANCE will give the first indication of whether ezetimibe
is working or not, it still won't provide definite information on
whether clinical events will be reduced with the drug. But three
clinical end point trials are underway. These are the SEAS trial in
patients with aortic stenosis, being coordinated by Dr Terje
Pedersen (Ulleval University Hospital, Norway) of 4S fame; the
IMPROVE-IT trial in 10 000 ACS patients, being run by the Duke and
TIMI clinical trial groups; and the SHARP trial in 9000 patients
with chronic kidney disease, conducted by the Oxford, UK, group.

Media Swoop on Delays

The lay press were quick to highlight the delays with the ENHANCE
study and to drum up speculation that this was not good news. Forbes
ran a story quoting another expert in the field, Dr Allen J Taylor
(Walter Reed Army Medical Center, Washington, DC), as saying the
delay "starts to raise suspicion. The more time it takes, the more
you start to naturally wonder what is wrong, and quoting Dr Robert
Califf (Duke University, Durham, NC) as saying: "We'd all agree that
having this long a delay after a study's over is bad thing," but
adding: "I sure hope Zetia works. I'm taking it myself."

The Forbes article also quotes Dr Paul Thompson (Hartford Hospital,
Connecticut), highlighting the high stakes of the study: "A bad
result would cause Pfizer and AstraZeneca sales reps to turn up at
every hospital in the country 'within milliseconds'," he said. Dr
Prediman Shah (Cedars-Sinai Medical Center, Los Angeles, CA) is
reported as saying that it would not make "an iota of sense" for
Zetia not to work, given it lowers LDL, a view contradicted by Dr
Richard Lange (Johns Hopkins University, Baltimore, MD), who notes
that so far there is no evidence that patients get extra benefit by
adding Zetia. "They're going to have to explain exactly what the
delay was," Lange says. "At that point we'll have enough information
to know it passes the sniff test." The article also quotes Kastelein
as saying: "I certainly want it finished. There are all sorts of
conspiracy theories that are not good for my reputation."

The New York Times has Dr Bruce Psaty (University of Washington,
Seattle) questioning the change in end point. "This sounds highly
unusual to me. You need to live with your primary end point," he
comments. The article also quotes Dr John Crouse (Wake Forest
University, Winston-Salem, NC), who conducted a similar trial with
rosuvastatin, and points out that measuring plaque can be
complicated and that Merck and Schering might simply have run into
delays in analyzing their data. "It's easy for things not to go the
way you would hope they would go," he said.

Another study--this time randomized and double-blind--has found that
flavonoid-rich dark chocolate might be good for the heart [1].
Writing in the November 20, 2007 issue of Circulation, Dr Andreas J
Flammer (Cardiovascular Center, Zurich, Switzerland) and colleagues
report that compared with "cocoa-free" chocolate, a dark chocolate
rich in flavonoids induced coronary vasodilation and reduced
platelet adhesion in heart transplant recipients, even on top of
standard secondary prevention CVD drugs.

The authors say the findings suggest a role for this type of
chocolate in preventing graft atherosclerosis in transplant
recipients, and possibly in reducing the risk of atherosclerosis in
a wider population.

"This beneficial potential provides a strong rationale to further
investigate the clinical effects of cocoa in cardiovascular
disease," the authors write.

Commenting on the study for heartwire, Dr Franz H Messerli (Columbia
University, New York) said the results were an important part of an
ongoing story.

"I don't think we can conclude that dark chocolate is going to be
the next nitroglycerin, but still. . . . This is the first study
that shows that, indeed, chocolate improves coronary blood flow, and
significantly so, in patients who already were on vasodilators--ACE
inhibitors and beta blockers," he said. "So over and above
conventional therapy, when you give dark chocolate at the dose it
was given in this study, you get improved coronary blood flow."

Vascular Benefits

Flammer and colleagues assessed coronary vasomotion using
quantitative coronary angiography and cold-pressor testing before
and two hours after giving 22 heart transplant recipients 40 g of
dark chocolate (70% cocoa) or cocoa-free chocolate. On the second
measurement, coronary artery diameter increased significantly from
baseline, endothelium-dependent coronary vasomotion improved, and
platelet adhesion decreased in the flavonoid-rich group. No
significant changes were seen in the group eating the control
chocolate.

To assess whether these improvements paralleled changes in serum
antioxidants, Flammer et al also measured concentrations of
flavanols (a flavonoid subclass) in the serum and found that
epicatechin concentrations correlated with coronary vasomotion, but
catechin concentrations did not. This last observation adds weight
to hypothesis that epicatechin is a "possible mediator" of improved
coronary vasomotion with chocolate consumption, the authors note.

"Our results suggest a short-term effect of flavonoid-rich dark
chocolate in terms of inducing coronary vasodilation and improving
coronary vasomotion and shear-stress-dependent platelet adhesion,
which results in the potential to beneficially affect
atherothrombosis," they conclude.

Hurdles Ahead

In an accompanying editorial [2], Dr Norman Hollenberg and Naomi DL
Fisher (Brigham and Women's Hospital, Boston, MA) note that despite
the evidence amassing in support of chocolate's cardioprotective
properties, physicians, the public, and the mainstream media must be
wary of interpreting the results. For one, they write, the
term "dark" is misleading, since color can have nothing to do with
flavanol content and many manufacturers actually use processing
techniques that destroy flavanols, even when the product tastes (and
is labeled) "dark."

"If the industry wants us to use chocolate as a health food, then
they will have to change their behavior," the editorialists
write. "Specifically, what the world needs is a label on each
package that describes the flavanol content of the chocolate. It
should be obvious that the percent of cocoa, like the color of
chocolate, does not represent a measure of flavanols at all. . . .
Probably the most effective mechanism is for the lay press to stop
talking about dark chocolate or percent cocoa and start discussing
flavanol content."

But an even bigger hurdle will be determining the true "health
benefits" of chocolate in a large, well-designed, appropriately
controlled trial--an expensive prospect in the nutrition industry,
they note, where a positive study "does not create intellectual
property," making it difficult for a company to justify the expense
of the trial as an investment.

"This is a problem we have to overcome if we are to obtain the
evidence that we need to make appropriate recommendations to the
community," Hollenberg and Fisher write. To heartwire, Messerli
mentioned that he knows of at least one company attempting to study
chocolate's antihypertensive effects in a large, well-designed trial.

Messerli, as well as the editorialists, points out that any evidence
of cocoa's antioxidant health benefits do not outweigh some of the
hazards of over-indulging in what is for many a favorite treat.

"We still have to consider the caloric load: there's absolutely no
question that chocolate is very high in calories and fairly high in
fat," Messerli said. "But it's no longer an absolute no-no as it
used to be."

Chocolate for the study was provided by Nestlé, and one of the study
coauthors is an employee of the Nestlé Research Center. Messerli
disclosed participating on one advisory board (for Mars).

Flammer AJ, Hermann F, Sudano I, et al. Dark chocolate improves
coronary vasomotion and reduces platelet reactivity. Circulation
2007; 116:2376-2382. Abstract

Hollenberg NK, Fisher ND. Is it the dark in dark chocolate?
Circulation 2007; 116:2360-2362. Abstract

A first examination of the literature on the elective use of drug-
eluting stents (DES) in the cerebrovascular circulation has found
that they appear to produce more favorable outcomes than either
medical therapy alone or bare metal stents (BMS) in this patient
population. The findings, which also show that the use of DES in
this off-label indication appear to be both safe and feasible, were
reported earlier this month at the American Heart Association 2007
Scientific Sessions by Dr Nirav J Mehta (Winthrop University
Hospital, Mineola, NY).

Senior author, Dr Srihari S Naidu (Winthrop University Hospital),
told heartwire: "We now understand that intracranial stenosis is a
marker for recurrent stroke, and when the stenosis is >70%, that
risk is quite high. We are still at the juncture of determining
whether medical therapy or stents are preferable in these patients.
Over the past few years, neurosurgeons and cardiologists have
expanded their territories to include intracranial stenosis, but
there are very limited data on intracranial stenosis and the use of
stents in general, and even more limited data utilizing DES."

Interventional cardiologist Naidu said his institution, which is
also a major stroke center, "was starting to use DES off-label in
these scenarios, so we thought we would look at the literature."

DES Better Than BMS, Medical Therapy in Cerebral Circulation

Mehta and Naidu found three case-control series using DES in a
literature search, which included a total of 88 patients with 94
lesions in the cerebrovascular circulation. Patients received
aspirin 325 mg one to four days before the procedure, clopidogrel
daily for three days prior to the procedure (or a 300 mg loading
dose on the same day), and heparin. There was no use of GP IIb/IIIa
inhibitors. Double antiplatelet therapy was used for six to nine
months following procedures.

In the 94 lesions, 54 paclitaxel-coated stents (Taxus) and 34
sirolimus-coated stents (Cypher) were implanted; six stents could
not be delivered.

There was an overall 4% risk of a recurrent event at nine months.
There were two major strokes due to stent thrombosis. One of these
appeared to be due to an under-expanded stent, which, Naidu
explained, "we know from the coronary literature appears to be a
risk factor for stent thrombosis."

These results compare with a case series in 29 patients using BMS,
which found a 10.3% risk of stroke or death within a year with the
Wingspan stent, and with the Warfarin-Aspirin Symptomatic
Intracranial Disease (WASID) trial, which showed an 18% risk of a
recurrent event within a year with medical therapy alone, Naidu told
heartwire.

He says that although the different results are obviously not
directly comparable, "it appears that DES may be better than BMS,
which may be better than medical therapy. Our numbers indicate that
the risk at nine months is lower with DES than you would expect from
BMS or medical therapy. The take-home message is that DES seem to be
feasible and appear to improve outcomes compared with historical
controls or other studies of BMS and medical therapy."

However, he cautioned, "further research of a randomized nature is
warranted." He also stressed that use of DES in the cerebrovascular
circulation is currently an off-label indication.

Data Add Legitimacy to an Experimental Procedure

Naidu said that this research has persuaded doctors at his
institution to allow neurosurgeons to perform procedures with DES in
significant intracranial stenosis. "For patients who have had a
stroke and have ipsilateral proven stenosis, I don't think it's
unreasonable to go ahead and treat those lesions, if we have the
technology and the stents are available. These results add some
legitimacy to doing such procedures in these patients without having
direct randomized data." He said that neurosurgeons are performing
the procedures at his hospital, but in other places interventional
cardiologists are doing this.

The DES that are used are coronary stents, "so we can only use the
DES in arteries of the cerebral circulation that are comparable
sizes, and there is a very narrow window (2.5-3.5 mm in diameter),
so we are limited to carotids that are small, or vertebral or middle
cerebral arteries that essentially come in those sizes."

Careful selection of patients to receive DES for this indication
remains paramount, he added. "In the coronary circulation, there are
a lot of factors that come into play in terms of whether patients
are candidates for DES. There are certain demographic and patient-
related factors that need to be considered, such as compliance with
clopidogrel. Some of these issues may come into play with the
cerebral circulation."

He said that his institution is employing the same protocol for
clopidogrel after DES implantation in the cerebral circulation as in
the coronary (i.e., one year of therapy). "The factors in the
cerebral circulation that predict stent thrombosis may be the same
as those in the coronary circulation or they may be different--we
really don't know and our data are currently so limited." However,
he said, the one factor it makes most sense to take into
consideration right now is the premature discontinuation of
antiplatelet therapy, "since in the coronary literature this has the
highest hazard ratio."

He also pointed out that although the data on BMS in the cerebral
circulation "are limited, they are not terrible. A 10.3% recurrent
event rate isn't bad and it may obviate the need for clopidogrel."

Mehta NJ, Naidu SS. Drug-eluting stents for cerebrovascular disease:
feasibility, safety and intermediate-term outcomes. Circulation
2007; 116 (16 Supplement):II_418. Abstract 1942.

A new study has suggested that the major benefit of the ban on
smoking in public places is being seen in nonsmokers [1].

The study, published in the Journal of Drug Education, is said to be
the first to distinguish between smokers and nonsmokers when
examining any reduction in MI rates. Although the actual number of
events in the study was small, results showed a large drop in the MI
rate of nonsmokers after a smoking ban was introduced, but no change
in the MI rate of smokers.

Lead author Dr Dong-Chul Seo (Indiana University, Bloomington)
said, "our results suggest that the benefits of the smoking ban
appear to come more from the reduced exposure to secondhand smoke
among nonsmokers than from reduced consumption of tobacco among
smokers."

To heartwire, he commented: "It was thought that a smoking ban in
public places would make smokers cut down, but perhaps they are just
smoking the same amount in different places. The big difference
seems to be in nonsmokers who no longer have to breathe smoke-filled
air."

Seo and his colleague, Dr Mohammad Torabi (Indiana University),
explained that epidemiologic studies have shown that environmental
tobacco smoke (which includes both exhaled mainstream smoke and
sidestream smoke from burning cigarettes) increases the risk of MI.
Tobacco smoke has been shown to cause endothelial dysfunction of the
coronary circulation in healthy nonsmoking young adults. Therefore,
a total of 519 US municipalities now have 100% smoke-free
workplaces, restaurants, and/or bars.

The researchers conducted the current study to investigate whether
the smoking ban led to any changes in hospital admissions for MI. To
do this, they compared hospital admissions for MI in Monroe County,
Indiana, which has had a public smoking ban in place since August
2003, with those in Delaware County, also in Indiana, which has
urban population rates, mean household income, and heart disease and
cancer mortality rates similar to Monroe Country but did not
instigate a smoking ban.

During the study period, Bloomington Hospital and Ball Memorial
Hospital were the only hospitals that served heart patients in
Monroe County and Delaware County, respectively. Seo and Torabi
identified all patients with a primary or secondary diagnosis of
acute MI admitted to either of these hospitals between August 1,
2001 and May 31, 2005. They excluded patients who had had previous
cardiac procedures or who had hypertension or high cholesterol in an
attempt to focus on MIs without any other obvious cause. Rates of MI
and smoking status were compared in both counties before and after
the smoking ban was implemented in Monroe County.

Results showed that in Monroe County there was a significant drop in
the number of nonsmoking patient admissions for MI in the 22-month
period after the smoking ban implementation (August 2003 to May
2005), compared with the 22-month period before the ban (August 2001
to May 2003). In Delaware County, no such drop was seen. In
contrast, there was no significant change in the number of
admissions for MI among smoking patients between the two time
periods in the two counties.

The authors point out that there have been no admissions for MI
among nonsmokers in Monroe County since January 1, 2005, when the
existing smoking ban was expanded to previously exempt bars and
clubs.

They note, however, that the total number of analyzed admissions was
small in this study, and that research that evaluates the effect of
a nonsmoking ban over a longer period of time is therefore desirable
to confirm these findings.

Seo told heartwire that he was not surprised by the dramatic effect
on MI rates shown in this study so soon after the smoking ban came
into force, noting that just a short exposure to smoke can cause
cardiovascular damage. "Exposure to secondhand smoke for just 30
minutes can rapidly increase a person's risk for MI, even if they
have no risk factors. It causes blood vessels to constrict, thus
reducing the amount of oxygen that can be transported in the blood,
and induces platelet aggregation," he added.

Seo D-C, Torabi MR. Reduced admissions for acute myocardial
infarction associate with a public smoking ban: Matched controlled
study. J Drug Education 2007; 37(3):217-226.

Among children with congenital or acquired heart disease, more than
1 in 4 is overweight or obese, according to results of a study
published in the November issue of Pediatrics.

"Obesity may pose additional cardiovascular risk to children with
acquired and congenital heart disease," write Dr. Meryl S. Cohen, of
Children's Hospital of Philadelphia, Pennsylvania, and
colleagues. "Many children with heart disease are sedentary as a
result of physician-, parent-, and/or self-imposed restrictions."

To estimate the prevalence of obesity and overweight in children
with heart disease, the team performed a cross-sectional review of
children seen at two cardiology outpatient clinics. They compared
differences in the prevalence of obese (BMI in the 95th percentile
or higher) and overweight (BMI in the 85th to 95th percentile)
children with national data and healthy controls.

Cardiology outpatient letters were reviewed to determine whether
obesity was discussed with referring practitioners.

Among 1523 children with heart disease, the authors identified five
diagnostic subgroups: "mild" heart disease (n = 401), arrhythmia (n
= 447), biventricular repair (n = 511), univentricular palliation
(Fontan; n = 108), and heart transplantation (n = 56).

Dr. Cohen and colleagues report that 26.2% of patients with any type
of heart disease were overweight or obese. The prevalence of
overweight and obese was significantly lower than healthy controls
only in the Fontan patients (15.9%). Among patients with any form of
heart disease, systolic blood pressure was significantly higher in
obese and overweight subjects compared to those with normal BMI (p <
0.001).

Weight counseling occurred in only 13.3% of obese patients and 8.7%
of overweight patients.

"Appropriate interventions for obese pediatric cardiac patients need
to be developed," Dr. Cohen and colleagues conclude. "Given the
known benefits of normal weight and exercise participation, advising
against inactivity, obesity, and other unhealthy lifestyle choices
and communicating these concerns to the referring physician should
be important parts of the pediatric cardiologist's care of children
with cardiac disease."

Pediatrics 2007;120:e1157-e1164.

A new analysis of data from the Nurses' Health Study (NHS) suggests
that adherence to a Dietary Approaches to Stop Hypertension (DASH)-
style diet is associated with a lower risk for both coronary heart
disease (CHD) and stroke in middle-aged women over 24 years of
follow-up.

Teresa Fung, ScD, RD, from Simmons College, in Boston,
Massachusetts, and colleagues at the Harvard School of Public Health
found a 24% reduction in CHD events and an 18% reduction in stroke
among women who appeared to adhere more closely to this pattern of
eating, which is high in fruit, vegetables, legumes, nuts, whole
grains, and low-fat dairy products and low in red and processed
meats, sweetened beverages, and sodium.

The main aim of this analysis was to develop a tool to measure
adherence to the DASH pattern of eating, utilizing the detailed
nutrition information and long-term outcomes available in the NHS,
Dr. Fung told Medscape Neurology & Neurosurgery.

"We found that individuals who do adhere to that score, long term,
have a lower risk of coronary heart disease and stroke," she said.

Eating for Lower Risk

The DASH diet, particularly in combination with restricted sodium,
has been shown in randomized trials to lower blood pressure and is
advocated now by the National Heart, Lung, and Blood Institute; the
American Heart Association; and the United States Department of
Agriculture as a healthy eating pattern.

However, although it lowers blood pressure, the effect of this
dietary pattern on cardiovascular end points such as stroke and
coronary heart disease has not been established.

For this analysis, Dr. Fung and colleagues developed a tool that
scored adherence to the DASH-style diet among 88,517 women who were
enrolled in the NHS prior to the development of the DASH diet per se
but who provided dietary information 5 times during 22 years of
follow-up beginning in 1980, with validated food frequency
questionnaires. The score was based on 8 food and nutrient
components: fruits, vegetables, whole grains, nuts and legumes, and
low-fat dairy, and a reverse-scoring scheme for consumption of red
and processed meats, sweetened beverages, and sodium.

Participants were aged 34 to 59 years at enrollment and were free of
cardiovascular disease or diabetes. A total of 1867 cases of
incident nonfatal myocardial infarction, 883 CHD deaths, and 1977
strokes were documented over follow-up.

After adjustment for age, smoking, and other cardiovascular risk
factors, the relative risk for total CHD for those in the top 20%
for adherence to the DASH diet (quintile 5) vs those in the bottom
20% for adherence (quintile 1) was significantly reduced, as well as
the risk for nonfatal and fatal events.

The DASH score was also significantly associated with a lower risk
for total stroke.

The benefit of the DASH pattern of eating was greater for women with
hypertension than those without hypertension at baseline, Dr. Fung
noted.

In the future, they hope to use this type of approach, scoring for
adherence to dietary patterns and looking at cardiovascular
outcomes, for other diets. For example, she noted, the recent
OMNIHEART trial showed that substituting proteins and unsaturated
fats for carbohydrates in the diet could reduce blood pressure and
improve lipid profiles.

"So if we could come up with something that can measure somebody's
adherence to the DASH diet, as well as the characteristics of the
OMNIHEART diet, that would be good," she said.

Dr. Fung disclosed that she consults for the UNO Chicago Grill. No
other potential conflicts of interest were reported.

American Heart Association 2007 Scientific Sessions: Abstract 2369.
Presented Monday, November 5, 2007.

Albuminuria, even in low levels within the "normal" range, is an
independent predictor of cardiovascular and all-cause mortality, a
new analysis of the PEACE trial shows [1]

The study, published online November 19, 2007 in Circulation and
scheduled for its December 4, 2007 issue, was conducted by a group
led by Dr Scott Solomon (Brigham and Women's Hospital, Boston, MA).

Solomon commented to heartwire: "We found that virtually any degree
of albuminuria, even albumin below the level we call
microalbuminuria, placed a patient at significantly higher risk of
cardiovascular events. A number of other studies have been
suggestive of this--HOPE in higher-risk vascular disease patients
and LIFE in hypertension patients--but ours was a particularly low-
risk population, so we've extended the findings to this low-risk
group with stable CHD. We should stop thinking about cut-off values
for microalbuminuria. If albumin is detectable in the urine, the
patient is at increased risk."

A new window to the health of the vasculature

Solomon explained that as such low levels of albumin cannot be
detected with a dipstick test, they used a spot assay that measures
the urinary albumin-to-creatinine ratio (ACR), which gives a more
accurate measure of albumin status, as it takes into account the
fact that the concentration of albumin in urine varies, depending on
the amount of water consumed. "This is still a very easy,
noninvasive, and cheap test. All you need is a urine sample. We do
many far more invasive and expensive tests than this to risk-
stratify patients. This test gives us a new window to the health of
the vasculature that we should take advantage of," he added.

Noting that a previous analysis of the PEACE population had shown
that a reduced glomerular filtration rate (GFR) was also associated
with increased cardiovascular risk, Solomon said: "We have now shown
that both measures of kidney function are markers of increased risk.
If either one is compromised, then risk is increased, and if both
are affected, then risk is very much increased. These two studies
are telling us that we cardiologists need to pay more attention to
kidney function in our patients and to understand that these are not
patients who will ever come to dialysis or even necessarily see a
nephrologist, but they do have mild kidney disease that puts them at
increased risk for a cardiovascular event."

He pointed out that whether or not patients with minor renal
dysfunction should be treated differently is open to debate but
added: "There is a fair amount of evidence that inhibitors of the
renin angiotensin system and ACE inhibitors in particular are of
benefit to CHD patients with reduced renal function. So I would say
that if you are undecided about whether to give an ACE inhibitor or
not, this test could help you make that decision."

A measure of treatment efficacy

In the paper, the authors also note that microalbuminuria may
represent an early marker of diffuse vascular endothelial
dysfunction, and clinicians should consider serial quantification of
ACR as a marker of risk, because its reduction may be a metric of
treatment efficacy.

The main PEACE trial evaluated the effects of trandolapril vs
placebo in 8290 patients with stable coronary artery disease and
normal left ventricular ejection fraction. In the current analysis,
the urinary ACR was assessed in a core laboratory in 2977 patients
at baseline and in 1339 patients at follow-up (mean 34 months). The
majority of patients (73%) had a baseline ACR within the normal
range (<17 µg/mg for men and <25 µg/mg for women).

Results showed that independent of the estimated GFR and other
baseline covariates, a higher ACR, even within the normal range, was
associated with increased risks for all-cause mortality (p<0.001)
and cardiovascular death (p=0.01). An increase in ACR over time was
also associated with increased risk of cardiovascular death.

While the effect of trandolapril therapy on outcomes was not
modified significantly by the level of albuminuria, trandolapril
therapy was associated with a significantly lower mean follow-up ACR
(12.5 vs 14.6 µg/mg, p=0.0002). Solomon suggested that the power of
this analysis may have been insufficient to show an effect of
trandolapril on outcomes. "We did see an effect of the drug on
albuminuria and a definite relationship between degree of
albuminuria and outcomes, but we probably had too few patients to
show an actual relationship between trandolapril and outcomes," he
commented to heartwire.

Solomon SD, Lin J, Solomon CG, et al. Influence of albuminuria on
cardiovascular risk in patients with stable coronary artery disease.
Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.107.723270. Available
at: http://circ.ahajournals.org.

Current methods of radiotherapy (RT) for breast cancer possibly
present some risk of cardiac toxicity, although its clinical
relevance is uncertain, according to researchers.

"Old style RT methods are associated with a small, but clinically
meaningful, increased rate of cardiac events -- maybe a 2% to 4%
increase in absolute risk," Dr. Lawrence B. Marks told Reuters
Health. "Newer RT methods supposedly eliminate this risk. However,
even in patients treated in the modern era, one can still detect
subtle changes on heart scans that appear to be associated with the
RT."

As reported in the October 15th issue of Cancer, Dr. Marks and
colleagues at Duke University Medical Center, Durham, North Carolina
prospectively followed 160 patients with left-sided breast cancer.

Forty-four of these patients had serial post-RT single-photon
emission computed tomography scans to assess changes in regional
cardiac perfusion, wall motion, and ejection fraction.

There were no significant alterations in wall motion or in ejection
fraction over the course the 3 to 6 years of follow-up. However,
over the entire follow-up period, the crude rate of perfusion
defects was 68%.

Nevertheless, Dr. Marks stressed, "The clinical meaning of these
changes is unclear, as these imaging changes have not been linked
with clinically meaningful toxicities."

However, "given the prior experience with the 'older' techniques,
care should be taken to minimize the cardiac exposure. But, it is
critical to know that the benefits of RT almost always far exceed
these tiny risks, and so patients should not avoid RT if it is
needed for their cancer treatment."

Cancer 2007;110:1840-1850.

Uncontrolled hypertension likely has a direct effect on disability
and functional status in older adults, even those who are stroke-
free with no other major diseases linked to high blood pressure, a
new study suggests [1]. High systolic blood pressure was linked not
only to the development of disability in people with no functional
problems earlier in life but also to more rapid functional decline
in people with mild or moderate disability at a younger age.

"Previous research has concentrated on the fact that hypertension
leads to stroke, and stroke leads to disability from neurological
loss," lead author on the study, Dr Ihab Hajjar (Harvard Medical
School, Boston, MA), told heartwire. "The independent association
between high blood pressure and loss of function has not been
addressed before, although it makes sense that it would [play a
role]. This gives us some additional evidence that hypertension may
affect some functional aspects that we don't usually think of."

The study appears in the November 20, 2007 issue of Hypertension.

Blood-pressure impact on day-to-day life

Hajjar and colleagues looked at a stroke-free, multiracial
population participating in the Charleston Heart Study--999 subjects
in total--followed between 1960 and 1993. A variety of tests used to
assess functional status were performed over the three decades of
the study, as were measurements of systolic and diastolic blood-
pressure levels at baseline and over the follow-up period.
Functional tests measured everything from physical strength
(pushing, pulling, lifting, etc) to mobility indexes (walking, using
a wheelchair), to personal-hygiene ability (bathing, grooming,
dressing, etc).

Hajjar and colleagues found that increases in systolic blood
pressure (but not diastolic blood pressure) over time were
associated with functional disability at follow-up, even in subjects
with no disability at study outset. Subjects with mild disability at
baseline who had uncontrolled systolic hypertension at different
points during the study were more likely to experience more rapid
functional decline than people without hypertension.

"We found that blood pressure is not only associated with new
disability, but also with a more rapid decline in function, which
was somewhat surprising to us," Hajjar commented. "It definitely
adds more evidence that the association is real and alarming."

Importantly, however, men and women diagnosed with hypertension who
successfully lowered their blood pressure to target levels faced a
much lower risk of developing disabilities--more or less equal to
that of people with no hypertension in the study.

"The lack of association between controlled hypertension and
disability risk suggests that adequate control of hypertension may
prevent functional decline," the authors write. "However, this could
also be related to the small sample size of those with controlled
hypertension" and will need to be further explored in larger
studies. Women appeared even more likely to develop disability from
hypertension than men, and since hypertension is more common in
women than men, this may be one explanation for the higher rates of
disability in women than in men, they add.

To heartwire, Hajjar emphasized that cardiologists may need to tweak
their thinking about hypertension. "We always think of blood
pressure and hypertension as risk factors for cardiovascular types
of outcomes: we think of stroke, congestive heart failure, CAD, and
renal failure. But our study enlarges the extent of damage that
hypertension causes in our patients, specifically in older patients
who, even without hypertension, are already at an increased risk of
developing loss of function. And even if we look at hypertensive
individuals earlier in life, they were more likely to have these
types of functional losses."

Hajjar I, Lackland D, Cupples LA, Lisitz LA. Association between
concurrent and remote blood pressure and disability in older adults.
Hypertension 2007; DOI: 10.1161/HYPERTENSIONAHA.107.097667.
Available at: http://hyper.ahajournals.org.

Papworth Hospital can resume heart transplant operations after a
review failed to find one single reason for a sharp rise in recent
deaths, the health watchdog said on Monday.

Operations were suspended at the Cambridge hospital earlier this
month after it discovered seven of the 20 transplant patients had
died within 30 days, a rate of 35%, between January and September
this year.

An eighth died following a transplant in October.

Papworth's average rate is 7%, with the average across all
transplant centres 10%.

It notified the Healthcare Commission, which following a two-week
review, said there were no common factors to explain the increase.

The independent watchdog did find that the ischemic time of the
transplanted heart was longer for those patients who died. But the
times, on average, were lower than in previous years and generally
in line with the national average.

The review team, which included leading heart surgeons, found the
patient selection procedure was extremely rigorous, and there was no
evidence of inadequate care or that the deaths could have been
prevented.

Nigel Ellis, head of investigations at the Healthcare Commission,
said: "Heart transplantation is extremely high-risk surgery carried
out on very ill patients. In so many ways, the Papworth Hospital
Transplantation Service represents best practice and its good
reputation is well deserved."

It added: "But the number of deaths since January has clearly been
high. This is why we are asking the trust to put in place a number
of important checks and safeguards."

The NHS trust agreed to implement the commission's recommendations,
including ensuring hearts are stored in transit in a similar way to
other UK trusts, and a review of the ways hearts are kept cool
during surgery.

It also agreed to look at post-operative care arrangements, and to
inform patients of recent events before they undergo a heart
transplant.

On a national level, the commission recommended mortality rates
should be monitored and a threshold established.

Steven Tsui, clinical director, transplant services at Papworth
Hospital, said: "We believe the process we have gone through in this
review has been rigorous and proper and will help us continue to
provide the best possible outcomes for our patients."

A new drug for the treatment of atrial fibrillation (AF) or flutter
post-cardiac surgery--vernakalant hydrochloride injection (Cardiome
Pharma Corp)--was better than placebo in converting AF or flutter to
sinus rhythm, results from the ACT II trial suggest. Dr Peter R
Kowey (Lankenau Hospital, Wynnewood, PA) presented the trial results
during last week's American Heart Association 2007 Scientific
Sessions.

Vernakalant (previously RSD1235) is a an antiarrhythmic that blocks
early-activating K+ channels and frequency-dependent Na+ channels;
in the previous ACT I trial, the drug was significantly better than
placebo in converting recent-onset acute atrial fibrillation to
sinus rhythm within 90 minutes of infusion in nonsurgical patients,
as previously reported by heartwire. ACT II was designed to look
specifically at patients who developed AF or atrial flutter
following CABG or valvular surgery, a sizable group: ACT II
investigators estimate that up to 40% of patients develop these
arrhythmias following cardiothoracic surgery.

As Kowey told heartwire, beta blockers are used in this population
to prevent atrial flutter or fibrillation from developing. "But once
it's occurred, there are very few drugs available that work well,
and quickly," he said. In ACT II, rate-control drugs were permitted,
and Kowey called this a "reasonable" strategy, as long as patients
aren't having severe symptoms and are protected against
thromboembolism.

At the End of ACT II: Significant Differences

ACT II enrolled 190 patients who had undergone CABG or valvular
surgery within seven days and who had developed AF or atrial flutter
within 24 hours of surgery. Patients were randomized to either
vernakalant or placebo in a 2:1 fashion. The primary efficacy end
point of the study was conversion to sinus rhythm (lasting at least
one minute) within 90 minutes of first exposure to the study drug;
secondary end points assessed time to conversion and percentage of
conversion lasting at least one minute.

As Kowey et al report, the proportion of vernakalant-treated
patients converting from AF or atrial flutter to sinus rhythm within
90 minutes was significantly greater than that of placebo-treated
patients. Median time to conversion was 12 minutes, as opposed to
the more randomly distributed time to conversion among the minority
of placebo-treated patients who did indeed develop normal rhythm. In
all, 75% of those who were converted successfully did so after the
first dose of the drug: according to the study protocol, patients
were given a first infusion of vernakalant or placebo within the
first 10 minutes of randomization at a dose of 3 mg/kg. This was
followed by a second infusion of 2 mg/kg between 25 and 35 minutes
postrandomization if patients were still in AF/atrial flutter--just
25% in this study.

Among those successfully converted to sinus rhythm, 60% remained in
sinus rhythm for 24 hours, and 57% remained as such for seven days.
Kowey emphasized that most postsurgery patients who convert from AF
or atrial flutter to sinus rhythm tend to remain in sinus rhythm,
but even if they don't convert, he has previously published data
indicating that most people who develop post¡Vcardiac surgery atrial
arrhythmias tend to be back in normal rhythm within four to six
weeks.

"The key issue is safety and cost: if a drug is not terribly
expensive and it's safe, then it's something to try. If it doesn't
work, you can move on to something else, but in most patients for
whom it does work, it represents a distinct advantage in terms of
getting rid of the arrhythmia quickly," he said. "The reason this is
important is that when you have AF, it can cause some symptoms, some
hemodynamic compromise, and it tends to keep people in the hospital
longer. The other thing it does is that it may mean that doctors
have to use anticoagulants, and surgeons don't like using
anticoagulants in people who have fresh surgery. So for all those
reasons, it would be a good thing to get rid of AF if you could, but
if you couldn't, or if it came back for some reason, it's not the
end of the world because it is self-limited."

No Safety Issues

There were no deaths in the trial, and drug discontinuations,
serious adverse events, and any adverse events were comparable
between the placebo-treated and vernakalant-treated patients.

"Of concern whenever you're using a drug that has electrical effects
is whether or not it promotes arrhythmia or promotes heart failure,
heart block, hypotension, or noncardiac safety issues," Kowey
reminded heartwire. "In this particular study of cardiac-surgery
patients, it appeared to be very well-tolerated, with not much in
the way of adverse effects that were different from what we saw in
the placebo-treated patients."

The FDA's cardiovascular and renal drugs advisory committee will
review the data on vernakalant, both for surgical and nonsurgical
use, on December 11, 2007. Asked about the upcoming review, Kowey
said that the consistency of the safety and efficacy results for
vernakalant across all the trials has been "remarkable."

That said, "the proof's in the pudding," Kowey said. "The FDA is
going to slice and dice it and chew on it and the advisory panel
will have the chance to weigh in. . . . We're obviously hopeful that
we'll have new things to help our patients, but we want to make sure
that they're safe and effective."

New research suggests that folic acid before conception and during
pregnancy helps prevent severe congenital heart disease. Dr Raluca
Ionescu-Ittu (McGill Adult Unit for Congenital Heart Disease,
Montreal, QC) reported findings from a population study at the
American Heart Association (AHA) 2007 Scientific Sessions last week.


Ionescu-Ittu told heartwire that there was one previous clinical
trial showing a similar association, in 1998, but congenital heart
disease was only a secondary outcome in that study. Since
then, "there have been some case-control studies and some animal
studies," she noted, "but even the AHA, in a scientific statement
this year, said that we really need some evidence at a population
level, and these are the first such data."

The researchers found a 7% reduction in births with severe
congenital heart disease after 1998, when the fortification of white
flour with folic acid became mandatory in Canada, compared with the
period before fortification.

An Encouraging Beginning

Using administrative data from Quebec for the prefortification (1990-
1998) and postfortification (1999-2004) periods, the researchers
looked at live and still births with severe congenital heart disease-
-Tetralogy of Fallot, endocardial cushion defect, univentricular
hearts, truncus arteriosus, or transposition complexes.

Before fortification there was a 1% increase in severe congenital
heart disease per year (p=0.34), but after fortification there was a
significant 6% reduction (p=0.006).

"Patients with severe congenital heart disease require a lot of
surgical intervention, and even a 7% reduction in birth prevalence
is really important," says Ionescu-Ittu.

Although this reduction is smaller than that seen for neural-tube
defects, Ionescu-Ittu said she believes that higher doses of folic
acid will be required to see larger reductions in the prevalence of
congenital heart disease. "We believe the true impact on congenital
heart disease is stronger than the one we observed."

"It would be good to follow this up with a trial using higher doses
of folic acid, where congenital heart disease is set up as a primary
outcome," she said, noting that, to her knowledge, no such trial is
planned.

"This is a beginning for congenital heart disease, but it's a very
encouraging beginning," she concluded.

For this work, Ionescu-Ittu and colleagues were awarded the T
Duckett Jones Memorial Lecture and Outstanding Research Award in
Pediatric Cardiology.

Pretransplant seropositivity for Toxoplasma gondii is associated
with worse outcomes after heart transplant, according to a report in
the November 13th issue of the Journal of the American College of
Cardiology.

"It is very surprising to note that no attention has previously been
given to the significance of T. gondii seropositivity amongst heart
transplant recipients," Dr. Satish Arora told Reuters Health. "T.
gondii is a life-long infection and although chronic latency is
maintained by an adaptive T-cell response, it is known that an
excessively vigorous response can lead to pathological effects,
including endothelial cell activation."

Dr. Arora from Rikshospitalet-Radiumhospitalet Medical Center, Oslo,
Norway and colleagues examined the association between recipient T.
gondii seropositivity and development of cardiac allograft
vasculopathy (CAV), acute cellular rejection, and mortality among
288 heart transplant patients.

The investigators found that 77 (27%) of the recipients were T.
gondii seropositive. Significantly more seropositive patients (40%)
than seronegative patients (24%) died during the median 5.5 years of
follow-up, with survival curves diverging after about 4 years.

Seropositive patients were 4.4 times more likely than seronegative
patients to develop CAV, the report indicates, and higher CAV-
related mortality largely accounted for the higher mortality among
seropositive patients.

"Our results indicate that seropositive heart transplant recipients
have a two-fold risk of all-cause mortality and four-fold risk of
CAV mortality," Dr. Arora said. "Consequently, if confirmed in other
independent studies, more intensive follow-up and CAV surveillance
may be appropriate for this group of patients. Furthermore, although
speculative, novel immunomodulatory agents may have an additional
beneficial advantage for this group of patients."

J Am Coll Cardiol 2007;50:1967-1972.

Patients who experience allergic reactions to clopidogrel appear to
benefit from a desensitization protocol that enables them to
continue taking the drug long term, which is particularly important
after placement of a drug-eluting stent (DES) [1].

This is the conclusion of a new study, published in the November 20,
2007 issue of the Journal of the American College of Cardiology
(published online November 5, 2007).

The authors, led by Dr Karl von Tiehl (Scripps Clinic, La Jolla,
CA), say: "Clopidogrel desensitization appears safe and highly
effective in inducing a sustained remission in clopidogrel-sensitive
patients who require prolonged dual antiplatelet therapy after
[placement of] drug-eluting stents. Our data support [the idea] that
this approach should be considered in all stable outpatients with
clopidogrel sensitivity who meet our inclusion and exclusion
criteria to avoid the potential adverse effects of ticlopidine and
to avoid the thrombotic risk of discontinuation of thienopyridine
therapy."

Approximately 4% of patients allergic to clopidogrel

Von Tiehl et al explain that long-term treatment with aspirin and
clopidogrel is recommended after placement of a DES to prevent stent
thrombosis and cardiac events but that potentially allergic
reactions to clopidogrel have been reported in approximately 4% of
patients, usually requiring drug discontinuation. They point out
that the alternative thienopyridine, ticlopidine, is more expensive,
dosed more often, and associated with a more frequent and serious
adverse side-effect profile, including blood dyscrasias, limiting
its clinical safety and utility.

They therefore investigated the possibility of desensitizing such
patients to their allergic reactions to clopidogrel. Such
desensitization protocols already exist for several medications,
including aspirin, and involve introducing the drug in very small
incremental amounts and gradually building up to the therapeutic
dose.

The study was conducted in 24 consecutive patients with suspected
allergic reactions to clopidogrel after DES implantation, 20 of whom
were outpatients. When possible, clopidogrel was discontinued and
patients were transitioned to ticlopidine 250 mg orally twice a
daily for five days before desensitization for both drug elimination
and symptom resolution. The clopidogrel desensitization protocol was
administered by a dedicated drug-desensitization nurse and
supervised by an allergist, who confirmed and treated any reactions
during the protocol. The use of steroids, antihistamines, and
antileukotrienes was stopped for seven days before desensitization
if feasible. Beta blockers were held on the day of desensitization
if possible.

The protocol involved oral administration of an aqueous solution
containing increasing amounts of clopidogrel. The first dose given
was solvent only, followed 30 minutes later by 0.005 mg of
clopidogrel in solution. Thereafter, doubling doses of dilute
clopidogrel were given every 30 minutes until a single 75-mg tablet
was given. All patients were monitored for adverse reactions. If a
potentially allergic reaction occurred, the patient was given
diphenhydramine (oral or IV) or oral cetirizine for symptom control.
Once symptoms subsided and 30 minutes had elapsed since the previous
dose of clopidogrel had been given, the same dose was repeated. If
no reaction occurred, then the protocol was continued. If a reaction
reoccurred, the patient was given the same treatment as mentioned
previously, then the next dose of clopidogrel given was half of the
provoking dose.

Success in all 24 patients

Results showed that during desensitization, allergic-type reactions
occurred in four patients and angina occurred in one patient.
Desensitization was acutely successful in all 24 patients, and by
six-month follow-up, one patient had persistent but improved
pruritus controlled with oral antihistamines and 23 remained
asymptomatic, with only two patients requiring repeat
desensitization.

Von Tiehl et al note: "This study demonstrates that primarily
outpatient-based clopidogrel desensitization is feasible, safe, and
effective and induces a sustained remission for at least six
months." They add, however, that a sustained response to
desensitization requires excellent patient compliance, as even brief
discontinuation of the offending drug can cause symptoms to recur
once the drug is restarted. Therefore, the recurrence of clopidogrel
sensitivity in patients who have been previously desensitized may
serve as a warning of noncompliance.

The authors write: "Premature discontinuation of dual antiplatelet
therapy has been clearly shown to be a strong, independent risk
factor for stent thrombosis, which frequently results in MI and
death. Therefore, efforts to reduce discontinuation of clopidogrel
up to 12 months after DES implantation are crucial."

They further point out that the most common period for the onset of
clopidogrel reactions is within the first 10 days after PCI, which
coincides with the highest risk of stent thrombosis when not treated
with a thienopyridine. "Clopidogrel desensitization may therefore be
an important approach to prevent discontinuation and subsequent
major adverse cardiac events in clopidogrel-sensitive patients after
DES [implantation]," they say.

von Tiehl K F, Price M J, Valencia R et al. Clopidogrel
desensitization after drug-eluting stent placement. J Am Coll
Cardiol 2007; 50:2039¡V2043.

The Canadian team of cardiologists and surgeons who have pioneered
much of the research into percutaneous aortic valve replacement
using the Edwards Sapien valve under Dr John Webb (St Paul's
Hospital, Vancouver, BC) say results on their first 100 patients
speak to the durability of the device and the sustained symptom
relief it provides.

Dr Robert Boone (St Paul's Hospital, Vancouver, BC) presented
results out to 12 months during a poster session at the American
Heart Association (AHA) 2007 Scientific Sessions. "These are initial
results on the first 100 patients, including 31 patients out to one
year," Boone said. "The valve appears to be structurally intact, the
mean gradient is low, and the valve area is high, which is very
reassuring."

In all, 102 procedures were performed in 100 subjects, all of whom
received the device for compassionate use by the Canadian Health and
Welfare department, after being turned away as unsuitable for open-
heart surgery. Predicted mortality in this group was 32% at 30 days,
but as the researchers showed last week, observed mortality was much
lower, at 15%. Echocardiographic results postprocedure, then at one
month, six months, and 12 months showed that aortic valve area and
mean gradient were significantly improved from baseline and remained
reasonably constant over the follow-up period. Compared with
baseline, predischarge echocardiograms indicated that left
ventricular ejection fraction improved, while mitral regurgitation
decreased, with both improvements remaining constant or trending
toward even better outcomes over subsequent months. NYHA class fell
from a mean of more than 3 at baseline to roughly 1.5 at 12 months
in the patients with one-year follow-up.

Boone also showed data on procedural success rates, dividing the 100
patients into quartiles according to the timing of their procedures.
While implant success was just 76% in the first 25 patients, success
rates for the subsequent 75 patients were high: 96% for each
successive group. Of note, 25 patients were treated using the
transapical approach instead of the transfemoral approach used in
the other 75 patients. Mortality among the transapically treated
patients was 24% at 30 days, as compared with 12% in the patients
treated using the transfemoral approach.

"In our center, the default procedure is still the transfemoral
approach, and if the iliac/vascular access is difficult, then we
will use the transapical approach," Boone explained. He went on to
say that for a subsequent 25 patients who underwent transapical
aortic valve implantation--results not shown in the AHA poster--30-
day mortality dropped to 18%. "So that procedure is improving in
terms of technical success, but there is a learning curve, and a
patient-selection issue," Boone said. In fact, two of the patients
in whom the transfemoral approach was unsuccessful in this series
ultimately underwent successful transapical device implantation.

Reproducible results

Boone said the findings speak to the consistency of the results,
which mirror those of other operators elsewhere. He also pointed to
the fact that while the predicted mortality of each series of
patients has increased--pointing to higher- and higher-risk patients
undergoing the procedure--the success rate has remained consistent,
suggesting that there is a steep learning curve but ultimately a
reproducible treatment. He also noted that early cases were not done
under general anesthetic, something that is now the norm in Webb's
group.

Boone also points out that they now have more than 150 images
showing proper positioning of the valve, successful implantation
techniques, and problems encountered particularly early on in the
series--something other groups can learn from. "The procedure, while
technically demanding, can be done in other places," he said. "I
think it just needs proctoring, and it's not something that's going
to be rolled out instantaneously; people are first going to have to
come up with the skills."

Some will acquire those skills in the PARTNER trial, now enrolling
in the US and Canada, Boone noted.

New research links statin use to reduced cognitive decline, but it
uncovers a curious phenomenon: African American patients who stopped
taking statins appeared to reap an even greater cognitive benefit
than those who continued taking this cholesterol-lowering medication.

The findings, published in the November 6 issue of the journal
Neurology, seem to underline the complex nature of the relationship
between statins and dementia prevention, the researchers, with
senior author Kathleen S. Hall, PhD, a psychiatric epidemiologist
and associate professor of psychiatry at the Indiana University
School of Medicine, in Indianapolis, write.

Statins play an important role in the prevention of cardiovascular
disease (CVD), and given the apparent link between CVD risk factors
and risk factors for cognitive decline, it is possible that statins
could also play a role in prevention of dementia, the authors
conclude.

"However, given the inconsistency of the results of statin use on
cognitive function from observational studies and the complexities
involved in interpreting the results of these studies, it is likely
that only carefully designed randomized clinical trials of statins
will provide definitive answers to their potential role in dementia
prevention," they write.

Evaluating the Role of Statins

In 2001 and again in 2004, researchers at Indiana University School
of Medicine and Regenstrief Institute, also in Indianapolis,
evaluated the cognitive status of 1146 African Americans aged 70
years and older living in Indianapolis, Indiana as part of the
Indianapolis-Ibadan Dementia Project. Cognitive assessment included
tests of language, attention, calculation, memory, and orientation.
Participants provided blood samples for ApoE genotyping and were
also assessed for a number of risk factors, including smoking,
alcohol use, and social involvement.

The researchers also evaluated statin use. They noted that 25% of
the elderly African American sample was using statins in 2001,
perhaps not surprising since African Americans have a higher
prevalence of coronary risk factors than other populations in the
United States.

Adjusting for age at baseline, sex, education, and ApoE status,
researchers found less cognitive decline among statin users than
among non¡Vstatin users.

On the standardized cognitive change scores, statin users had a mean
change of -0.14 SD, while non¡Vstatin users had a mean change of
0.05 SD, a difference of 0.19 SD after adjustment for age at
baseline, sex, education, and ApoE status. Logistic regression
showed statin use may also be associated with less incident dementia
(OR, 0.32; P = 0.0673).

If statin use reduces cognitive decline, then it is reasonable to
assume that continued use of statins would produce a greater
reduction. However, that was not the case in this study. Researchers
found that those who continued to take statins from 2001 to 2004 had
greater cognitive decline than those who were taking statins in 2001
but were no longer taking them in 2004.

"When the 3 groups of statin users (statin use at both baseline and
follow-up; statin use only at baseline; and statin use only at
follow-up) are compared separately with the non¡Vstatin users at
either wave, a significant inverse association for cognitive decline
was seen only in the group that was using statins at baseline but
had discontinued use at follow-up," the authors write.

Participants who had stopped using statins by the 2004 evaluation
had similar health, demographic, clinical, and biochemical
characteristics as those who continued using the drug.

Researchers were "surprised" by these findings, they say. Neither
the lipid-lowering nor the anti-inflammatory effects of statins
could explain the effect of stains on cognitive decline, Dr. Hall
told Medscape Psychiatry.

They included measurements of lipids (low-density lipoprotein
cholesterol [LDL-C]) and inflammation (C-reactive protein [CRP], an
inflammatory marker for CVD) in their predictive models and found no
interactions between LDL-C or CRP and statin use. "Statin use
remained significantly associated with cognitive decline," the
authors write.

Since the study did not collect information on the compliance,
duration, or dosage of statin use, "it is possible, if perhaps
unlikely, that the statin users who had discontinued use at follow-
up had in fact longer exposure to statins than the other statin user
groups," the authors write.

It is possible that some other mechanism of statins ¡X for example,
their antioxidant effects or protective effect on endothelial
dysfunction ¡X is at work, said Dr. Hall. "We intend to explore
these possibilities in future studies," she said.

In addition to lowering lipids in plasma, statins also lower the
level of a major product of brain cholesterol metabolism. "Statin
use plays an important role in the prevention of cardiovascular
disease," Dr. Hall said in a press release. "And there may be a link
between cardiovascular risk factors and risk factors for cognitive
decline and Alzheimer's disease."

The study was funded by the National Institute on Aging. The authors
report no conflicts of interest.

Neurology 2007;69:1873-1880. Abstract

Two decades after the National Institutes of Health (NIH) mandated
inclusion of women in clinical research--a policy that became US law
in the NIH Revitalization Act of 1993--women are still
underrepresented in cardiovascular clinical trials, a new analysis
shows. According to Dr Esther SH Kim (Cleveland Clinic, OH), who
presented the results at the American Heart Association 2007
Scientific Sessions, the proportion of women in clinical trials
testing therapies for CVD is no higher today than it was in 1997.

"Even though the mandate was made 16 years ago, we're nowhere near
being equally represented with men," Kim told heartwire. "I think
we're losing a lot of knowledge. For example, we're learning from
these ACS trials that the therapies we give to men may not be as
beneficial in women and may in fact be doing harm when we apply these
findings with a broad brush to both genders."

Kim and colleagues reviewed the NIH clinical trials database
(www.clinicaltrials.gov), looking only for phase 3 or 4 National
Heart, Lung, and Blood Institute¡Vfunded trials in adult men and
women that were published between 1997 and 2006 and that tested drugs
or strategies for the reduction of stroke, MI, or death--a total of
19 trials. Over this time, the proportion of women in trials ranged
from 10% in the MUSTT trial to 47% in ALLHAT and MOST, but over the
entire period, the mean proportion of female participants remained
low, at 27%. There was a trend toward greater representation of women
in trials that enrolled lower-risk patients, but this did not reach
statistical significance, Kim noted.

NIH not at fault

Kim believes enrollment of women in NIH-funded studies, if anything,
might be even better than privately funded studies. "If the NIH,
which has such strict monitoring of enrollment of women in its
trials, couldn't do it, then how is the average Joe in an industry-
sponsored study supposed to do it?" she asked.

Upping enrollment of women is going to take collaboration between the
NIH and public agencies attempting to raise awareness of CVD among
women, she says, insisting that her intention with this study
was "not to bash the NIH."

"They did put the policy in place, and they did make it law," she
points out. "Any time you apply for a grant you have to specify what
your enrollment procedures will be to try to meet that mandate, and
you need to report back to the NIH to show how you're doing. And if
you're not performing up to their standards, they'll make you add a
site, put more brochures out, or go out into the community. So they
really make an effort to try to get women enrolled."

She rejects the idea that the NIH should become stricter, to force
enrolling sites to up their quota of women. By the time it's apparent
that enrollment of women is lagging, she says, "We've typically
already spent millions and millions of dollars to get the trial up to
that point, and we don't want to lose the very important information
we've got from the population that is already enrolled. So I'm not
sure that cutting off funding or stopping the study is going to be
the best thing for the American public."

Upping quotas

A key problem, she speculates, may be the exclusion of older patients
from CVD trials. "We know that women present with heart disease at an
older age, so by excluding older patients we may also be excluding a
large population of women," she said.

Another explanation may be that physicians seeing a woman complaining
of chest pain or other symptoms may not be referring them on to
cardiologists, where they might be more likely to be offered the
opportunity to participate in trials. As such, education campaigns
must also target GPs and other public-health workers.

This is not the first time researchers have addressed the question of
female participation in clinical trials; a paper by Harris and
Douglas in 2000 [1] addressed the same question and found at that
time that women made up 38% of publicly funded trials; however, when
trials that enrolled only women were excluded from the analysis,
enrollment rates were similar to what Kim et al are reporting in 2007.

"So this is not new news, it's just that we haven't come very far
from 2000," she said.

Harris DJ, Douglas PS. Enrollment of women in cardiovascular clinical
trials funded by the National Heart, Lung, and Blood Institute. N
Engl J Med 2000; 343:475-480. Abstract

The Thoratec Corp announced yesterday that last month it initiated a
recall of some of its implantable ventricular assist devices (IVADs)
manufactured since 2004 [1]. The devices had been distributed
directly to 87 hospitals throughout the world, which were sent recall
notification letters on October 19, according to the company
statement.

The affected devices have a catalog number of 10012-2555-001 and
serial numbers of 488 or higher; the identifier is on both the device
packaging and the Y connector at the end of its percutaneous
driveline, Thoratec said.

The potential hazard involves the pneumatic driveline when the device
is used in the paracorporeal position rather than after preperitoneal
implantation. The external position is allowed by the device's
instructions for use, the company notes. The driveline can be damaged
if "bent at a sharp angle relative to its junction with the pump
housing." The company said it has received seven reports of such
incidents, five of which resulted in patient injury and one of which
was fatal, out of 45 cases involving paracorporeal placement of which
it is aware.

"Hospitals having ongoing patients with IVADs in the paracorporeal
position should contact Thoratec for further instructions if they did
not receive the October 19, 2007 Recall Notification Letter," the
company said.

Thoratec Corp. Urgent Thoratec Corporation worldwide recall of
implantable ventricular assist device. November 8, 2007. Available
at: http://phx.corporate-ir.net/phoenix.zhtml?c=95989&p=irol-
newsArticle&ID=1074762&highlight=.

Using genetic tests as well as clinical factors improved the accuracy
and efficiency of warfarin dose initiation, but the primary end point
of a reduction in out-of-range INRs was not significantly changed in
the overall population in the Couma-Gen study [1]. Subgroup analysis
suggested, however, that pharmacogenetic guidance might reduce out-of-
range INRs in certain patient groups--those without any variant
genotypes or those with multiple variant genotypes.

The study was presented today at the American Heart Association (AHA)
2007 Scientific Sessions and published simultaneously online in
Circulation. Lead investigator Dr Jeffrey Anderson (University of
Utah, Salt Lake City) said: "In our study, patients using genotype-
guided warfarin dosing needed fewer dose changes and were able to get
to their optimum INR in a more efficient way. But the primary end
point of out-of-range INRs was not statistically different in the
genotype-guided treatment." He noted, however, that the study was
conducted on an inpatient basis with careful management by a
dedicated anticoagulation service, leading to rapid correction of
inappropriate warfarin doses, which likely contributed to better-than-
expected outcomes in the standard dose arm.

Anderson explained that several gene variants have been discovered
that affect interindividual dose variability of warfarin and that the
FDA has already endorsed the idea of using these gene variants to
guide warfarin dosing. "There is very strong evidence that genetics
influence the correct dose. The FDA has just taken this to the next
logical step, saying that lower doses should be considered if the
patient has multiple variants. This may be somewhat premature in many
people's eyes, as it hasn't been shown to really affect outcomes yet,
and our study hasn't shown this definitively, either. I think this
approach has a lot of promise for the future, but it's maybe not
ready for right now," he commented.

Anderson stressed that larger trials are needed and are now being
planned, with a National Institutes of Health trial in 2000 patients
to start next year.

Former AHA president Dr Raymond Gibbons (Mayo Clinic, Rochester, MN)
shared Anderson's views. "This is an area of enormous potential
importance, but we need more time and more evidence before it becomes
part of clinical practice. I definitely do not think doctors should
rush out there and start giving genetic tests to all the patients
they want to put on warfarin at the moment. Maybe one day this will
happen, and yes, it does make sense, but we need evidence that it
will have a real benefit, and that's not there yet."

Gibbons added that for warfarin treatment, the potential of genetic
testing would be useful only in the initial dose selection, which is
important, but that it would not help in the chronic management of
these patients. "People's genetics don't change over time, but what
they eat, what they weigh, and how they metabolize drugs do, and it
is this that affects the long-term variability in warfarin levels,"
he said.

"A very promising first step"

Discussant of the trial at the late-breaking clinical-trials session,
Dr Julie Johnson (University of Florida, Gainesville), described the
study as "a very promising first step. This trial did suggest a
reduction in adverse events such as INRs over 4 and minor bleeds,
which, while not significant, probably would have been in a larger
study. It also showed a significant reduction in the number of dose
changes needed to get to a stable INR, which would probably reduce
the number of clinic visits necessary and therefore reduce costs,"
she noted.

The Couma-Gen study randomized 206 patients being initiated on
warfarin to pharmacogenetic-guided or standard dosing. The genetic
tests were performed on buccal swab samples with a rapid
assay. "There are companies out there that offer this test, but you
usually have to send off the sample and will not get the results for
a few days. We managed to achieve this turnaround in just one hour.
That is what is needed for this test to be useful in a clinical
setting," Anderson said. The researchers then entered the genetic
information along with data on weight, age, and sex into a computer
program, which provided an individualized dose for each patient.
Results showed that age, sex, and weight explained 12% of the
variability of warfarin dosing, while genetics explained 35% of the
variability.

Patients were followed for three months, and INR was measured on days
0, 3, 5, 8, 21, 60, and 90. While out-of-range INRs did not differ
significantly between arms in the whole population, exploratory
subset analysis suggested that those with the wild-type genotype (no
genetic variants) and carriers of multiple variant alleles showed
promising reductions in out-of-range INRs with pharmacogenetic
guidance.

Explaining this subset analysis finding, Anderson noted that about
40% to 45% of patients have one genetic variant and 70% of patients
have one or more variants, so the wild-type patients are in the
minority. "The average patient therefore has one variant, and this is
who we are targeting our standard dose of warfarin at. That is
probably why patients in this study with one variant did not show any
benefit of this genetic approach--they are already treated well with
the standard dose. But wild-type patients and those with more than
one genetic variant did show benefit. When we just use standard-dose
warfarin we are underdosing wild-type patients and overdosing
patients with more than one genetic variant," he added.

Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of
genotype-guided versus standard warfarin dosing in patients
initiating oral anticoagulation. Circulation 2007; DOI:
10.1161/CIRCULATIONAHA.107.737312. Available at:
http://circ.ahajournals.org.

New data suggest that renal replacement therapy (RRT) is underused in
patients with heart failure (HF). This is the conclusion of a Mayo
Clinic retrospective cohort study of the association of RRT with
improved survival in patients with HF. The results of the study were
presented here at Renal Week 2007, the American Society of Nephrology
Annual Meeting, by Kelly Liang, MD. She is a fellow in the Division
of Nephrology and Hypertension at the Mayo Clinic College of Medicine
in Rochester, Minnesota.

Dr. Liang noted that, at present, use of RRT in patients with HF may
often be deferred because of concerns regarding the ability of HF
patients to tolerate RRT and because of uncertainty regarding the
effect of RRT on outcomes. The results of the Mayo Clinic study, she
said, suggest that there is a need for further investigation of
earlier use of RRT in HF patients in selected clinical situations,
because RRT has the potential to improve symptoms, prevent repeated
hospitalizations, slow the progression of HF, and improve outcomes.

According to Dr. Liang, the study analyzed all patients who were
admitted with a first hospitalization for HF at the Mayo Clinic
during a 16-year period, excluding patients who had received RRT
before admission. Of the 6276 included patients, 304 (4.84%)
commenced RRT (defined as chronic dialysis or renal transplantation).
Therefore, Dr. Liang said, despite the recognized adverse effect of
renal dysfunction on outcomes in HF, among patients admitted for HF
over a 16-year period, only approximately 5% eventually received RRT.

Assessment of the effect of RRT on survival in HF is difficult to do
retrospectively, Dr. Liang noted. Patients who progress to RRT have a
higher risk for death (because of higher comorbidities). However,
when adjustments are made for differences in baseline
characteristics, including worse prognostic factors, those who
progress to RRT have no significant increase in mortality compared
with those who do not. Furthermore, those who progress to RRT at the
time of HF admission do better than those who do not receive RRT
early on. These data support use of RRT in HF patients, Dr. Liang
said.

"When we looked at patients receiving RRT within the first month of
hospitalization, we found that there was a decrease in the hazard
ratio for mortality in those who did receive RRT early on, suggesting
that survival was better if you received RRT early on," Dr. Liang
noted.

David Wheeler, MD, one of the moderators of the session, commented on
the presentation. "The study looked at survival of patients with
heart failure and whether the initiation of RRT had any impact on
survival in these patients. Many patients with heart failure also
have kidney disease, so in a way it's logical to offer them dialysis.
But I think that kidney specialists worry that these patients really
form a very high-risk group.

"What this study in fact showed was that, taking patients with heart
failure, those who went on to dialysis actually did better than those
who didn't get dialyzed, which I think was somewhat of a surprise to
many of us who would have predicted that the outcome for patients
with heart failure who get dialyzed is really very poor," Dr. Wheeler
said.

"I think what this study is basically suggesting to us is that we
shouldn't shy away from offering dialysis to patients with heart
failure because it could potentially improve their survival," he
concluded. Dr. Wheeler is a senior lecturer in nephrology at the
University College London and is a member of the advisory board of
the United States Kidney Disease Outcomes Quality Initiative.

This study was funded by the Nephrology Division Small Grants Program
at the Mayo Clinic.

Dr. Liang has disclosed no relevant financial relationships. Dr.
Wheeler has received grants/research support from Amgen and Genzyme;
he is a consultant for Amgen; he has received honoraria from Abbott,
Amgen, AstraZeneca, Genzyme, Novartis, and Shire Pharmaceuticals; and
he is on the advisory boards of Amgen, Genzyme, and Roche.

Renal Week 2007: Abstract SU-FC004. Presented November 4, 2007.