High-dose vitamin E does not increase mortality in Alzheimer's
disease (AD) patients and, in fact, has been associated with
improved survival in this population.

New research presented at the American Academy of Neurology (AAN)
60th Annual Meeting found that AD treatment regimens that included
vitamin E at a dose of 2000 IU/day were associated with a 26% lower
mortality rate than those that did not include the supplement.

"We think this study is reassuring in that rather than causing harm,
treatment with vitamin E appears to be protective when you measure
outcomes in terms of overall survival. It also suggests additional
research on the use of vitamin E and treatment of Alzheimer's
disease is warranted," study investigator Valory Pavlik, PhD, from
Baylor College of Medicine, in Houston, Texas, told reporters
attending an AAN press conference.

Based on research suggesting vitamin E may have a protective effect
against AD in the general population and another study published in
2000 indicating high-dose supplementation may slow AD progression,
Dr. Pavlik said clinicians at Baylor's Alzheimer's Disease and
Memory Disorders Center have been using the supplement as an adjunct
to antidementia treatment.

Recent meta-analyses have suggested that the supplement may have a
harmful impact on outcomes, including mortality, in cardiovascular
patients, which raised concerns this practice may also be
detrimental in the AD population and were the impetus for this study.

Generalizable Findings?

"The extent to which these results were generalizable to dementia
patients is not clear, but nevertheless they raised some controversy
about the use of vitamin E," said Dr. Pavlik.

To determine whether AD patients taking high-dose vitamin E had
reduced survival, investigators analyzed survival history of 847
probable AD patients attending the center from 1990 to 2004.

Deaths in the cohort were ascertained by telephone follow-up and
were all confirmed by linkage to the National Death Index.
Investigators then determined the relative risk of dying in
individuals taking vitamin E alone or with another antidementia
drug.

Less than 10% of the group took vitamin E alone, and approximately
15% of the study cohort did not take the vitamin. The average follow-
up period was 4.9 years, with a range of 1 to 15 years.

After adjusting for demographic variables and disease severity at
baseline, the investigators found that individuals taking regimens
that included high-dose vitamin E had a 26% reduced mortality risk
compared with individuals not taking the supplement.

Impact on Quality of Life?

To determine whether this main result was driven by vitamin E or
antidementia medications, the investigators conducted 2 further
comparisons. They looked at individuals who were taking vitamin E,
with or without additional antidementia medication, and compared
them with individuals taking no medication at all.

Among those taking vitamin E with or without another drug, the
mortality rate was 23% lower over time, compared with those taking
no drug, said Dr. Pavilk.

In addition, investigators compared patients taking cholinesterase
inhibitors alone with those taking no drug and found individuals
taking the antidementia treatment had a slightly higher-than-average
mortality rate. However, Dr. Pavlik, emphasized this finding was not
statistically significant.

In a follow-up interview with Medscape Neurology & Neurosurgery,
study coauthor Rachelle Doody, MD, also from Baylor College of
Medicine, said it is important to note that in addition to a
possible extension of life, other research by Baylor investigators
has shown that vitamin E may have an impact on AD patients' quality
of life.

"Our research suggests AD patients who persist with their
antidementia therapy from the beginning of the disease to the end
and who also take high-dose vitamin E are more likely to live longer
at a higher level of ability," she said.

Dr. Pavlik has no disclosures.

American Academy of Neurology 60th Annual Meeting: Abstract P03.076.
Presented April 15, 2008.

In children and adolescents with type 1 diabetes, consumption of a
low glycemic index diet may reduce glucose excursions and improve
overall glycemic control, according to results of a National
Institutes of Health-sponsored study.

"As the participants all used a basal-bolus insulin regimen, and
carbohydrate consumption was standardized, the findings suggest that
a low glycemic index diet has utility for improving glycemic control
to a clinically meaningful degree above that obtained by careful
carbohydrate counting and contemporary insulin regimens," Dr. Tonja
R. Nansel of the National Institute of Child Health and Human
Development noted in comments to Reuters Health.

As reported in the April issue of Diabetes Care, Dr. Nansel and
colleagues tested the effects of high glycemic index and low glycemic
index meals using continuous blood glucose monitoring in 20 type 1
diabetics between 7 and 16 years old.

As mentioned, all participants used a basal-bolus insulin regimen, in
which insulin dose was calculated based on amount of carbohydrate
consumed, and a correction factor was applied based on blood sugar
levels. The two diets were matched for calories and macronutrients
(carbohydrate, protein, and fat).

"When consuming the low glycemic index diet, blood glucose levels
were in the target range of 70 to 180 mg/dL 66% of the time compared
to 47% of the time when consuming the high glycemic index diet," Dr.
Nansel reported. "This difference was statistically significant."

When consuming the low glycemic index diet, study subjects also
demonstrated significantly lower daytime mean blood glucose levels
compared to the high glycemic index diet (137.6 versus 184.2
mg/dL). "They also showed significantly lower blood glucose area over
180 mg/dL, and lower high blood glucose index, a measure of blood
glucose variability," Dr. Nansel said.

There were no marked differences between the two conditions in the
blood glucose area under 70 mg/dL or the low blood glucose index.

There were no significant differences between the two dietary
conditions during the nighttime hours. "The absence of a difference
in nighttime blood glucose parameters supports the understanding that
a low glycemic index diet affects blood glucose through reduction of
postprandial excursions," Dr. Nansel pointed out.

Blood glucose levels falling below 80 mg/dL were treated with 15
grams carbohydrate from juice. Treatment for blood glucose below 80
mg/dL occurred more frequently during the low glycemic index dietary
condition (13 subjects) than the high glycemic index condition (8
subjects), the researchers found.

"Considering both the greater frequency of mild hypoglycemia that was
observed and the greater actual amount of carbohydrate consumed per
unit of insulin in the low glycemic index condition," Dr. Nansel
pointed out that "it is plausible that a low glycemic index diet may
reduce insulin dose requirement."

"Consistent consumption of a low glucose index diet may reduce
insulin requirement while improving blood glucose control, but
careful attention should be given to blood glucose monitoring and
adjustment of insulin dose during transition to a low glycemic index
diet," she added.

Diabetes Care 2008;31:695-697.

The plasma concentration of asymmetric dimethyl arginine (ADMA), a
naturally occurring endogenous L-arginine metabolite, predicts
cardiovascular outcomes in type 1 diabetics with diabetic
nephropathy, according to a report in the April Diabetes Care.

"If confirmed in other studies, ADMA might in the near future turn
out to be a new tool for risk-stratification and identification of
type 1 diabetic individuals at particularly high risk of adverse
cardio-renal outcomes and a practical tool for guidance on the need
for additional intensification of treatment in this group of
patients," Dr. Lise Tarnow from Steno Diabetes Center, Gentofte,
Denmark, told Reuters Health.

Dr. Tarnow and associates investigated the predictive value of
circulating ADMA levels on the risk of fatal and nonfatal
cardiovascular disease, progression to end-stage renal disease
(ESRD), rate of decline in glomerular filtration rate and all-cause
mortality in 397 type 1 diabetic patients with overt diabetic
nephropathy and in 175 diabetic controls without nephropathy.

ADMA can inhibit all three isoforms of nitric oxide synthase, the
authors explain.

Among the type 1 diabetics with diabetic nephropathy, significantly
more patients with ADMA levels above the median (43.4%) than similar
patients with ADMA levels below the median (19.4%) suffered a fatal
or nonfatal major cardiovascular event, the authors report.

In separate analyses, plasma ADMA significantly predicted nonfatal
major cardiovascular events but was weaker in predicting
cardiovascular mortality.

Patients with ADMA levels above the median experienced a rate of
decline in glomerular filtration rate greater than that experienced
by patients with lower ADMA levels, the report indicates. Patients
with higher ADMA levels were 3.2 times as likely as patients with
lower ADMA levels to develop ESRD.

Overall mortality was 67% higher among patients with higher ADMA
levels than among patients with lower ADMA levels, the investigators
say.

The risk of cardiovascular events was similar for patients with
persistent normoalbuminuria regardless of ADMA level, but there was a
strong trend toward higher mortality among normoalbuminuric patients
with ADMA levels above the median.

"Plasma ADMA levels predict fatal and nonfatal cardiovascular events
in patients with type 1 diabetic nephropathy," the authors
conclude. "In addition, elevated ADMA levels suggest an increased
risk of progressive diabetic kidney disease."

"Although not yet proven or even investigated in humans, it is likely
that agents stimulating nitric oxide synthase or otherwise increasing
nitric oxide levels will be protective against cardiovascular events
and progressive renal disease in type 1 diabetic nephropathy," Dr.
Tarnow explained.

"We are currently investigating the genetic predisposition to
increased ADMA by studying the genes involved in synthesis and
degradation of the compound," Dr. Tarnow said. "Furthermore, studies
on the effect of antihypertensive treatment and other
cardioprotective regimens on ADMA levels are in progress."

Diabetes Care 2008;31:747-752.

A new analysis from the CREATE registry, published in the April 26,
2008 issue of the Lancet, provides a first true glimpse of the scope,
treatments, and outcomes of acute coronary syndromes in India [1].
The picture is bleak: according to Dr Denis Xavier (St John's Medical
College, Bangalore, India) and colleagues, people admitted for ACS in
India are younger, poorer, sicker, and more likely to die than ACS
patients in the developed world.

According to Dr Salim Yusuf (McMaster University, Hamilton, ON),
senior author on the study, the findings should serve as a wake-up
call to cardiologists and academics seemingly preoccupied with
cardiovascular disease in Western countries, which accounts for just
20% of the world's CVD burden.

"This calls for much more awareness in developing countries," he told
heartwire. "Very few scientists are working in this area, but if you
really want to solve the problem of heart disease, you don't focus on
new GP IIb/IIIa inhibitors or new stents that, in the full scheme of
things, are actually quite unimportant. In a recent issue of JAMA
there are two papers, both of which have no relevance whatsoever to
beating the heart-disease burden in the world, yet these are the
types of things being published in the major journals. Even if we
made significant progress in these focused areas, which we're not
even making any more, the real progress needs to be made in the low-
and middle-income countries."

Slow to get help, dying young

Xavier et al's paper examined the incidence of STEMI and non-STEMI
among almost 21 000 patients from 89 centers in 50 Indian cities.
They found that more than 60% of these patients were diagnosed with
STEMI, mean age was 57.5 years (although STEMI patients tended to be
even younger), and the vast majority were from lower-middle-income or
poor families.

Times from symptom onset to hospital admission were at least double
that of Western countries, where patients typically take 130 to 170
minutes to get help: in Xavier et al's registry, STEMI patients took
a median of 300 minutes from symptom onset to hospital admission,
while non-STEMI and unstable-angina patients took a median of 420
minutes to get to the hospital. Authors of the study point to the
lack of organized emergency transport systems and ambulance services.

"There is no real system in India for managing heart-attack patients,
no education of patients to recognize symptoms and come to the
hospital early, and no proper ambulance system--most people come by
public transportation or taxi or some other mode of transportation,"
Yusuf explained. "All of this means that there is a delay in
implementing effective therapies."

Once admitted, almost all STEMI and non-STEMI patients were treated
with antiplatelet drugs (primarily aspirin, with clopidogrel used in
just 15%), but use of ACE inhibitors or angiotensin-receptor blockers
(ARBs), thrombolytics, beta blockers, statins, and PCI/CABG were all
far lower than rates seen in the West.

Not surprisingly, 30-day death, reinfarction, and stroke rates were
higher for STEMI patients than non-STEMI, and mortality, notably, was
significantly higher in poor patients than in rich patients, a
difference eliminated when adjusted for treatment use.

"These are major, major issues that call for governmental action, a
national health-insurance system, and education of patients about the
signs and symptoms of a heart attack," Yusuf commented. "Government
insurance that provides some sort of basic care in acute emergencies
is urgently needed, so patients don't worry whether they can afford
treatment. In India, often when a patient is first admitted with a
heart attack and a thrombolytic is needed, the hospital will start to
discuss with the patient's relatives whether it's worth doing,
whether they can afford the cost."

While the number of health insurance companies is on the rise in
India, plans are typically provided through larger employers, and a
disproportionate number of Indian workers are actually self-employed,
Yusuf noted.

Yusuf emphasized that this paper provides key information previously
unknown about ACS in a country expected to account for 60% of the
world's CVD by 2010 and where risk factors like obesity and diabetes
are soaring.

"India has the largest percentage of heart disease in the world, and
this is the first paper to clarify how people are being treated," he
told heartwire. "The key thing is that the pattern of presentation of
patients is similar to what we saw in the West 25 or 30 years ago:
patients arrive late, they're younger (by about a decade compared
with the West), and they have more ST-segment MI rather than non-
STEMI. This is classical when disease is on the rise. And added to
that, you have the burden of a healthcare system that's not geared
toward dealing with these kinds of things."

Yusuf also stated that India may be "a good example for what is
happening in most of the world."

"We are all very much focused on treatment as it applies to Western
countries, but the problem with that is that only 20% of heart
disease actually occurs in these countries," he said. "If you want to
deal with the global problem, we have to find a way of paying
attention to the developing countries. And this paper identifies the
problems."

Treatment targets

In an editorial accompanying the study [2], Dr Kim Eagle (University
of Michigan Medical Center, Ann Arbor) calls this registry
analysis "a major milestone" that, by identifying the issues,
provides opportunities for tackling them. He proposes efforts
targeting tobacco use; policies and education to switch the emphasis
from saturated to polyunsaturated fat in Indian diets; and screening
for hyperlipidemia and hypertension--relatively cheap and simple
strategies that have had an enormous impact in other parts of the
world.

Eagle also observes that world-class medical care already exists in
India but suggests that provision of this caliber of care to the
minority who can afford it may be distracting from the goal of
providing relatively inexpensive drugs on a much wider scale.

"On average, these strategies are not expensive," Eagle writes. "Most
of the decline in coronary mortality in the US is believed to be
secondary to improving risk-factor profiles and effective primary and
secondary treatments of acute coronary syndrome with aspirin, beta
blockers, statins, and, when appropriate, ACE inhibitors or
angiotensin-receptor antagonists. Expensive interventions, such as
revascularization, account for only 5% of this benefit. There is no
reason why similar results cannot be achieved in India and
elsewhere."

CREATE registry authors declared having no conflicts of interest;
Eagle disclosed receiving research funding from Sanofi-Aventis,
Pfizer, Bristol-Myers Squibb, and Merck. Sanofi-Aventis India was one
of several funding sources for the study, via an unrestricted
educational grant.

Xavier D, Pais P, Devereaux PJ, et al. Treatment and outcomes of
acute coronary syndromes in India (CREATE): a prospective analysis of
registry data. Lancet 2008; 371:1435-1442.
Eagle K. Coronary artery disease in India: challenges and
opportunities. Lancet 2008; 371:1394-1395.

hello doc, thanks for the info. God bless..


----- Original Message ----
From: dr_allen_wang <no_reply@yahoogroups.com>
To: heart119@yahoogroups.com
Sent: Thursday, April 24, 2008 6:43:24 AM
Subject: [Heart119] Dark Chocolate With Added Plant Sterols Reduces Cholesterol
and Blood-Pressure


The regular consumption of a heart-healthy chocolate bar (CocoaVia,
Mars Inc) can lower total- and LDL-cholesterol levels as well as
reduce systolic blood pressure, a new study has shown [1]. The
benefits of eating the chocolate, a dark chocolate product
supplemented with plant sterols, occurred without any weight gain,
suggesting the cocoa-flavanols- rich treat might be helpful in the
dietary management of cardiovascular risk, say investigators.

The study is published in the April 2008 issue of the Journal of
Nutrition.

Senior investigator Dr John Erdman (University of Illinois, Urbana-
Champaign) told heartwire that the specialized chocolate bars, which
are supplemented with plant sterols in addition to the naturally
occurring cocoa flavanols, are likely to be consumed by individuals
looking to make healthier choices. The product is now available in
US stores, including Walgreen's and CVS Pharmacy, usually in the
same aisle as but separate from regular chocolate candy.

"There are two components of the chocolate bar; the first is that it
contains plant sterol esters, which have been added, which have been
demonstrated to reduce serum cholesterol, " said Erdman. "The second
aspect is the cocoa flavanols, which are not added but are present
in cocoa and the cocoa bean and preserved in the chocolate bar. The
flavanols are what have received the most interest in terms of
vascular effects."

Previous studies have shown that the consumption of cocoa-flavanols-
containing foods can improve endothelial function, platelet
reactivity, and insulin sensitivity and reduce blood pressure, he
said. The purpose of this study was to test whether vascular
protection with the addition of plant sterols would be observed in a
slightly hypercholesterolemi c patient population (baseline total
cholesterol levels ranged from 202 mg/dL to 284 mg/dL) who regularly
ate the chocolate product.

In total, 49 adults followed the American Heart
Association' s "Eating Plan for Healthy Americans" diet for two weeks
prior to randomization. After the two-week run-in period, the
subjects were randomized to two groups, with one eating two of the
dark chocolate bars daily, and the other eating two nutrient-matched
dark chocolate bars that did not contain plant sterols. Participants
consumed the chocolate bar for four weeks and then were switched to
the other for an additional four weeks.

Regularly eating the plant-sterol- containing chocolate bar reduced
total cholesterol 2.0% and LDL cholesterol 5.3%, both significantly.
This reduction was on top of the 7% reduction in total cholesterol
that occurred during the two-week dietary run-in phase. Consumption
of the chocolate product also reduced systolic blood pressure 5.8 mm
Hg at eight weeks.

Speaking with heartwire, Erdman said the extent of the reduction in
blood pressure was surprising, and the reduction is likely
attributed to cocoa flavanols increasing the synthesis of nitric
oxide. The Kuna Indians, he noted, an indigenous population in
Panama, consume a large amount of cocoa rich in flavanols, and
despite a diet that also has a large amount of salt, have a very low
prevalence of hypertension and cardiovascular disease mortality.

Erdman said that because Mars funded the study, which he said
wouldn't have been done if the company hadn't, there are some who
will be quick to dismiss the results. Sponsorship from the food
industry, he said, is looked upon more disparagingly by some in the
scientific community than sponsorship from drug companies, something
he doesn't exactly understand. "We've run cholesterol studies in the
past, and I can tell you we ran this study just like we ran any
other trial," he said..

The CocoaVia chocolate bar contains about 100 calories and 6 g of
total fat. While investigators tested the chocolate bar, there are a
host of other CocoaVia products on the market, including snack bars
and chocolate-covered almonds.

Mars Inc sponsored the study. Erdman is a consultant and chairs the
Mars Scientific Advisory Council. Mars also employs Dr Catherine
Kwik-Uribe, one of the authors of the paper.

Allen RR, Carson L, Kwik-Uribe C, et al. Daily consumption of a dark
chocolate containing flavanols and added sterol esters affects
cardiovascular risk factors in a normotensive population with
elevated cholesterol. J Nutr 2008; 138:725-731. Abstract





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An analysis of disease-specific mortality outcomes across all US
counties showed overall gains from the 1960s through the 1990s, with
a consequent increase in life expectancy for both men and women [1].
But within the numbers are also some regional trends suggesting that
for some Americans--those living in regions with the fewest gains
during the 1960s and 70s--health outcomes in the subsequent two
decades were actually worse than before.

Lower mortality from heart disease and stroke accounted for most of
the survival gains overall and, throughout the first two of the four
decades, disparities narrowed between the worse-off and better-off
parts of the US. But the trend reversed in the 1980s and 90s in
regions that had previously been less well off; their CV gains were
partly erased--and in some cases were overwhelmed--by greater
mortality from obesity, diabetes, lung cancer, and other disorders,
especially among women.

The study's main observation--that regional health disparities in
the US narrowed throughout the 1960s and 70s and then, in some
places, widened over the next two decades--was unlikely to have been
caused by population-migration patterns, said Dr Majid Ezzati
(Harvard School of Public Health, Boston, MA) and colleagues in a
report published online today in the open-access journal PLoS
Medicine. Their analysis, they say, suggests that only the
unlikeliest of migration scenarios could have produced the results
they found.

Of the US counties with significant declines in health in the 1980s
and 90s, all of those showing the effect for men and >96% of
counties showing that for women "were in the Deep South, along the
Mississippi River, and in Appalachia, extending into the southern
portion of the Midwest and into Texas," according to the authors.

That regional health disparities worsened starting in the 1980s is
consistent with other data, Ezzati told heartwire, "but the part we
absolutely did not expect, and this is a much bigger issue, is that
the worse off are just not getting better and, in fact, some of them
are getting worse."

In the 1960s and 70s, "cardiovascular mortality had been going down
so fast, the net effect [given mortality from other causes] was
beneficial," Ezzati said, whereas in the 1980s and 90s in regions
that had previously fared least well, mortality stopped going down
fast enough to counteract the increased mortality from other
diseases, like lung cancer, chronic lung disease, and diabetes. "So
the net effect was stagnation," he said, or in some regions,
increased overall mortality.

"This stagnation and reversal of mortality decline, although
affecting a minority of the nation¡¦s population, is particularly
troubling because an oft-stated aim of the US health system is the
improvement of the health of 'all people and especially those at
greater risk of health disparities,'" write Ezzati et al in their
report, taking a quote from a flyer distributed to the public by the
US Centers for Disease Control and Prevention [2].

The group obtained their four decades of county- and sex-specific
data from several government sources, including the National Center
for Health Statistics and the US Census, and grouped counties on the
basis of whether their outcomes over time improved or worsened
relative to the national average. From 1961 to 1999, the analysis
showed, the average life expectancy overall rose from 66.9 to 74.1
for men and from 73.5 to 79.6 for women.

Between 1961 and 1983, the group writes, no counties showed a
significant mortality increase, and most showed declines. Driving
the declines was a steep reduction in CV mortality. From 1983 to
1999, life expectancy dropped significantly in 11 US counties for
men and in 180 counties for women; the mean decrease was by 1.3
years for both sexes.

Ezzati speculated that the patterns by sex were related to
differences between men and women in smoking, blood pressure, and
obesity. "Smoking for American women peaked about two decades after
it did for men, so its effects continue later. Obesity was more
prevalent among women, and it went up faster. During the 1980s,
blood pressure went down for both men and women; in the 1990s, it
continued to go down for men but actually went up for women," he
said. "So in some sense, the three drivers I've identified have
certainly disfavored women more than men."

Ezzati M, Friedman AB, Kulkarni SC, Murray CJL. The reversal of
fortunes: Trends in county mortality and cross-country mortality
disparities in the United States. PLoS Medicine 2008. DOI
10.1371/journal.pmed.0050066.
CDC achieving greater health impact. CDC's strategic imperatives.
Available at http://www.cdc.gov/osi/goals/SIHPGPostcard.pdf.

Short-term exposure to ozone as a component of smog, at
concentrations typical of many regions of the US, "is likely to
contribute to premature deaths," especially among people with
chronic lung or heart disease or other risk factors, concludes an
analysis [1] by the National Research Council (NRC) of the National
Academies, a private agency that advises the US government.

The report, compiled by a 13-member panel of experts, "recommends
that ozone-related mortality be included in future estimates of the
health benefits of reducing ozone exposure." Although it
acknowledges that much is unknown about the health impact of current
ozone regulatory standards, the report concludes that reductions in
environmental ozone are likely to save lives.

"The health-benefits estimates should be accompanied by a broad
array of analyses of uncertainty but should give little or no weight
to the assumption that there is no causal association between
estimated reductions in premature mortality and reduced ozone
exposure," notes the 165-page report, which was released yesterday.

The NRC expert panel surveyed the existing evidence base regarding
the effects of ozone on human health and identified numerous
knowledge gaps for future research. The study had been commissioned
by the Environmental Protection Agency (EPA) to look at the health
and economic impact of how it regulates levels of ozone as an air
pollutant. The EPA is an arm of the executive branch and therefore
answers to the US president.

Some news reports are framing the NRC conclusions as a reproach of
Bush administration environmental policies. "The findings contradict
arguments made by some White House officials that the connection
between smog and premature death has not been shown sufficiently and
that the number of saved lives should not be calculated in
determining clean-air benefits," according to a story today from the
Associated Press (AP) that circulated widely in the country's
newspapers [2].

"The report is a rebuke of the Bush administration, which has
consistently tried to downplay the connection between smog and
premature death," goes a quote in the AP story from "Frank
O'Donnell, president of Clean Air Watch, a Washington-based advocacy
organization."

Also, according to the story, "Vickie Patton, deputy general counsel
for the Environmental Defense Fund, said the academy's
findings 'refute the White House skepticism and denial' of a proven
link between acute ozone exposure and premature deaths."

The NRC report further concludes that "the effect of acute ozone
exposure on mortality is likely to be larger than average in persons
with preexisting disease, especially lung and heart diseases," but
cautions that the increased risk isn't necessarily confined to the
sickest and recommends that future studies look at how much of ozone-
related mortality occurs in people who aren't at such high risk.

Committee on Estimating Mortality Risk Reduction Benefits from
Decreasing Tropospheric Ozone Exposure, National Research Council.
Estimating mortality risk reduction and economic benefits from
controlling ozone air pollution. Available at:
http://www.nap.edu/catalog/12198.html.
Hebert HJ. Panel says link between smog and premature death is
clear. Associated Press, April 23, 2008. Available at:
http://customwire.ap.org/dynamic/stories/S/SMOG_DEATH?
SITE=NYONI&SECTION=HOME&TEMPLATE=DEFAULT&CTIME=2008-04-22-11-57-30.

The regular consumption of a heart-healthy chocolate bar (CocoaVia,
Mars Inc) can lower total- and LDL-cholesterol levels as well as
reduce systolic blood pressure, a new study has shown [1]. The
benefits of eating the chocolate, a dark chocolate product
supplemented with plant sterols, occurred without any weight gain,
suggesting the cocoa-flavanols-rich treat might be helpful in the
dietary management of cardiovascular risk, say investigators.

The study is published in the April 2008 issue of the Journal of
Nutrition.

Senior investigator Dr John Erdman (University of Illinois, Urbana-
Champaign) told heartwire that the specialized chocolate bars, which
are supplemented with plant sterols in addition to the naturally
occurring cocoa flavanols, are likely to be consumed by individuals
looking to make healthier choices. The product is now available in
US stores, including Walgreen's and CVS Pharmacy, usually in the
same aisle as but separate from regular chocolate candy.

"There are two components of the chocolate bar; the first is that it
contains plant sterol esters, which have been added, which have been
demonstrated to reduce serum cholesterol," said Erdman. "The second
aspect is the cocoa flavanols, which are not added but are present
in cocoa and the cocoa bean and preserved in the chocolate bar. The
flavanols are what have received the most interest in terms of
vascular effects."

Previous studies have shown that the consumption of cocoa-flavanols-
containing foods can improve endothelial function, platelet
reactivity, and insulin sensitivity and reduce blood pressure, he
said. The purpose of this study was to test whether vascular
protection with the addition of plant sterols would be observed in a
slightly hypercholesterolemic patient population (baseline total
cholesterol levels ranged from 202 mg/dL to 284 mg/dL) who regularly
ate the chocolate product.

In total, 49 adults followed the American Heart
Association's "Eating Plan for Healthy Americans" diet for two weeks
prior to randomization. After the two-week run-in period, the
subjects were randomized to two groups, with one eating two of the
dark chocolate bars daily, and the other eating two nutrient-matched
dark chocolate bars that did not contain plant sterols. Participants
consumed the chocolate bar for four weeks and then were switched to
the other for an additional four weeks.

Regularly eating the plant-sterol-containing chocolate bar reduced
total cholesterol 2.0% and LDL cholesterol 5.3%, both significantly.
This reduction was on top of the 7% reduction in total cholesterol
that occurred during the two-week dietary run-in phase. Consumption
of the chocolate product also reduced systolic blood pressure 5.8 mm
Hg at eight weeks.

Speaking with heartwire, Erdman said the extent of the reduction in
blood pressure was surprising, and the reduction is likely
attributed to cocoa flavanols increasing the synthesis of nitric
oxide. The Kuna Indians, he noted, an indigenous population in
Panama, consume a large amount of cocoa rich in flavanols, and
despite a diet that also has a large amount of salt, have a very low
prevalence of hypertension and cardiovascular disease mortality.

Erdman said that because Mars funded the study, which he said
wouldn't have been done if the company hadn't, there are some who
will be quick to dismiss the results. Sponsorship from the food
industry, he said, is looked upon more disparagingly by some in the
scientific community than sponsorship from drug companies, something
he doesn't exactly understand. "We've run cholesterol studies in the
past, and I can tell you we ran this study just like we ran any
other trial," he said.

The CocoaVia chocolate bar contains about 100 calories and 6 g of
total fat. While investigators tested the chocolate bar, there are a
host of other CocoaVia products on the market, including snack bars
and chocolate-covered almonds.

Mars Inc sponsored the study. Erdman is a consultant and chairs the
Mars Scientific Advisory Council. Mars also employs Dr Catherine
Kwik-Uribe, one of the authors of the paper.

Allen RR, Carson L, Kwik-Uribe C, et al. Daily consumption of a dark
chocolate containing flavanols and added sterol esters affects
cardiovascular risk factors in a normotensive population with
elevated cholesterol. J Nutr 2008; 138:725-731. Abstract

Administration of octreotide increases serum glucose levels in
patients with sulfonylurea-induced hypoglycemia, according to a
report in the April Annals of Emergency Medicine.

"Patients with sulfonylurea-induced hypoglycemia are at high risk
for persistent hypoglycemia," Dr. Charles J. Fasano from Albert
Einstein Medical Center, Philadelphia, told Reuters
Health. "Octreotide is an effective treatment in this clinical
scenario."

Dr. Fasano and associates investigated whether administration of
octreotide acetate in addition to standard therapy increased serum
glucose levels measured at serial intervals in 40 patients
presenting to the emergency department with sulfonylurea-induced
hypoglycemia.

Patients given octreotide had consistently higher glucose values
than did patients given placebo during the first 8 hours, the
authors report, but there were no differences between the groups in
subsequent hours.

Ten of the 22 (45%) octreotide-treated patients had solitary
hypoglycemic events, the report indicates. Five of these events were
at the first hourly serum glucose measurement.

In contrast, 6 of 18 (33%) placebo-treated patients experienced 13
hypoglycemic events, including 3 patients who had 2 to 4
hypoglycemic events.

No adverse events were reported at 24 and 72 hours, the researchers
note.

"Our results suggest that it would be prudent to admit all patients
with sulfonylurea-induced hypoglycemia to the hospital for frequent
blood glucose determinations," the investigators say. "We found that
although patients who received a single dose of octreotide were less
likely to experience multiple subsequent hypoglycemic episodes
compared with placebo, such patients are still at risk of further
solitary hypoglycemic events."

"This is one of only a handful of prospective, double-blind antidote
studies in emergency department patients," Dr. Fasano said. "Future
studies may perhaps delineate the ideal dosing regimen and role of
quantitative serum markers."

"We are currently enrolling patients in a similar follow-up study
utilizing octreotide at time zero and 6 hours with quantitative drug
levels and c-peptide and insulin levels," Dr. Fasano added.

"We and most toxicology experts recommend the administration
octreotide for sulfonylurea-induced hypoglycemia," Dr. Fasano
concluded.

Ann Emerg Med 2008;51:400-406.

Around 40% of blacks carry a genetic variant that appears to act
like a natural beta blocker and seems to protect them after heart
failure, prolonging their lives, new research has shown [1]. The
findings may help explain why beta blockers don't appear to benefit
some African Americans, say Dr Stephen B Liggett (University of
Maryland, Baltimore) and colleagues in a study published online
April 20, 2008 in Nature Medicine.

While white patients with heart failure participating in clinical
studies of beta blockers have shown clear benefit from the drugs,
the effects of beta blockers in African Americans have been
ambiguous. Second author Dr Sharon Cresci (Washington University, St
Louis, MO) told heartwire: "I think this is so exciting. I believe
this gene has significantly contributed to the discrepancies that
have been found in such studies. If researchers were able to go back
and genotype patients from their studies, it would probably help
clarify some of their findings."

But she and her coworkers stress that it is too early, on the basis
of just this one study, to advocate not prescribing beta blockers to
blacks who carry the genetic variant. "The research is a step toward
individualized therapy tailored to personal genetic makeup," she
says. "I think we are working toward genotyping patients for many
genetic variants and I believe we are on the threshold of that, but
we are not there yet. We need a prospective study."

Variant prolongs life to same degree as beta blockers

The researchers explain in their paper that the heart has two forms
of G-protein-coupled receptor kinase (GRK): GRK2 and GRK5. They
sequenced the DNA of 96 people of European American, African
American, or Chinese descent to look for differences and found that
most people, no matter their race, had exactly the same gene
sequence encoding GRK2 or GRK5.

But there was one common variation, called GRK5-Leu41, in which
leucine is substituted for glutamine at position 41 in GRK5--and 41%
of African Americans carried at least one allele of this variant.

To determine the effect of the GRK5-Leu41 variant, the team then
studied the course of progression of heart failure in 375 African
American patients. They looked at survival time or time to heart
transplant, comparing people with the variant and those without.
Some of these patients were taking beta blockers and some were not.

In patients not taking beta blockers, those with the variant lived
almost twice as long as those with the more common version of the
GRK5 gene. In those taking beta blockers, the drugs prolonged life
to the same degree as the protective GRK5 variant but did not
further increase the already improved survival of those with the
variant.

"These results offer an explanation for the confusion that has
occurred in this area since clinical trials of beta blockers began,"
senior author Dr Gerald W Dorn (Washington University) said in a
press release from the university [2].

"By mimicking the effect of beta blockers, the genetic variant makes
it appear as if beta blockers aren't effective in these patients,"
he explains. "But although beta blockers have no additional benefit
in heart-failure patients with the variant, they are equally
effective in white and African American patients without the
variant."

Too soon to withhold beta blockers

"Our study demonstrates a mechanism that should lay to rest the
question about whether beta blockers are effective in African
Americans--they absolutely are in those who don't have this genetic
variant," Dorn adds.

Cresci said the feeling among the group was that it is too soon to
advocate testing blacks with heart failure for this specific genetic
variant to decide whether or not they should take beta
blockers. "Beta blockers are very safe, and they have a variety of
effects that we don't completely understand. We're not able to say
you can take patients off beta blockers based on one or two
polymorphisms. That seems a little risky at this point."

However, she said that the team is conducting more investigation in
this area, and she could not rule out that it might be possible to
tailor therapy to individuals using this variant in the future.

"This is a very significant step toward individualized therapy.
Medical research is working to identify many genetic variants that
someday can ensure that patients receive the medications that are
most appropriate for them. Right now, we know one variant that
influences beta-blocker efficacy, and we are continuing our research
into this and other relevant genetic variants."

She adds that GRK5 is also a potential therapeutic target in
patients with heart failure.

Liggett SB, Cresci S, Kelly RJ, et al. A GRK polymorphism that
inhibits beta-adrenergic receptor signaling is protective in heart
failure. Nat Med 2008; DOI: 10.1038/nm1750. Available at:
http://www.nature.com. Abstract
Ericson G. Many African-Americans have a gene that prolongs life
after heart failure [press release]. April 20, 2008. Available at:
http://mednews.wustl.edu/news/page/normal/11578.html?emailID=19141.

High serum total cholesterol levels in midlife increase the risk of
developing Alzheimer's disease 3 decades later, new research shows.

Alzheimer's disease was 1.5 times more prevalent in men and women
who had total cholesterol levels of 249 to 500 mg/dL when they were
middle-aged than in people with normal cholesterol levels, according
to a retrospective study that involved 9752 members of a Kaiser
Permanente health plan in northern California.

The study results send a message to physicians, study coauthor Alina
Solomon, MD, from the University of Kuopio, in Finland, who
collaborated with researchers at Kaiser Permanente, told Medscape
Neurology & Neurosurgery: "Minding heart health may protect the
brain."

Dr. Solomon presented the results here at the American Academy of
Neurology (AAN) 60th Annual Meeting.

Heart Health

In this multiethnic cohort, the patients were 40 to 45 years old
when they had health evaluations between 1964 and 1973. They stayed
with the health plan through at least 1994, so that the researchers
were able to check their most recent medical records, from 1994 to
2007, for a documented diagnosis of Alzheimer's disease.

On retrospective chart review, the authors found that 504 patients
had Alzheimer's disease, with a mean age at diagnosis of 68.8 years.
High cholesterol increased Alzheimer's risk regardless of midlife
diabetes, hypertension, and obesity; smoking; and late-life stroke,
according to Dr. Solomon.

They found that subjects in the highest quartile for cholesterol
level in their 40s had an increased risk for AD compared with those
in the lowest quartile.

Even less severely elevated cholesterol was associated with an
increased risk for dementia, said Dr Solomon. Patients whose total
cholesterol levels were between 221 and 248 mg/dL were still more
likely to have a diagnosis of Alzheimer's disease later in life
compared with patients with cholesterol levels below 198 mg/dL.

Possibly, the study underestimated the risk of Alzheimer's disease,
Dr. Solomon said in an interview with Medscape Neurology &
Neurosurgery. Some patients may have had the disease, but it was not
yet diagnosed at the most recent visit, she theorized. In addition,
she said, some patients may have received lipid-lowering medications
when they became available, but the authors did not have this
information.

Because the data from the 1960s and early 1970s did not have
information on triglycerides and low-density-lipoprotein (LDL)
cholesterol, the authors were unable to analyze whether these
measures had an effect on Alzheimer's risk.

The researchers did observe a trend toward an increased risk for
vascular dementia in this patient population, but the difference was
not statistically significant, according to the abstract.

Based on their study findings, Dr. Solomon advised physicians not to
delay in treating patients in their 40s who have high cholesterol
levels. She said she would prescribe dietary and other lifestyle
modifications first and, if necessary, medication. However, it is
not yet clear whether statins will protect against the development
of Alzheimer's disease, she stated.

A "Hot Topic"

A study published online January 16 in Neurology found that statin
use did not lower the risk of Alzheimer's disease.

That study's principal author, Zoe Arvanitakis, MD, associate
professor in the department of neurological sciences at Rush
University Medical Center, in Chicago, Illinois, spoke to Medscape
Neurology & Neurosurgery after viewing Dr. Solomon's poster at the
AAN meeting. Their study had important differences from the new
study in that it looked at patients in their late 70s, she said, and
their follow-up was only for up to 13 years.

"It may be that you need to take statins a lot longer to benefit,"
said Dr. Arvanitakis, who had no relationship with Dr. Solomon's
research. "This is a hot topic and an ongoing story."

A new study shows that the radiation emitted by cardiac computed
tomography angiography (CCTA) varies widely, depending on a number
of variables, and that education of CT personnel is required to help
minimize radiation. Dr Jorg Hausleiter (German Heart Centre, Munich,
Germany) reported the findings of the Prospective Multicentre Study
on Radiation Dose Estimates of Cardiac CT Angiography in Daily
Practice (PROTECTION 1) during a late-breaking abstracts session at
the recent American College of Cardiology 57th Annual Scientific
Session.

"For the first time, we have demonstrated that radiation varies
significantly--both by site and by the machine employed. There is
great potential to reduce the dose," Hausleiter told
heartwire. "There are already strategies to reduce the dose, but
these are used very rarely in daily practice, and we need better
education of CT personnel, such as radiologists and cardiologists.
Also, they need to understand that there is no standard, one-size-
fits-all approach--they need to adjust the procedure to the
individual."

However Hausleiter stressed to heartwire that the benefits of CCTA
are still great in terms of the impact that the information obtained
may have on the diagnosis and treatment of cardiac disease. "And
most of the patients we are scanning are 60 years old, and it will
take 10 to 20 years before any cancer might develop from radiation,
so the risk is minimal to them. But obviously, the lower the dose,
the better," although he added this is of most importance in a
younger patient.

Radiation doses "all over the place"

As background, Hausleiter explained that use of CCTA is increasing,
and it is now used widely to rule out coronary artery disease, "but
the downside is that there is radiation associated with the
procedure. However, a lot of people--both physicians and patients--
are not aware of the dose of radiation emitted."

In the study, which was observational and industry-independent, the
researchers examined 50 sites worldwide and analyzed 1965 CT
angiographies performed during one month. The majority (94%) of
machines were 64-slice; the remainder 16-slice. Most were a single-
source configuration, with just one being dual source. They
determined the magnitude of CCTA radiation dose estimates and the
use and efficacy of radiation dose-saving algorithms.

Unexpectedly, the radiation dose estimates differed significantly
between the study sites, ranging from 5.7 mSv to 36.5 mSv, with a
median of 15.4 mSv. "We were very surprised by this. The doses were
all over the place at different sites. Some were 10 mSv and below,
while others were 25 or 30 mSv or higher," Hausleiter said.

Use of dose-saving strategies erratic

Next, they examined a number of dose-saving algorithms. First, they
looked at automatic exposure control, which Hausleiter explains
adjusts the tube current to the anatomy of the patient. They found
that this did not reduce the dose of radiation, something Hausleiter
said he was not surprised by, "because I've done previous work on
this that has shown it does not reduce radiation dose in cardiac
studies."

Second, they looked at so-called "ECG pulsing," whereby radiation is
used at 100% only during diastole and then reduced to 20% to 25% for
the remaining phases of cardiac contraction. Almost 80% of centers
did use this method, and this reduced radiation by 20%, he noted.

Third, the "100-kV" strategy, whereby the tube voltage can be
reduced from 120 kV to 100 kV in nonobese patients, "is actually
very effective, reducing the radiation dose by 50%," Hausleiter
said. But unfortunately, this was used in only 6% of the population
who were scanned. "There were only a few centers aware of it; the
majority were not using it," he noted. He added that only three of
the four manufacturers whose machines were studied actually have
this capability, with Philips being the one that doesn't. They also
studied image quality at 100 kV and found that it was as good as the
image seen at 120 kV.

Finally, they evaluated the sequential scan-dosing algorithm, also
known as "step-and-shoot." Hausleiter explained that this is "an old
methodology that is being reintroduced, and you can get dose
reductions of about 68% compared with conventional spiral imaging."
With spiral imaging, the table is moving all the time at the same
speed while the radiation tube rotates around the body, he noted,
but with the sequential method, the table stops at one position to
acquire images rather than being in continuous motion, so that
radiation is administered only in predefined snapshots during the
cardiac cycle, rather than during the whole cycle.

"We found it reduced the dose very effectively, and the image
quality was as good as in spiral data sets in this observational
study," he noted. But again, this strategy was employed in only 6%
of the population scanned. However Hausleiter points out that "most
of the scanners don't have 'step-and-shoot' capability. It is just
beginning to be installed or upgraded in machines, so it's not
surprising it's been used so rarely."

Other factors play a role, including, surprisingly, the make of
machine

Hausleiter explained that his team then performed a linear
regression analysis to look at individual predictors of radiation
dose and found some other surprises. The length of the scanned
arteries plays a big role, they discovered. "If you look carefully
and try to minimize the scan length rather than scanning the entire
thorax, you can reduce the radiation dose." Also, the length of time
that a center had been performing CCTA had some effect on radiation
dose, too--"it was a tiny effect, but it was significant," he noted.

"But most surprising of all was the tremendous impact of the
different CT systems: four vendors producing five 64-slice systems,"
he noted. After correcting for all other variables in a multivariate
adjustment, they found that some systems have a significantly higher
radiation dose than the others. The Siemens single-source 64 was the
best, emitting the lowest doses of radiation, followed by the
Phillips 64 and the Siemens dual-source 64. The worst two studied
were the Toshiba 64 and the GE 64.

But Hausleiter declined to say which system he would recommend
buying; rather, he commented: "You need to be aware of the
capabilities of the machine and keep looking at the updated systems,
as all the manufacturers have something in the pipeline. This is a
field that is rapidly evolving, and there are always additional
possibilities to reduce the radiation dose."

In conclusion, he noted: "This study will increase the awareness of
the radiation exposure of cardiac CTs. In addition, we think this
study will result in an increased use of already available dose-
saving algorithms, which will substantially lower the radiation
exposure of patients. Finally, it strengthens the need for further
education of cardiologists and radiologists about CT technology to
ensure low radiation exposure to the patient."

The new wave of left-ventricular assist devices (LVADs), none yet
approved for sale in the US but some available in Europe, go for
small size and greater durability to make them more patient-friendly
and, potentially, cut the need for replacement due to wear and tear,
compared with the pulsatile-pump first-generation devices.

Some of these advanced, magnet-driven LVADs were able to sustain
>80% of transplant-listed patients for at least six months or until
transplantation if it occurred earlier, in several small
observational studies presented here last week at the International
Society for Heart and Lung Transplantation [ISHLT] 2008 Annual
Meeting [1,2,3]. And, although the reported studies involved
handfuls of patients, the risk of complications--especially the most
daunting ones in LVAD therapy (stroke, infections, and bleeding)--
appeared low with all the devices.

What makes these so-called "third-generation" LVADs different from
the long-available pulsatile HeartMate XVE (Thoratec) and Novacor
LVAS (WorldHeart) pumps is a continuous-flow propulsion system
driven by electromagnets that spin an impeller--the rotor that
actually moves the blood--that is levitated in position so that it
doesn't actually touch the pump housing. With their impellers
levitated by more magnets or the dynamic forces of the blood itself,
these pumps have only the one moving part and little of the wear and
tear that ages the mechanical pulsatile pumps.

In various stages of development, these new devices include:

Centrifugal pumps with magnetically powered, hydrodynamically
levitated impellers, such as the VentrAssist (Ventracor) and the
HeartWare HVAD (HeartWare).

"Maglev" pumps, with magnetically powered, magnetically levitated
impellers, such as the DuraHeart LVAS (Terumo Heart) centrifugal
pump, the Levacor VAD (WorldHeart) centrifugal pump, and the Incor
(Berlin Heart) axial-flow pump.
Dr Andrew J Boyle (University of Minnesota, Minneapolis), who
presented the VentrAssist study at the ISHLT meeting, would also
include in the mix mechanically driven axial-flow LVADs like the
HeartMate 2 (Thoratec), which have been dubbed "second generation."
That device, available in Europe for about three years, was given a
unanimous vote of confidence by an FDA premarket advisory panel in
December, 2007, heartwire reported at the time, and appears headed
for approval. The HeartMate 2, about the same size as the
VentrAssist, is probably as much of a clinical advance over
pulsatile pumps as are the new magnetically driven devices, Boyle,
who has participated in trials of both pumps, told heartwire.

Boyle says he avoids terms like "second generation" for the
HeartMate 2 and the "third-generation" label commonly given to the
magnetically driven devices. "That's just a marketing ploy. The
reality is that all of them, other than the [HeartMate] XVE and the
Novacor [LVAS], are the new generation," he said. "Whether they are
called second or third generation, I think that's all baloney." They
use different engineering approaches to address the same problems,
he said, "but I think where the rubber meets the road, which is in
outcomes, there will be similar results."

And, Boyle said, the new-generation devices will probably all have
the same longevity. "I don't think wear and tear within the pump is
going to be an issue for any of them." But whether greater
durability manifests clinically has yet to be shown--that's hard to
do in bridge-therapy studies, in which the time to transplantation
is often less than the lifetime of even the first-generation LVADs.

The HeartMate XVE, currently the gold standard and approved for both
bridge and destination therapy in the US, has a lifetime of about 15
to 18 months, Boyle said. "Then you have to replace the whole pump,
usually because of bearing wear."

But, "with more and more people getting LVADs, there are more people
at the top of transplant lists, so waiting times are lengthening,"
Boyle observed. It's increasingly possible that in some areas of the
country "the waiting time for a donor to be found for a particular
patient will exceed the durability of the XVE." The new-generation
LVADs, he said, are expected to last five to 10 years. That's based
on bench testing, since destination-therapy studies have yet to be
done; Boyle has had patients live with one for up to 2.5 years, "and
there are longer times at other centers."

In the prospective experience he reported at the ISHLT meeting, 28
patients awaiting a donor heart were implanted with the VentrAssist
at four US centers. Of those, 23, or 82%, met the primary end point
of survival to transplant or on circulatory support for at least 180
days. All were in NYHA functional class 4 at the start. At 14 weeks,
>90% were in either class 1 or 2, with none in class 4. At 180 days,
>78% were still in class 1 or 2, while those in class 3 had grown to
22%; but again, none were in class 4.

The 38-point mean improvement in quality-of-life score (based on the
Minnesota Living with Heart Failure Questionnaire)
was "statistically and clinically significant," Boyle said.

The overwhelming majority of serious adverse events occurred within
the first 30 days after device implantation; adverse-event rates
were comparable to what has been observed with other LVADs,
according to Boyle.

Similar complication rates were reported at the meeting for the
magnetically driven, hydrodynamically levitated HeartWare HVAD. In a
23-patient series presented by Dr Georg Wieselthaler (Vienna General
Hospital, Austria), 9% had strokes (all ischemic), 4% had transient
ischemic attacks, 13% developed bleeding requiring reoperation, and
13% had infections at the percutaneous entry site over six months.

Survival at 180 days with the HeartWare device was 91%; 9% had been
transplanted by that point. Both of the deaths were from sepsis. The
mean LVAD-support time was 272 days.

Reporting on the maglev DuraHeart pump at the ISHLT sessions, Terumo
Heart CEO Dr Chisato Nojiri said that the adverse-event rates in his
33-patient series were about 0.22 per patient year for bleeding
requiring surgery, 0.40 per patient year for infections at the
percutaneous site or device pocket, and 0.28 per patient year for
any stroke. There were no instances of device-related thrombosis.

With the addition of 22 patients implanted with the device after
European market approval based on the first 33 patients, the 180-day
rate of survival for the DuraHeart was 82% (mean support time, 214
days). About one-fourth of the patients had been on the device for
at least a year; among those, the mean duration of support was 568
days, according to Nojiri.

An FDA-approved bridge-to-transplant trial with a target enrollment
of 140 patients is in the works for the DuraHeart pump, the company
recently announced. At least 32 patients have been enrolled in the
HeartWare device's corresponding trial, according to Wieselthaler.
And, observed Boyle, a similar pivotal trial for the VentrAssist
pump has entered 48 of a projected 140 patients for the bridge
cohort and 20 out of an as-yet undetermined total number of
destination-therapy patients.

Boyle reports being on the VentrAssist scientific advisory board;
his coauthor Dr John Woodard is chief science officer for Ventracor,
and coauthor Dr Yoshifumi Naka (Columbia University Medical Center,
New York, NY) reports being a consultant to Ventracor, Terumo Heart,
Thoratec, and Cardiomems.

Boyle AJ. The VentrAssist LVAD as a bridge to cardiac
transplantation: Results of the US Feasibility Trial. International
Society for Heart and Lung Transplantation 2008 Annual Meeting;
April 12, 2008; Boston, MA. Abstract 518.
Wieselthaler GM. Experience with the novel Heartware HVAD with
hydromagnetically levitated rotor in a multi-institutional trial.
International Society for Heart and Lung Transplantation 2008 Annual
Meeting; April 12, 2008; Boston, MA. Abstract 515.
Nojiri C. Long-term circulatory support with the DuraHeart maglev
centrifugal left ventricular assist system for advanced heart
failure patients eligible to transplantation: European experiences.
International Society for Heart and Lung Transplantation 2008 Annual
Meeting; April 12, 2008; Boston, MA. Abstract 514.

The US Food and Drug Administration has market-approved regadenoson
(Lexiscan), a selective A2A adenosine-receptor agonist, for resting
stress-myocardial perfusion scans, the product's developer and owner
CV Therapeutics and marketer-distributor Astellas Pharma US have
jointly announced [1].

Lexiscan was approved based on two identical phase 3 trials [2] in
which the agent produced perfusion scans of similar quality to those
made using another Astellas product, adenosine injection
(Adenoscan), according to the announcement. Lexiscan is administered
as a non¡Vweight-adjusted rapid bolus, which, published reports
observe, is a less complicated regimen than what is required for
adenosine; it's also expected to have a more favorable side-effect
profile by virtue of its adenosine-receptor selectivity.

CV Therapeutics. CV Therapeutics and Astellas announce FDA approval
for Lexiscan (regadenoson) injection [press release]. April 10,
2008. Available at: http://www.cvt.com/PressRelease.aspx?
releaseID=1128317.
Iskandrian AE, Bateman TM, Belardinelli L, et al. ADVANCE MPI
Investigators. Adenosine versus regadenoson comparative evaluation
in myocardial perfusion imaging: Results of the ADVANCE phase 3
multicenter international trial. J Nucl Cardiol 2007; 14:645-658.
Abstract

Almost 16 months after an FDA hearing into drug-eluting stent (DES)
safety emphasized the need for a randomized clinical trial to
determine, once and for all, the optimal duration of clopidogrel
(Plavix, Sanofi-Aventis) plus aspirin after DES implantation,
researchers, government agencies, and industry sponsors cannot agree
on how it should move ahead.

The clinical trial proposed by Dr Mitchell Krucoff and colleagues at
the Duke Clinical Research Institute and dubbed Clopidogrel: Optimal
Duration of Antiplatelet Therapy (CODA) is currently in limbo while
the various parties try to agree on key aspects of trial design,
duration, and who should head up the study.

In an interview with heartwire, Krucoff explained that the CODA
trial, designed with a patient-oriented end point of death, MI, and
stroke vs bleeding, was developed within the larger private-public
partnership between the FDA and Duke University, dating back to a
2006 'memorandum of understanding' that created a collaborative
Cardiovascular Safety and Research Consortium, originally to
evaluate drug effects on cardiac repolarization. According to
Krucoff, apart from answering the public-health question of optimal
duration of clopidogrel therapy post-DES, CODA, as designed, will
also help fill a key gap in the "regulatory landscape": namely, how
to test drugs necessary for the safe use of drug-device combinations.

Companies not convinced by CODA

Despite the urgent nature of the question--with roughly 10 million
DES-treated patients worldwide and no clear answers as to how long
they should take clopidogrel and aspirin--CODA has stalled. Krucoff
and colleagues, on the FDA's advice, have filed an investigational
device exemption (IDE) for the trial, and they've held "think-tank
meetings" with the four major DES manufacturers as well as smaller
DES companies; thienopyridine developers Sanofi-Aventis/Bristol-
Myers Squibb and Eli Lilly (responsible for clopidogrel and the next-
generation thienopyridine, prasugrel, respectively); the National
Institutes of Health, and the FDA. Ideally, all of these parties
would be funding the CODA trial.

But the device companies have balked at the notion of coughing up
support for a trial with a patient-oriented end point that won't
specifically establish the safety of a DES or determine the ability
of dual antiplatelet therapy to reduce the risk of late stent
thrombosis and how long such therapy is warranted to mitigate this
risk. The CHARISMA study, for example, suggested that long-term dual
antiplatelet therapy in patients with vascular disease reduces
death, MI, and stroke, but that benefit may not be specific to DES.
Acting via their umbrella trade organization, Advamed, the companies
have met with the FDA to propose changes to the CODA trial design.

"We have not yet seen the Advamed proposal," Krucoff told
heartwire. "My understanding is that the Advamed proposal [seeks to]
change the primary end point from what the current CODA IDE
submission proposes. We tried to make CODA a big, simple, clinical
trial because there is nobody tumbling head over heels to fund this.
Our goal was to make this as logistically feasible and inexpensive
as possible and have it still provide some prospective insights, on
an expedited basis, as to what we should be doing with the 10
million people with DES in their hearts. Our understanding is that
the Advamed proposed trial would be a more complex, slightly larger
trial, with a more device-specific rather than patient-oriented end
point."

Advamed and its member companies are pushing for a primary end point
of late stent thrombosis, as defined by the Academic Research
Consortium, which would require a larger trial and more funding.
Given the uncertainty over just how long the stent-thrombosis risk
endures, trial follow-up would likely also need to be extended.
Sources also tell heartwire that the DES manufacturers are also
calling for a bare-metal-stent arm, since the risk of late stent
thrombosis following bare-metal-stent implantation is also unknown.

"Such a trial would, indeed, be feasible if the device industry is
willing to put up additional funds," Krucoff said. "Our hope is that
these will not go forward as separate efforts but as a collaborative
effort with both the short-term issue of what to do with the
millions of patients with DES and also the longer-term issue of
helping us try to rearrange the regulatory landscape so that it is
more accommodating and defined for this drug-device interaction."

Heading up the trial

A separate issue is whether Duke would still head up the trial if
the CODA trial design is rejiggered. Krucoff believes that, given
the FDA-Duke collaboration already in place, Duke should have a key
role to play. Others have told heartwire that the sponsors are
asking the FDA to reopen the decision as to which research group
would lead the trial and permit other academic research centers to
bid.

"There's all kinds of levels of politics here, everything from ego,
to money, to whatever," Krucoff admitted. "As in any hot-topic area,
there may be some competition as to who runs the trial. That for me,
frankly, is a secondary issue. The important thing is for us to get
as immediate an answer as possible for patients and also help evolve
the landscape for evaluating these issues long term."

Asked if the CODA trial would still go ahead if the FDA agrees to a
new, Advamed-supported trial, headed by a different group, Krucoff
hedged.

"There are a lot of hypotheticals," he said. "If our trial were
totally redundant, and they had all the money and we had none, would
we go ahead? No. But what we're most enthusiastic about right now is
that these efforts are progressing. They are trying to achieve the
same definition and information, and our hope is that this will come
forward as a single, collaborative effort. . . . The details,
frankly, of who does what with regard to the trial itself I'm sure
are going to be subject to all of the usual issues that make people
decide to do a trial at this center or that center, or with this PI
or that PI, with this research organization or that research
organization. So nothing is written in stone."

MATRIX registry results

Results from the MATRIX registry study, presented at last week's
American College of Cardiology 57th Annual Scientific Session/i2
Summit-SCAI Annual Meeting, reinforced the need for a randomized
controlled trial to settle the DES-safety/clopidogrel-duration
issue. According to Dr George Dangas (Columbia University, New York,
NY), who presented the landmark analysis, patients treated with drug-
eluting stents who are no longer on clopidogrel after one year are
more likely to die than patients still taking the drug. But that
signal of increased risk is muddied somewhat by a lack of
information on patients who stopped and restarted the drug over the
study period, investigators for the study noted.

Among the 1510 patients treated with a sirolimus-eluting stent in
MATRIX, a low but measurable rate of clopidogrel discontinuation
over time was associated with higher all-cause mortality. At two
years, patients off clopidogrel had a statistically significant,
threefold higher increase in all-cause mortality and a twofold,
statistically significant increase in death/MI.

But the devil is in the details: patients still on clopidogrel at
one year were also more likely to have a target lesion
revascularization or target vessel revascularization--a chicken-and-
egg scenario that suggests some patients were taking clopidogrel at
one year or beyond because they had undergone repeat procedures.
Indeed, more than one-third of patients who were off clopidogrel at
30 days were back on it at six months and at one year; almost half
of the patients who were off clopidogrel at six months were back on
it at one year; while 44% of patients who were off at six months
were back on it at two years. Even more striking, one out of 10
patients who were off clopidogrel at one year were back on it at two
years. The numbers likely speak to patient-level finances, disease
progression, and comorbidities, as well as uncertainty among
physicians as to whether one year of dual antiplatelet therapy is
sufficient or whether a lifetime on both aspirin and a
thienopyridine may be the safest bet for avoiding stent thrombosis
post-DES. To confuse matters further, stent thrombosis after one
year occurred in 0.3% of patients still taking clopidogrel at 12
months, but in no patients not taking it at this cutoff.

Discussing the results after Dangas's presentation, Dr Bill Knopf
(Piedmont Hospital, Atlanta, GA) urged the audience to take the
findings with a grain of salt, since follow-up to date on the 1510
patients is incomplete: just 88% at one year and 70% at two years.
He called the lack of difference in late subacute stent-thrombosis
rates based on 12-month clopidogrel coupled with the higher rate of
death and MI "a bit of a disconnect" and said that the zigzagging of
patients on and off clopidogrel and the effect of this
pattern "needs to be sorted out."

"There is a higher death/MI rate with discontinuation of Plavix at
one year, leaving open the question of what is the optimal dosing of
Plavix and what is the mechanism for this death/MI-rate increase."
Knopf concluded. "At the end of the day, with a registry study, it
opens a lot of questions that don't all get answered, and that leads
us to larger randomized trials to determine what might be the
optimal strategy."

Also commenting on the MATRIX results, Dr Gregg Stone (Columbia
University), a coinvestigator for the MATRIX registry, emphasized
the difficulties of using a landmark analysis to address whether the
benefits of long-term clopidogrel outweigh bleeding risks in a group
of patients who go on and off the drug. In MATRIX, for example,
there was a trend toward being off clopidogrel being associated with
both cardiac and noncardiac deaths, suggesting that those patients
may just be sicker, Stone noted.

"Registries such as this, like the Duke/Eisenstein registry, suggest
that long-term Plavix may be beneficial and may be associated with
reduced mortality; however, given the potential for unmeasured
confounders to cloud the result, a large-scale randomized clinical
trial is clearly warranted if we're going to know the answer to this
very important question."

A St Louis cardiologist is calling upon the US FDA to reconsider a
black-box warning it placed on ultrasound contrast agents at the end
of last year, following a new study she coordinated that shows that
the benefits of such agents outweigh the risks. Dr Melda Dolan
(Saint Louis University School of Medicine, St Louis, MO) presented
her data during a late-breaking clinical-trials session at the
American College of Cardiology 57th Annual Scientific Session last
week.

"Based on the results of our study, we believe the FDA should
reconsider its stance on contrast agents, because the benefits
outweigh the potential, although not established, risk," said Dolan.
She maintains that the black-box warning, instituted in October
2007, was issued without a formal examination of the risks and
benefits of using the agents. "Our research indicates that contrast
agents can be safely used," she said. Furthermore, her study
suggests withholding their use in patients who require them could be
detrimental, "leading to a failure to detect life-threatening
cardiac events," she noted.

Dolan told heartwire that in the week since her presentation she has
not heard from the FDA. "There are of course some rumors, but I
don't want to predict what they will or won't do based on rumors."
She is in the process of preparing a manuscript of her study, which
will be combined with data from the Mayo Clinic, to include
information on the use of contrast agents in around 40 000 patients,
she says.

Use of contrast agents plummets since warning

Dolan explained that contrast agents were introduced during the late
1990s and are administered intravenously in about one in five
patients undergoing transthoracic echocardiography, including stress
echo, to obtain optimal images. Contrast agents greatly enhance the
quality of the images taken and the doctors' ability to assess
cardiac function, she noted.

But last October, following reports of a number of deaths and
serious adverse reactions shortly after or during infusion of
contrast agents, the FDA placed a black-box warning on such
products, and use of the agents plummeted.

As reported by heartwire, there have since been calls for the
warning labels to be removed, with experts arguing that the very
patients who are excluded from undergoing echocardiograms with these
contrast agents are precisely the ones in whom they are needed.

Benefits of contrast agents outweigh risks

Dolan and her colleagues compared short-term outcomes in almost 24
000 patients undergoing a resting transthoracic echo with a contrast
agent with those from approximately 6000 who did not need contrast
agents; they found no difference between the groups in deaths or
serious adverse events occurring within 30 minutes. At 24 hours,
there were three nonfatal MIs and one death in the contrast-agent
group, none of which could be attributed to contrast agents. This
compared with seven nonfatal MIs and one death in the 6000 patients
who did not get contrast agents.

They then looked at 4011 patients undergoing stress echo and
receiving contrast agents for suboptimal images and 1923 matched
patients with optimal image quality without contrast and compared
these with angiography for accuracy and sensitivity. Those who had
the contrast agents reached or exceeded the levels of sensitivity of
those who did not. Hence, the benefits of contrast use in patients
with suboptimal images are significant--they make suboptimal studies
equivalent to optimal studies and prevent additional costly tests--
and these benefits outweigh the possible risks, said Dolan.

Finally, the researchers assessed use of contrast agents in 6075
patients analyzed to determine the added benefit of myocardial-
perfusion imaging with respect to long-term follow-up. They found
that myocardial-perfusion assessment with contrast echo adds
significant prognostic value, with these analyses significantly
increasing the ability of stress echo to predict adverse events,
Dolan emphasized.

"The message that patients should take home from our study is that
there are risks to every treatment, from medications to surgery. But
when the benefits of a treatment or test greatly outweigh the risks,
it may be worthwhile to take a small risk for a great benefit," she
concluded.

Children from families with low socioeconomic status who undergo
heart transplantation have twice the risk for graft failure as
pediatric heart recipients from wealthier families, reported
investigators here at the International Society for Heart and Lung
Transplantation 28th Annual Meeting and Scientific Sessions.

Low socioeconomic position remained an independent risk factor for
graft failure in children even after controlling for multiple
clinical and demographic factors, said Tajinder P. Singh, MD, MBBS,
from the Department of Pediatric Cardiology at Children's Hospital
Boston, and an assistant professor of pediatrics at Harvard Medical
School.

"This is really the first time, in children, that this has been
looked at from a socioeconomic as opposed to a racial standpoint,"
said session moderator Robert J. Boucek, MD, chief of the Division
of Cardiology at Seattle Children's Hospital and Regional Medical
Center, in an interview with Medscape Transplantation.

"Several studies previously demonstrated that there is an
association between race, so that nonwhites ¡X specifically, black
patients ¡X have worse long-term survival," Dr. Singh said in an
interview. "[T]hey seem to have more rejections of the heart
transplant, and there is a lot of emphasis on genetic and
immunologic studies to differentiate different races and how their
biology is different."

Dr. Singh continued, "Based on some clinical observations, I
wondered whether somebody had systematically looked at the
socioeconomic data in these people. The problem is we in medical
records do not record what the patient or family income is, what the
parents education is, what occupation they're in ¡X maybe
occupation, but it's not systematically and consistently written
down."

Zip codes, which some investigators use to identify patient
demographic, social, and financial characteristics, cast too wide a
net and may skew averages too heavily in one direction or another,
Dr. Singh said. To get around this problem, he and his colleagues
used block groups ¡X the smallest units available in US census
databases that also contain socioeconomic data.

"All data on block groups are reported every 10 years by the US
census bureau; it's meant to be permanent, and it's meant to be
relatively homogeneous with regards to people's socioeconomic
status ¡X it's literally your neighborhood," he said.

The investigators looked at US census data from 2000, extracting
data on 6 variables of wealth, income, education, and occupation for
each transplant recipient. They then calculated a summed
socioeconomic z-score for 126 heart transplant recipients who
survived to discharge at Children's Hospital Boston from 1990 to
2005.

They also created multivariate Cox proportional hazards models to
determine the risk of graft failure, defined as time to death or to
retransplantation, for the children in the lowest tertile of
socioeconomic status compared with those in the middle and upper
tertiles, who served as control patients.

The patients ranged in age from 6 days to 23 years (median, 8.9
years) at the time of transplant. The distribution of age, sex,
diagnosis, and treatment year was similar among the groups. Whites
accounted for significantly fewer children on the lowest rung of the
socioeconomic ladder, at 67% vs 90% of control patients (P < .01).

In all, there were 37 graft failures. The authors found in a
univariate analysis that being in the low-socioeconomic group was
associated with a more than 2-fold risk for failure (hazard ratio
[HR], 2.3; 95% confidence interval [CI],1.2 ¡V 4.4), and being a
member of a nonwhite race was associated with a nearly 3-fold
increase in risk (HR, 2.9; 95% CI,1.4 ¡V 5.9).

In multivariate models controlling for patient age, diagnosis (eg,
congenital heart disease vs dilated cardiomyopathy), transplantation
era, and race, the effect of race on graft failure was slightly
attenuated but still significant (HR, 2.5; 95% CI,1.2 ¡V 5.4), and
the effect of low socioeconomic position remained relatively
unchanged (HR, 2.1; 95% CI, 1.0 ¡V 4.3; P = .04).

All of the children in the study, both rich and poor, were insured,
Dr. Boucek noted, suggesting that "it's not an issue of access, but
it may be care before leading to transplant that accounts for the
differences."

The Children's Hospital Boston researchers will be expanding the
study to look at a larger population, with centers in New York City,
Atlanta, and Loma Linda, California, and to look at data on both
children and adults transplanted in Boston hospitals over the last
decade.

Dr. Singh and Dr. Boucek have disclosed no relevant financial
relationships.

International Society for Heart and Lung Transplantation 28th Annual
Meeting and Scientific Sessions: Abstract 192. Presented April 10,
2008.

J Heart Lung Transplant. 2008;27(2 suppl):S129.

The American College of Cardiology (ACC) and WebMD announced this
week their joint initiative to help educate both clinicians and
patients about cardiovascular risk reduction. The collaborative
effort, known as "Cardiovascular Risk Reduction: Putting Guidelines
Into Practice to Improve Outcomes," will target the educational
needs of healthcare professionals, including cardiologists, primary
care physicians, and other clinicians, as well as those of patients.

"The combination of the two organizations' expertise and reach to
physicians and patients presented a unique opportunity to reduce
cardiovascular risk in this country," Steve Zatz, MD, executive vice
president of professional services for WebMD, told Medscape
Cardiology.

For this initiative, ACC has teamed up with Medscape, the primary
portal for physicians and healthcare professionals available through
WebMD, which is the leading provider of health information for both
consumers and clinicians. Resources provided by the initiative for
healthcare practitioners will include continuing education
activities, cardiovascular news, and patient information.

"Medscape and the ACC are collaborating on the development of
content with each focusing on our respective audiences," Dr. Zatz
said. "The collaboration will provide Medscape's members with the
latest information regarding the management of cardiovascular risk.
We will help clinicians both improve their knowledge and their
ability to communicate and motivate their patients to reduce their
cardiovascular risk."

"The ACC has long been known for providing the latest clinical
information to cardiovascular professionals," Jack Lewin, MD, chief
executive officer of the ACC, said in a news release. "As we broaden
our reach to provide of-the-minute cardiovascular information to
patients as well, we are delighted to be working with WebMD, which
has a strong presence and hard-earned reputation in this arena. For
professionals, we are very excited to be working with Medscape to
deliver the latest educational tools to our physicians, those in
other specialties, and their patients."

Although the specific details of future projects are not yet clear,
editorial content for the new initiative will be directed by a
multidisciplinary steering committee, including leading US experts
in cardiology and primary care. Christopher Cannon, MD, an associate
professor of medicine at Harvard Medical School, Boston,
Massachusetts, will chair the steering committee. Dr. Cannon is also
editor in chief of ACC's Cardiosource, which offers current clinical
information to practicing cardiologists.

"One of the benefits of online communication is being able to
provide content in multiple formats, so that we can match the
delivery of information with the learning style of the user," Dr.
Zatz said. "Content will be available as text, audio, and full-
motion video and graphics so that it will be as engaging as possible
to our audience."

Scott C. Ratzan, MD, editor-in-chief of the Journal of Health
Communication: International Perspectives, is not involved in the
ACC-WebMD collaboration but was asked to provide independent
commentary. He recommends that content areas to be covered should
include "something that can be measured over time ¡X behavior or
social change ¡X that ultimately contributes to health."


"These types of initiatives that ultimately impact the health
literacy of individuals to help people make informed health
decisions advance quality health and well-being," Dr. Ratzan
said. "There should be an evaluation plan that measures [the effect
of this type of initiative] as well as key indicators that
illustrate change."

Nathan D. Wong, PhD, FACC, FAHA, professor and director of the Heart
Disease Prevention Program in the Division of Cardiology at the
University of California, Irvine, also provided independent
commentary for Medscape Cardiology.

"With both WebMD/Medscape and the ACC being highly respected
organizations within the cardiology community, educational
information for both physicians and the public sponsored jointly by
the two will be highly regarded as the premier source of guidelines
and recommendations," Dr. Wong said.

"Of course, it will be important to have some dialogue with the
American Heart Association, which also provides educational
materials through their Web site, to ensure there is not too much
overlap, as each of the organizations brings important attributes to
the area of cardiovascular risk education," he added.

Content areas that Dr. Wong believes should be covered by the new
initiative include appropriate use of lipid therapies, including
combination treatment, to increase patients getting to goals for
lipids; strategies for improving hypertension control, particularly
systolic hypertension, which remains the principal problem in most
hypertensive patients; resources for smoking cessation; and
resources for lifestyle management, particularly aimed to enhance
compliance to nutritional and physical activity recommendations that
target the US obesity epidemic.

For clinicians, educational materials from this intiative will be
available at www.medscape.com/acc and at www.cardiosource.com, ACC's
clinical Web site. Clinician-directed patient education materials
will be available at Medscape's forthcoming Patient Education Center
and at CardioSmart (www.cardiosmart.org), the ACC's new site on
cardiovascular disease, prevention, and management for healthcare
professionals to use with their patients.

For consumers and patients, information will be available at
www.webmd.com and at the newly-launched ACC CardioSmart site
(www.cardiosmart.org), which will offer award-winning news and
videos provided by WebMD. These patient-friendly sites are intended
to promote active participation in cardiovascular health, disease
prevention and treatment, and improved physician-patient
relationships and communication.

New data from the Avoiding Cardiovascular Events in Combination
Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)
trial were presented today at the American College of Cardiology
2008 Scientific Sessions [1]. They showed that a single-tablet dual-
mechanism therapy initiated in high-risk hypertensive patients
significantly reduced the risk of morbidity and mortality by 20%
compared with conventional therapy.

ACCOMPLISH, a major morbidity and mortality trial, compared the
effects of two forms of antihypertensive combination therapies on
major fatal and nonfatal cardiovascular events. It was stopped early
because treatment with antihypertensive combination therapy--the ACE
inhibitor benazepril plus the calcium-channel blocker amlodipine--
was more effective than treatment with the ACE inhibitor plus
diuretic.

Lead investigator Dr Kenneth Jamerson (University of Michigan, Ann
Arbor), who presented the results of the study during the late-
breaking clinical-trials session, said he was "absolutely thrilled"
to present the findings of a study designed to challenge current
guidelines in defining the optimal strategy for blood-pressure
control and preventing cardiovascular events in high-risk patients.

"If you use the combination of a calcium-channel blocker with an ACE
inhibitor, you get exquisite blood-pressure control," said Jamerson,
who added that similar control was observed with the ACE inhibitor
and diuretic. Despite the similar blood pressure, the combination
with the calcium-channel blocker and ACE inhibitor reduced
cardiovascular morbidity and mortality 20%.

During a press conference announcing the results, Jamerson told the
media that the findings are "paradigm-shifting" and the data are a
clear win with a clear message. He said the ACCOMPLISH findings
challenge the guidelines, especially in terms of starting with a one-
drug strategy and the use of diuretics in combination with ACE
inhibitors.

Clear data, clear win, and a clear message

Current recommendations for the treatment of stage 1 hypertension
include the use of thiazide-type diuretics for most patients, with
additional consideration given to ACE inhibitors, angiotensin-
receptor blockers (ARBs), beta blockers, and calcium-channel
blockers. In patients with stage 2 hypertension--those with blood
pressure >160/>100 mm Hg--two-drug combination therapy, usually with
a diuretic and ACE inhibitor, is recommended.

ACCOMPLISH compared the effects of two forms of antihypertensive
combination therapies on major fatal and nonfatal cardiovascular
events. In total, 11 400 men and women aged 55 years or older who
had systolic blood pressure >160 mm Hg or were currently on
antihypertensive therapy and who had evidence of cardiovascular or
renal disease or target-organ damage were included in the trial.
Patients enrolled in the trial were obese, with 60% having diabetes
mellitus, and nearly all had been treated previously for
hypertension.

More than 70% had been treated with two or more hypertensive agents,
but, as was previously reported by heartwire at the American Society
of Hypertension 2007 Scientific Sessions, just 37.5% of patients had
their blood pressure controlled to <140/90 mm Hg at baseline, the
currently recommended target of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure. As part of the study protocol, all patients stopped their
medication and, without a washout period, were randomized to
combination treatment with benazepril plus hydrochlorothiazide or
amlodipine plus benazepril.

At 36 months, blood-pressure levels were significantly improved,
with more than 75% of patients in both treatment arms having blood-
pressure levels <140/90 mm Hg. Investigators report that combination
treatment with benazepril plus amlodipine reduced cardiovascular
morbidity and mortality, defined as cardiovascular death,
fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for
unstable angina, and coronary revascularization, by 20%, compared
with those treated with benazepril plus a diuretic.

Speaking with the media, Jamerson noted that the average patient in
the study was 68 years old, and the oldest patient was 98 years old.
Although hypotension might be a concern and can result in falls and
fractures in elderly patients or in the frail, this was not borne
out in the ACCOMPLISH study.

Dr Michael Weber (SUNY Downstate Medical Center, Brooklyn, NY), who
was on the executive committee of the ACCOMPLISH trial, agreed with
Jamerson, telling heartwire that the findings will change the
guidelines.

"Right now, there is a recommendation that when you're putting
together combination treatment for hypertension you need to normally
include a diuretic as one of the two agents," said Weber. "I'm sure
that recommendation will change. It might not change to the point of
stating that a calcium-channel blocker like amlodipine be the
preferred partner, but it will take away the recommendation for
diuretics, and adding the calcium-channel blocker will invariably be
a part of that."

Dr Salim Yusuf (McMaster University, Hamilton, ON) said the
study "looks good" but held back full praise until the complete
findings are published. He agreed, though, that, based on the
presented data, the ACCOMPLISH study will challenge current
guidelines.

Jamerson KA, on behalf of the ACCOMPLISH investigators. Avoiding
cardiovascular events in combination therapy in patients living with
systolic hypertension. American College of Cardiology Scientific
Sessions; March 31, 2008; Chicago, IL.

A new study of pioglitazone (Actos, Takeda Pharmaceuticals) suggests
that it can prevent progression of atherosclerosis and produce
meaningful improvements in cardiovascular risk factors over 18
months, as compared with glimepiride (Amaryl, Sanofi-Aventis) [1].
Experts say results of the Pioglitazone Effect on Regression of
Intravascular Sonographic Coronary Obstruction Prospective
Evaluation (PERISCOPE) trial, presented here at the American College
of Cardiology 2008 Scientific Sessions, raise new questions about
how best to lower blood sugar levels in type 2 diabetics.

Dr Steven Nissen (Cleveland Clinic, OH), who presented the results
during a late-breaking trial session here, called the results
a "huge surprise."

"What we saw was that the people who got one of the most widely used
therapies--glimepiride, a sulfonylurea--had unequivocal progression
of coronary atherosclerosis by [intravascular ultrasound] IVUS,
while pioglitazone had a little less plaque at the end of the study,
and the difference between the two therapies was highly
statistically significant. . . . To our knowledge, this is first
time that a diabetes study has been shown to slow progression of
coronary atherosclerosis."

Nissen emphasized that while no one study should change clinical
practice, particularly one based on a surrogate end point--in this
case, atherosclerosis progression as measured by IVUS. The trial did
not address impact on clinical events. But Nissen also pointed out
that the PERISCOPE results come in the wake of PROACTIVE, which
showed a nonsignificant 10% reduction in its primary end point of
all macrovascular events and a significant 16% reduction in its
secondary end point of death, MI, and stroke with pioglitazone. "I
think the totality of information suggests this is a beneficial
therapy, but PERISCOPE alone doesn't answer all the questions," he
said.

But commenting on the study for heartwire, Dr Roger Blumenthal (John
Hopkins University, Baltimore, MD) warned against making too much of
a small imaging study on top of a larger clinical trial that failed
to meet its primary end point. "We need more supportive data. Right
now the totality of evidence is not enough to change guidelines," he
said. "The chance of this having a significant impact on clinical
practice is the same as a snowball's chance in Hades."

The PERISCOPE results have also been published online March 31, 2008
in the Journal of the American Medical Association.

All eyes on PERISCOPE

In PERISCOPE, 543 patients with type 2 diabetes underwent coronary
IVUS and then were randomized to receive either glimepiride (1-4 mg)
or pioglitazone (15-45 mg) for 18 months, at which time IVUS studies
were repeated. According to study investigators, mean percent
atheroma volume decreased by 0.16% in pioglitazone-treated subjects
but increased by 0.73% in glimepiride-treated patients. When the
analysis was repeated to include patients who had not completed the
study, the results also showed an increase for glimepiride and a
decrease for pioglitazone. Both agents lowered glycohemoglobin and
fasting insulin levels, although pioglitazone's effects on these end
points were statistically greater. Pioglitazone also produced
statistically meaningful changes in HDL and triglyceride levels.

Adverse events in the trial were clearly different between the two
drugs. More patients taking glimepiride developed hypoglycemia and
angina, while patients taking pioglitazone were more likely to
develop edema, gain weight, or suffer bone fractures.

Commenting on the study, Dr Salim Yusuf (McMaster University,
Hamilton, ON) highlighted the fracture results, which occurred in 3%
of the pioglitazone-treated patients.

"This was a significant excess in fractures with pioglitazone, and
no matter how good a surrogate end point, even if it is truly
related to the outcome you're interested in, which may be CV events,
it doesn't tell you the totality of the benefit/risk," he said.

Likewise, Dr Darren McGuire (UT Southwestern, Dallas, TX), speaking
with heartwire, also acknowledged that the fracture rate
was "surprisingly high"--higher than the signal of fracture risk
seen before with this drug.

"I think it is something to pay attention to," he said. "These drugs
are not completely benign, but in total their benefit-to-risk ratio
in select patients remains favorable."

Indeed, McGuire points out that PERISCOPE is not a standalone
imaging study, because of the promising secondary results in
PROACTIVE. "What the PERISCOPE study does is provide proof of
principle that the drug is to some degree modifying atherosclerosis."

Several observers have pointed out that the absolute changes in
atherosclerosis progression are small, a comment Nissen rejects. He
cites research in progress at his own institution that is examining
clinical outcomes in relation to IVUS results from statin trials. "I
can tell you that, with a p value with a lot of zeros before the
one, that changes of around 0.8% to 1.0% are associated with a very
substantial reduction in hard end points across all the trials we've
done. The differences we saw here are really very statistically
robust and they will translate into clinical benefits," he said.

Indeed, an editorial [2] by Drs P Gabriel Steg (Centre Hospitalier
Bichat-Claude Bernard, Paris, France) and Michel Marre (Universite
Paris VII, France) points out that, while small, the apparent affect
of pioglitazone is "well within the range of what is achieved with
some therapies demonstrated to improve cardiovascular outcomes, such
as high-dose statins."

A glimpse of things to come

Following Nissen's presentation, one of the session moderators, Dr
Greg Brown (University of Washington, Seattle), asked Nissen if the
PERISCOPE results have "changed [his] opinion about the glitazone
class," referring to the 2007 hullabaloo over rosiglitazone, sparked
in large part by a meta-analysis that Nissen coauthored.

Nissen called this a "fair question" but emphasized that, while
technically in the same class, rosiglitazone and pioglitazone affect
different genes. "They both affect a gene that is involved in
lowering blood sugar, but they have otherwise extraordinarily
different effects. We have to study each of these compounds
individually."

In the press conference, Nissen acknowledged that he and his
coauthors cannot yet explain the mechanism by which pioglitazone
alters atherosclerosis progression but that its effects on blood
pressure, lipids, triglycerides, and CRP are major candidates. "What
this study now tells us is: we must do a comparator effectiveness
trial looking at different diabetes treatment strategies. We can't
just focus on pricking the finger, getting the blood sugar down, and
saying, that's the goal of therapy. The goal in therapy is to
prevent complications of diabetes, and the most feared, most serious
complication is heart disease, which will kill 75% of diabetics."

Nissen SE, Nicholls SJ, Wolski L, et al. Comparison of pioglitazone
vs glimepiride on progression of coronary atherosclerosis in
patients with type 2 diabetes. JAMA 2008;
DOI:10.1001/jama.299.13.1561. Available at: http://www.jama.com.
Steg PG, Marre M. Does PERISCOPE provide a new perspective on
diabetic treatment? JAMA 2008; 299:1603-1604.

Severely obese adolescents who undergo bariatric surgery experience
substantial improvements in cardiac geometry, left ventricular mass,
and diastolic function after weight loss, new study findings
indicate.

In fact, reversal of cardiac abnormalities appears to be more likely
in teenagers than in similar adults, Dr. Holly M. Ippisch and
associates report in the April 8 issue of the Journal of the
American College of Cardiology.

"This might be an argument for earlier intervention at younger ages
in severely obese young people," the investigators suggest.

Dr. Ippisch and her colleagues evaluated outcomes for 38 patients
ages 13 to 19 years who underwent laparoscopic Roux-en-Y gastric
bypass surgery at Cincinnati Children's Hospital Medical Center in
Ohio. Weight prior to surgery averaged 175 kg, and mean body mass
index (BMI) was 60 kg/m.

Within the following year, mean weight and BMI fell to 116 kg and 40
kg/m, respectively.

Although most patients were still over their ideal body weight,
heart rate was reduced by 18 beats/min and systolic blood pressure
by 12 mm Hg, changes that "possibly reflect a decreased cardiac work
load," the authors report.

The proportion of patients with normal left ventricular geometry
rose from 36% at baseline to 79%, and left ventricular mass fell
significantly. Doppler imaging also indicated sizable reductions in
posterior wall and septal thicknesses, evidence of myocardial
remodeling that the investigators say has not been observed in
adults.

Despite these promising results in adolescents, the team concludes
that long-term follow-up is required to see if the improvements
persist, and "whether these findings translate into long-term
reduction in their future cardiovascular morbidity during adulthood."

J Am Coll Cardiol 2008;51:1342-1348.

Hospitals that participate in clinical trials appear to provide
better care for ACS patients than hospitals that do not participate
in clinical trials, according to a new study [1].

The study, published in the March 24, 2008 issue of the Archives of
Internal Medicine, was conducted by a team led by Dr Sumit Majumdar
(University of Alberta, Edmonton).

They explain that the quality of care for conditions such as acute
coronary syndromes has improved over recent years in response to new
evidence from clinical trials but that the rate of improvement has
been slow and there has been marked variability between hospitals.

Noting that clinical trials demand that trial subjects receive safe,
high-quality, protocol-driven care, they suggest the same elements
required for hospitals to participate in clinical trials could
induce beneficial changes in the hospital environment, thereby
leading to better processes and outcomes of care for patients
treated outside the trial setting.

To test this hypothesis, they studied 174 062 NSTEMI ACS patients
treated at 494 hospitals that were part of the CRUSADE registry.
Hospitals were classified into tertiles by percentage of patients
concurrently enrolled in NSTEMI ACS trials. In total, 4590 patients
(2.6%) were enrolled in clinical trials, with 145 hospitals having
no enrollment, 226 hospitals having low enrollment (a midpoint of 1%
enrollment) and 123 hospitals having high enrollment (a midpoint of
4.9% enrollment).

Results showed that adherence to clinical guidelines increased and
in-hospital mortality decreased with increasing tertiles of trial
participation.

Majumdar et al suggest that their results may be due to the trial
investigators being prominent opinion leaders who gain early
clinical experience with new drugs and devices, have many
opportunities to interact with colleagues and exchange ideas
regularly, and might develop additional capacity for training their
colleagues outside the trial setting. In addition, the trial
protocols for standard treatment might be so useful and effective
that they are integrated into the delivery of usual care after the
trial finishes.

But they also point out that their findings could be a result of
confounding by difficult-to-capture or unmeasured institutional
characteristics that are tightly linked with a hospital's ability to
participate in trials. "It could be that hospitals that foster and
reward a culture of high-quality cardiac care (ie, large, high-
volume, financially stable academic centers with cardiology training
programs and capacity for revascularization) also attract and
recruit the physicians who are most inclined to adopt new evidence;
who are predisposed to implementing treatment protocols, decision
support systems, and other interventions known to improve quality of
care; who insist on thorough documentation of eligibility and
contraindications data for each patient; and who willingly respond
to credible audit and feedback."

They say they adjusted for institutional characteristics that might
capture some of these attributes (eg, size, caseload, location,
revascularization capacity, teaching status, and cardiologist-
supervised care) and controlled for a host of patient-level
sociodemographic and clinical variables, but they admit the
potential for confounding still exists.

They conclude: "From the patient's perspective, even if our results
are somewhat confounded, it still seems sensible to seek care at
hospitals that participate in clinical trials. For policy makers and
physicians, our findings should assuage some of the concerns related
to the possible opportunity costs and potential downsides of
participating in the clinical-research enterprise."

Majumdar SR, Roe MT, Peterson ED, et al. Better outcomes for
patients treated at hospitals that participate in clinical trials.
Arch Intern Med 2008; 168:657-662. Abstract

In non-diabetics who are at risk for developing diabetes, treatment
with metformin leads to modest improvements in weight, lipid
profiles and fasting glucose, and substantial reductions in insulin
resistance and new-onset of diabetes, results of a meta-analysis
indicate.

Dr. Shelley R. Salpeter from Stanford University School of Medicine,
California and colleagues pooled data from 31 trials that compared
metformin with placebo or no treatment in 4570 adults at risk for
diabetes followed for 8267 patient-years.

Metformin treatment, compared with placebo or no treatment, reduced
body mass index by 5.3%, fasting glucose by 4.5%, fasting insulin by
14.4%, and calculated insulin resistance by 22.6%, according to the
report in the February issue of the American Journal of Medicine.

Metformin treatment also reduced triglycerides and LDL cholesterol
by 5.3% and 5.6%, respectively, and increased HDL cholesterol by
5.0% compared with placebo or no treatment.

"The incidence of new-onset diabetes was reduced by 40% (odds ratio,
0.6), with an absolute risk reduction of 6%, during a mean trial
duration of 1.8 years," the investigators found.

Dr. Salpeter and colleagues think metformin could be added to diet
and exercise if these lifestyle modifications alone are not
sufficient to reduce the risk of diabetes in at-risk individuals.

"Future long-term trials will be needed to show that the metabolic
benefits of metformin treatment result in a reduction in
cardiovascular morbidity and mortality," they conclude.

Am J Med 2008;121:149-157.

Combination therapy with simvastatin and fenofibrate is better than
monotherapy with either drug for treating mixed dyslipidemia in
patients with type 2 diabetes, according to a report in the February
15th American Journal of Cardiology.

"I believe every diabetic should be initially treated with a statin,
with an LDL goal of at least 100 and probably even 70 would be
better," Dr. Joseph Brent Muhlestein told Reuters Health. "I
secondarily also look at triglycerides and HDL. I then target
additional lipid therapy based on which of these three lipid values
remain the most off-goal."

Dr. Muhlestein from the Intermountain Medical Center and LDS
Hospital, Salt Lake City, Utah and associates investigated the
effects of simvastatin alone, fenofibrate alone, and the combination
of simvastatin and fenofibrate on lipid subparticles in 498 patients
with type 2 diabetes without coronary heart disease.

Combination therapy reduced dense VLDL cholesterol significantly
more than did fenofibrate or simvastatin monotherapy, the
investigators found. Simvastatin lowered intermediate density
lipoprotein (IDL) cholesterol significantly more than did
fenofibrate.

The percentage of LDL cholesterol pattern B constituting total LDL
cholesterol was significantly reduced by fenofibrate (a 13.7%
reduction) and by the combination (an 11.1% reduction), but not by
simvastatin.

Similarly, fenofibrate and the combination (but not simvastatin)
significantly increased the percentage of buoyant LDL cholesterol
constituting total LDL cholesterol.

"Thus," the investigators say, "fenofibrate and combination therapy
favored the shift from LDL cholesterol pattern B to the more
buoyant, less atherogenic LDL cholesterol."

Patients with higher triglyceride levels tended to experience
greater reductions in LDL cholesterol pattern B and dense VLDL
cholesterol with treatment, the researchers note.

"Diabetic dyslipidemia appears to be a very important contributor to
the overall cardiovascular risk associated with diabetes," Dr.
Muhlestein explained. "This risk comes from the combination of
elevated LDL, elevated triglycerides, and low HDL. Aggressive
treatment of this mixed dyslipidemia may be very important in saving
the lives of our diabetic patients."

"We are now testing a possible benefit of triple drug lipid therapy
in diabetics, comparing the double combination of simvastatin +
fenofibrate with the triple combination of simvastatin + ezetimibe +
fenofibrate," Dr. Muhlestein commented.

Am J Cardiol 2008;101:486-489.

The theory that treatment with thiazolidinediones (TZDs) is
associated with a decrease in circulating osteoprotegerin and a
lower prevalence of silent myocardial ischemia in patients with type
2 diabetes is supported by a French study published in the March
issue of Diabetes Care.

Dr. Antoine Avignon of Lapeyronie Hospital, Montpellier, France, and
colleagues note that TZDs are thought to reduce bone formation and
contribute to bone loss. Osteoprotegerin inhibits osteoclast genesis
by functioning as a decoy receptor for RANK ligand, a factor that
plays a role in bone remodeling.

The researchers tested 198 consecutive asymptomatic patients with
type 2 diabetes (average age 60.1 years) for silent myocardial
ischemia, defined as abnormal myocardial perfusion imaging (MPI)
results and/or a positive stress/exercise EKG.

The 46 patients on TZDs were compared with the 152 who were taking
other oral antidiabetes drugs.

TZD use was independently associated with decreased levels of plasma
osteoprotegerin, the team found.

Of 51 patients with silent myocardial ischemia, 35 had abnormal MPI.
Although the difference in prevalence of silent myocardial ischemia
between the TZD and non-TZD groups was nonsignificant, the
difference in incidence of abnormal MPI was significant (< 0.01).
Two (4%) of 46 patients receiving TZDs had abnormal MPI, while 33
(22%) of the 152 non-TZD patients had abnormal MPI.

Compared with patients with normal MPI, the 35 patients with
abnormal MPI had higher mean levels of osteoprotegerin.
Osteoprotegerin > 8 pmol/L was independently associated with MPI
defects (P < 0.01).

The researchers suggest that "TZDs could prevent diabetes-induced
osteoblast differentiation in arterial walls and medial
calcification, possibly via a reduction of osteoprotegerin plasma
levels."

They further suggest that TZDs' reported effect of improving
endothelial dysfunction, which is common in diabetes and can cause
abnormal MPI in the absence of significant coronary stenosis, might
explain the lower prevalence of abnormal MPI in the patients treated
with TZDs.

Diabetes Care 2008;31:593-595.

The FDA has granted market clearance to the automated VIDAS NT-
proBNP assay for measuring serum or plasma levels of the N-terminal
fragment of B-type natriuretic peptide (NT-proBNP), the test's
manufacturer, bioMérieux, has announced [1].

The approval was based on the agency's determination that the assay
is substantially equivalent to the Elecsys proBNP assay from Roche
Diagnostics [2], which is used in emergency departments to help
distinguish acute heart failure from syndromes with similar
presentations. The bioMérieux test is an enzyme-linked fluorescent
assay developed under a licensing agreement with Roche; the latter
company's assay is based on electrochemiluminescence.

FDA clears bioMérieux's VIDAS® NT-proBNP, a high medical value test
for diagnosis of heart failure. Press release. bioMérieux Corporate
website. 13 March 2008. Available at
http://www.biomerieux.com/servlet/srt/bio/portail/dynPage?
open=PRT_NWS_REL&doc=PRT_NWS_REL_G_PRS_RLS_160&crptprm=ZmlsdGVyPQ.
510(k) summary. VIDAS® NT-proBNP assay. Available at
http://www.fda.gov/cdrh/pdf7/K073091.pdf.

Measuring maximum carotid plaque thickness helps predict the risk of
vascular events in a multiethnic population, and the measurement may
be used as a "simple and noninvasive marker of subclinical
atherosclerosis," suggest the findings of a new study [1]. Compared
with patients with less carotid plaque assessed by ultrasound, those
with higher levels had nearly a 50% greater risk of combined
ischemic stroke, MI, and vascular death, report study investigators.

In addition, investigators also observed that Hispanics had a higher
incidence of vascular events compared with white and black
patients. "Taken together," write investigator Dr Tatjana Rundek
(University of Miami, FL) and colleagues in the April 1, 2008 issue
of Neurology, "these results may be of significant importance for
the development of primary-prevention programs for this vulnerable
and fastest-growing minority population in the United States."

Northern Manhattan Study

The study, an analysis of the Northern Manhattan Study (NOMAS), is
part of the incremental research showing that nonstenotic carotid
plaque increases the risk of vascular events, an association that
was observed in the Atherosclerosis Risk in Communities (ARIC)
study, the Cardiovascular Health Study, and the Rotterdam Study.
Investigators point out, however, that the evidence in patients from
lower socioeconomic and diverse racial and ethnic communities is
sparse.

Of the 2189 participants in NOMAS, an ongoing, population-based
study documenting the incidence of stroke, risk factors, and
vascular outcomes, 63% were Hispanic, 20% black, and 15% white.
Carotid ultrasound was performed in all patients, with the left and
right carotid bifurcations and internal and common carotid arteries
examined for the presence of plaque. Patients were followed for
nearly seven years.

In an unadjusted model, the risk of ischemic stroke, MI, and
vascular death was significantly greater in patients with maximum
carotid plaque levels >1.9 mm, a prespecified value of the 75th
percentile of plaque thickness among measured patients. However,
when adjusted for age, gender, race/ethnicity, education, and other
traditional risk factors, the association was not significant. The
combined incidence of these events, however, was significantly
associated with maximum carotid plaque thickness even after
adjustment for these factors.

In their discussion of the results, Rundek and colleagues state that
because maximum carotid plaque thickness appeared to be a stronger
predictor of MI and vascular death than ischemic stroke, small,
nonstenotic carotid plaque "may be a marker of generalized
atherosclerotic burden rather than a triggering lesion in the
causative pathway of ischemic stroke."

When investigators stratified the analysis by age, sex, and
race/ethnicity, the association between maximum carotid plaque
thickness >1.9 mm and vascular risk trended toward significance
among those older and younger than 65 years, as well as among men
and women.

Investigators observed that while the amount of atherosclerosis
overall was higher among whites and blacks, if carotid plaque was
present, there was a significant effect on the vascular risk of
Hispanics. Among the black, white, and Hispanic patients, Hispanics
had a more than twofold greater risk of vascular events with plaque
thickness >1.9 mm, whereas there was only a trend toward
significance among black and white participants.

They point out, however, that the comparison of outcomes from
different populations should be considered with caution, especially
if comparisons are made across different studies. They note that the
NOMAS subjects are older, mean age 61 years, with numerous
cardiovascular risk factors. Moreover, Hispanics in this trial are
typically from the Caribbean and might not be representative of
other Hispanics or minority groups.

Rundek T, Arif H, Boden-Albala B, et al. Carotid plaque, a
subclinical precursor vascular events. Neurology 2008; DOI:
10.1212/wnl.0000303969.63165.34. Available at:
http://www.neurology.org.

The contaminant found in samples of heparin that had been linked to
an increase in adverse reactions has now been identified as
oversulfated chondroitin sulfate.

In a telephone press conference, Dr Janet Woodcock (director of the
FDA Center for Drug Evaluation and Research) explained that
chondroitin sulfate was derived from animal cartilage and was used
as health supplement, but the oversulfated version did not occur
naturally and would have to have been chemically synthesized,
probably by simply adding extra sulfate molecules to chondroitin
sulfate, which is extensively available. "We do not know how this
substance got into the heparin supply, but we can say it did not
come straight from the pig," she said.

The oversulfated chondroitin sulfate is very closely chemically
related to heparin and appears to be heparin in standard tests,
Woodcock noted. The contaminant was found to make up 2% to 50% of
the total content of heparin active pharmaceutical ingredient in
some of the samples tested at the Changzhaou SPL plant in China to
which it has been traced, she added.

Woodcock and other FDA officials said that oversulfated chondroitin
sulfate would be cheaper to produce than heparin itself but would
not be drawn in on suggestions that it may have been deliberately
introduced to produce cheaper counterfeit heparin products. "We
cannot say whether it was deliberately or accidentally introduced,
but we are actively working to establish this," she commented.

Woodcock also pointed out that it had not been definitely
established that this contaminant had caused the increase in adverse
reactions seen with heparin but said there was an intensive
immunologic investigation under way to investigate whether this
compound could have caused such adverse reactions when mixed with
heparin.

She also noted that now that the contaminant has been identified,
more rigorous tests can now be made available to detect its presence
in heparin supplies.

One-year results from the ABSORB bioabsorbable everolimus stent
(BVS) trial, now published in the March 15, 2008 issue of the
Lancet, demonstrate the feasibility of using Abbott's BVS device and
the durability of its antirestenotic properties, at least over the
first 12 months [1]. But a mean loss in stent area over the follow-
up period, reflecting acute stent recoil, nonuniform structural
support, or dwindling stent strength related to bioabsorption,
remains one of the major challenges ahead for the device,
researchers say.

"There are many who think absorbable stents are the next great hope,
but many do not," lead author Dr John Ormiston (Mercy Hospital,
Auckland, New Zealand) told heartwire. "I think they are likely to
be [the next great hope], but there are challenges to overcome. This
paper tells us that a bioabsorbable [drug-eluting stent] DES--the
BVS--can work in simple lesions. We need information from more
complex lesions and in larger numbers of patients and from
randomized trials."

In recent years, particularly given concerns about the risk of late
stent thrombosis associated with permanent metal stents,
interventionalists have predicted that bioabsorbable drug-eluting
stents would be the wave of the future, eluting antirestenotic
agents and providing the required scaffolding during the healing
period, then dissolving away completely.

ABSORB at 12 months

As previously reported by heartwire, ABSORB enrolled 30 patients at
four centers internationally. The results published this week
represent one-year clinical follow-up, as well as angiographic,
intravascular ultrasound (IVUS), and optical coherence tomography
(OCT) results in smaller subsets within the overall group. In
ABSORB, designed as a single-arm feasibility study, all patients
received the investigational device.

As Ormiston and colleagues report, one patient had a non-Q-wave MI
during the 12 months of follow-up. They explain that this patient
had been admitted with chest pain and underwent target lesion
revascularization (TLR) and received a paclitaxel-eluting stent,
although this procedure did not actually meet the study definition
of TLR because the angiographic assessment suggested the stenosis
was less than 50% in diameter--below the prespecified cut-off for
ischemia-driven TLR in the study. There were also no instances of
stent thrombosis, the authors report.

Angiographic follow-up in 26 patients, as previously reported by
heartwire, indicated that binary restenosis occurred in three
patients (12%) and that the mean in-stent late loss was 0.44 mm at
six months. This amount of late loss, they note, is similar to that
reported for the Taxus paclitaxel-eluting stent (0.39 mm), higher
than that seen in trials of the metallic everolimus-eluting stent
(0.15 mm) but substantially lower than that of bare-metal stents
(typically greater than 0.8 mm).

Keeping the vessel open

IVUS analyses pointed to a significant reduction in stent area (the
amount of vessel propped open by the stent) and, in six patients,
incomplete stent strut apposition--a phenomenon also seen on OCT in
a subset of 13 patients. The reduction in stent area appeared to
have occurred in a nonuniform fashion throughout the stent length,
with less stent recoil occurring in areas with more stent struts,
the authors note.

These observations have been taken into account in the design of the
next-generation BVS, Ormiston told heartwire. "The next-generation
Abbott BVS design will have more uniform scaffolding so that the
vessel wall will be supported more uniformly and the drug applied
more uniformly. It will also have more radial strength that will
last longer," he explained. "This should reduce the small amount of
late recoil seen in the trial. In addition, the stent will be very
secure on the delivery balloon and have little chance of
dislodgement."

While several companies are developing bioabsorbable stents, one of
the outstanding questions remains just how quickly or slowly the
stent should degrade. The rate of absorption has profound
implications for stent efficacy, but also for long-term safety.

"As the stent is absorbed, its radial strength reduces and goes
away; then some time elapses before the stent is completely
absorbed," Ormiston noted. "In the ABSORB study at six months, there
were profound changes in the struts as observed by OCT, indicating
that absorption is well under way, but the stent had not been
completely absorbed."

In preclinical studies, the BVS appeared to absorb completely within
two to three years, but stent behavior may be very different in
diseased human arteries, Ormiston told heartwire. "In patients, it
seems to be absorbing faster than expected. There has been no
increase in MACE by 12 months, and it would be surprising if there
will be device-related MACE subsequently. Time will tell."

Better metal stents or disappearing stents?

In an accompanying editorial [2], Drs Carlo Di Mario (Royal Brompton
Hospital, London, UK) and Giuseppe Ferrante (Catholic University of
the Sacred Heart, Rome, Italy) ask whether there will indeed be a
real advantage of bioabsorbable stents over permanent metal stents
if, in fact, they take two to three years to dissolve; they point
out that there are no solid data proving that the risk of stent
thrombosis with metallic stents persists beyond three to four years.
Increasingly, researchers studying the mechanisms of late stent
thrombosis are concluding that the real culprit in stent thrombosis
is the polymer and drug-release kinetics, not the stent itself. Some
companies, as a result, are moving forward with metallic stents, but
with bioerodable polymers.

"Will the progress of metallic stents with thin struts covered by a
film of biodegradable polymer and less aggressive drugs be enough to
eliminate late stent thrombosis?" the editorialists ask. "We doubt
it. . . . Events as potentially deadly as stent thrombosis should
ideally be eradicated; and radical alternatives to conventional
stents, such as biodegradable stents, deserve to be the focus of
research investment."

Ormiston, similarly, acknowledged that it's an "intriguing question"
as to whether the late stent thrombosis problem will be solved by
the stent disappearing altogether. "It is an important hope that if
the strut disappears, there will be no potential for late stent
thrombosis. However, late stent thrombosis may be more complex than
an interplay of strut presence and endothelialization. I personally
believe that a bioabsorbable stent is the way of the future if
technical challenges can be overcome."

ABSORB investigators are moving ahead with a second cohort of 30
patients who will receive the next iteration of the BVS stent;
enrollment will begin later in 2008, Ormiston said.

Ormiston declared having no conflicts of interest; two of the study
coauthors are employees of Abbott, the study sponsor.

Ormiston J, Serruys PW, Regar E, et al. A bioabsorbable everolimus-
eluting coronary stent system for patients with single de-novo
coronary artery lesions (ABSORB): a prospective open-label trial.
Lancet 2008; 371:899-907.
Di Mario C, Ferrante G. Biodegradable drug-eluting stents: promises
and pitfalls. Lancet 2008; 371:873-874. The complete contents of
Heartwire, a professional news service of WebMD, can be found at
www.theheart.org, a Web site for cardiovascular healthcare
professionals.