In the largest secondary stroke-prevention trial to date, the
combination of aspirin and extended-release (ER) dipyridamole
(Aggrenox, Boehringer Ingelheim) did not meet prespecified criteria
for noninferiority vs clopidogrel (Plavix/Iscover, Sanofi-
Aventis/Bristol-Myers Squibb), but rates of recurrent stroke, the
primary outcome, were similar between the groups.


"Therefore, the study does not show that either aspirin plus
extended-release dipyridamole or clopidogrel is superior to the
other in the prevention of stroke," the investigators, with first
author Ralph L. Sacco, MD, from the Miller School of Medicine at the
University of Miami, in Florida, conclude.

"These findings provide additional safety and efficacy data
physicians need in making individual treatment decisions for
prevention of recurrent stroke or the combined end point of stroke,
myocardial infarction [MI], or death from vascular causes in their
patients with stroke," they write.

In a factorial design, the trial also examined the effect of early
blood pressure lowering after a stroke using telmisartan (Micardis,
Boehringer Ingelheim) vs placebo and found no benefit of the
addition of the angiotensin-receptor blocker (ARB) in prevention of
stroke recurrence, major cardiovascular events, or diabetes, at
least during the 2.5 years of follow-up in this study.

The results are published online as 2 papers August 27 in the New
England Journal of Medicine. The findings were previously presented
at the 17th European Stroke Conference, in Nice, France, and
reported by Medscape Neurology & Neurosurgery at that time.


Factorial Design

The PROFESS trial included 20,332 patients from 695 sites in 35
countries. All had had a noncardioembolic ischemic stroke within the
previous 120 days. They were randomized in a factorial design to
receive aspirin (25 mg) plus ER dipyridamole (200 mg) twice daily or
clopidogrel (75 mg) once daily. Subjects were then again randomized
to receive either 80 mg per day of telmisartan or placebo.


Current guidelines in Europe and the United States recommend that
for antiplatelet therapy after a stroke, aspirin, aspirin plus
dipyridamole, and clopidogrel are options for prevention of stroke
recurrence, but there is no recommendation for the use of 1 of these
agents over the others. Direct comparison of aspirin alone vs
aspirin and dipyridamole in the European and Australian Stroke
Prevention in Reversible Ischemia Trial (ESPRIT) and the European
Stroke Prevention Study 2 (ESPS2) had shown the combination to be
more effective than aspirin alone without increasing major bleeding.
The PROFESS trial aimed to provide information on a direct
comparison of the combination vs clopidogrel.

The planned antiplatelet comparison used a sequential analysis of
noninferiority first, then superiority, the researchers noted. The
margin chosen for noninferiority was 1.075, or a 7.5% noninferiority
difference.

In the end, the comparison for the primary outcome of recurrent
stroke did not meet this predefined criterion for noninferiority,
although the number of recurrent strokes was similar between the
groups

The secondary outcome, a composite of stroke, MI, and vascular
death, was identical between groups, they note. Other end points,
including deaths and MI, were not statistically different between
groups, with the exception of new or worsening heart failure, which
was significantly less frequent in the combination group.

Major hemorrhagic events were increased with the combination vs
clopidogrel; intracranial hemorrhage (ICH), including 128
hemorrhagic strokes counted in the primary outcome, was
significantly higher with the combination. There were no significant
differences between the 2 groups in the frequency of death, any
hemorrhagic event (major or minor), or thrombotic thrombocytopenia
purpura or neutropenia.

Despite the increase in bleeds, the net risk for recurrent stroke or
major hemorrhagic event was similar between the groups.

Adverse events leading to permanent discontinuation were increased
with the combination (16.4%) vs clopidogrel (10.6%). Headache was
more frequent with the combination, leading to permanent
discontinuation in 5.9% of the patients on combination therapy vs
0.9% on clopidogrel.

Dr. Sacco told Medscape Neurology & Neurosurgery that this study
provides more evidence that clopidogrel is as effective as ER
dipyridamole and aspirin in terms of reducing recurrent stroke.

"How we choose between the 2 agents is still going to be up to
clinicians," he said. "For those patients with more cardiac disease,
some of us may choose clopidogrel more often, and for others we
still have extended-release dipyridamole as an option."

Telmisartan vs Placebo

In a separate paper, the PROFESS researchers, with lead author Salim
Yusuf, MD, from McMaster University, in Hamilton, Ontario, published
results of the telmisartan-placebo comparison.

Previous studies, including the Heart Outcomes Prevention Evaluation
(HOPE) and the Perindopril Protection Against Recurrent Stroke Study
(PROGRESS), had shown a benefit associated with using an angiotensin-
converting enzyme (ACE) inhibitor initiated late after stroke, with
or without a large reduction in blood pressure. In this trial, the
PROFESS researchers investigated whether using a blocker of the
renin-angiotensin system, telmisartan, initiated early after a
stroke, would reduce recurrent stroke.

Despite a mean blood pressure difference between the groups of
3.8/2.0 mm Hg in favor of telmisartan, there was no difference
between groups on the primary end point of recurrent stroke, on
secondary outcomes of a composite of major cardiovascular events
(death from cardiovascular causes, recurrent stroke, MI, or new or
worsening heart failure), or in new-onset diabetes.

Subsequent analyses suggested there may have been an effect by time,
Dr. Yusuf noted when he presented these results in Nice, and the
researchers speculate that the trial may have been too short to see
a benefit with treatment. Suboptimal adherence in the treatment
group, as well as competing use of other blood pressure¡Vlowering
agents, reduced the blood pressure differential between the
groups, "which hurt our power," he said.

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

A third factorial analysis of the PROFESS data, looking for any
neuroprotective effects of dipyridamole, aspirin, or the ARB
telmisartan in those patients who did have a recurrent stroke, was
also presented at the European Stroke Conference by first author
Hans-Christof Diener, MD, from the University of Duisberg-Essen, in
Essen, Germany. Results of that analysis, that at least in the
preliminary analysis presented in Nice showed no evidence of any
such neuroprotective effects, will be published separately.

The study was funded by Boehringer Ingelheim. In selected countries,
the telmisartan comparison was supported by Bayer Schering Pharma
and GlaxoSmithKline. Dr. Sacco reports receiving consulting fees
from Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-Aventis and
lecture fees from Boehringer Ingelheim. Dr. Yusuf reports receiving
consulting and lecture fees from Boehringer Ingelheim, Sanofi-
Aventis, Bristol-Myers Squibb, AstraZeneca, and GlaxoSmithKline and
grant support from Sanofi-Aventis, Bristol-Myers Squibb, and
GlaxoSmithKline. Disclosures for other coauthors appear in the
papers.

N Engl J Med. Published online August 27, 2008.

Exposure to low-to-moderate levels of inorganic arsenic in drinking
water and food may increase the risk of type 2 diabetes, according to
data from the 2003-2004 US National Health and Nutrition Examination
Survey (NHANES).

High chronic exposure to inorganic arsenic is a documented risk
factor for diabetes, but the effect of lower levels of exposure is
unknown, Dr. Ana Navas-Acien, from Johns Hopkins Bloomberg School of
Public Health in Baltimore, and colleagues note in the Journal of the
American Medical Association for August 20.

The research team examined the prevalence of type 2 diabetes in
relation to arsenic exposure, as determined from urine samples from
788 subjects age 20 years and older. Analyses were adjusted for
biomarkers of seafood intake -- the primary source of organic
arsenic -- as well as sociodemographics and diabetes risk factors.

Subjects with type 2 diabetes had 26% higher total arsenic levels
than subjects without diabetes. In the fully adjusted model comparing
subjects in the 80th vs the 20th percentiles of total urine arsenic
(16.5 vs 3.0 g/L), the odds ratio for diabetes was 3.58.

Organic arsenic levels did not differ by diabetes status or glycated
hemoglobin levels.

The authors note that the primary sources of inorganic arsenic are
contaminated drinking water due to naturally occurring arsenic in
rocks and soils, and food. The US Environmental Protection Agency's
standard for arsenic in drinking water is 10 g/L. In the US,
approximately 8% of public water supply systems exceed this limit.
Dietary intake of inorganic arsenic ranges from 8.4 to 14 g per day.

"Given widespread exposure to inorganic arsenic from drinking water
worldwide, elucidating the contribution of arsenic to the diabetes
epidemic is a public health research priority," Dr. Navas-Acien and
her associates conclude.

Drs. Molly L. Kile and David C. Christiani, at Harvard University
School of Public Health in Boston, write in a JAMA editorial: "Animal
studies show that arsenic disturbs glucose production in the liver
and decreases insulin secretion and synthesis in pancreatic beta
cells. In addition, arsenic exposure causes hyperglycemia,
hyperinsulinemia, and low-insulin sensitivity in rats."

Thus, the editorialists advise, "It is prudent to minimize arsenic
exposure while its effect on metabolic diseases continues to be
researched."

JAMA 2008;300:814-822,845-846.

The risk of non-traumatic lower-extremity amputation remains high
among patients with type 1 diabetes, according to findings from a
Swedish study published in the August issue of Diabetes Care.

"Ulceration of the foot is the most common first indicator of
impending non-traumatic lower-extremity amputations (LEAs) related to
diabetes, and it has been estimated worldwide that one lower limb is
amputated every 30 s as a consequence of this condition," write Dr.
Junmei Miao Jonasson, of Karolinska Institute, Stockholm, and
colleagues.

For their current study, the researchers identified 31,354 patients
with type 1 diabetes (15,001 women and 16,353 men) in the Swedish
Inpatient Register between 1975 and 2004, and cross-linked the
records to other databases for identification of non-traumatic LEAs.

A total of 465 type 1 diabetic patients underwent non-traumatic LEAs.
The risk of amputation was 40% lower during the most recent calendar
period (2000 to 2004) than during the previous calendar period.
However, compared to the matched general population, the risk for non-
traumatic LEAs even in the most recent calendar period was
significantly higher among patients with type 1 diabetes
(standardized incidence ratio, 85.8).

The cumulative probability of non-traumatic LEA by age 65 years for
people with type 1 diabetes was 11.0% for women and 20.7% for men.

"In summary, even though our data do suggest that the risk of non-
traumatic LEA among patients with type 1 diabetes has attenuated in
recent years, patients diagnosed with this disease before age 31
years nonetheless have strikingly high absolute and relative risks of
non-traumatic LEAs," Dr. Jonasson and colleagues write.

"The apparent decline in the risks indicates that recent preventive
efforts have been effective, but the findings documented here
emphasize the need for the unrelenting application of measures
designed to prevent non-traumatic LEAs early in the course of type 1
diabetes," the team concludes.

Diabetes Care 2008;31:1536-1540.

Supplementation with B vitamins appears to be no better than placebo
in reducing the incidence of depression or depressive symptoms, new
research suggests.

A randomized, double-blind, placebo-controlled trial of 299 older men
showed treatment with vitamins B12, B6, and folic acid produced no
significant change in mood over 2 years.

"We investigated the association between vitamin use and depression
in 3 different ways, none of which showed an advantage of B vitamins
compared with placebo over 24 months: change in Beck Depression Index
[BDI] scores, incidence of clinically significant depressive
symptoms, and remission of depression," the authors write.

With first author Andrew H. Ford, MBBS, from South Metropolitan
Health Service, in Perth, Australia, the study is published in the
August issue of the Journal of Clinical Psychiatry.

Previous research has linked lower concentrations of B vitamins and
folate to depression. However, many of these reports have been
observational and or confounded by the fact that participants were on
antidepressants.

Prospective Design

The purpose of the current study was to prospectively determine
whether treatment with B vitamins over an extended period of time
reduced the onset of clinically depressive symptoms in a cohort of
men aged 75 years and older.

For the study, investigators recruited a random sample of 299
subjects who were participants in a large population-based study of
abdominal aortic aneurysm screening.

All subjects were being treated for or had a history of hypertension.
Individuals were excluded from the study if they had a BDI score of
18 or higher and significant cognitive impairment, as determined by a
Mini-Mental State Examination score of less than 24. In addition,
individuals who were already taking B vitamins were excluded from the
study, which was conducted from June 2001 to June 2004.

Participants were randomized to receive a single oral capsule
containing 400-µg B12, 2-mg folic acid, and 25-mg B6 or an identical-
looking placebo capsule. Study subjects were told to consume 1
capsule every morning for 2 years.

Study subjects and investigators were blinded to group membership
until the last follow-up assessment was completed.

The study's primary outcome was changes in BDI scores over the study
period. The researchers also examined the proportion of individuals
who were free of clinically significant depressive symptoms at
baseline but became depressed during the trial.

A total of 149 and 150 subjects were in the placebo and active-
treatment groups, respectively. With a 19.4% dropout rate, the final
analysis was based on the 241 who completed the 2-year trial.

Role as Adjunctive Therapy?

The study revealed that participants in the active-treatment group
were 24% more likely to remain free of depression during the trial,
but the difference between the groups was not significant.

Among 23 men — 12 in the vitamin group and 11 in the placebo
cohort — who had mild to moderate depression, there was no
difference between the 2 groups after 24 months of treatment.

Investigators also found that participants in the active-treatment
group had increased blood levels of B12 and folate and reduced levels
of plasma homocysteine. They also found that these blood levels were
similar in men with and without depression, a finding that suggests
the potential link between low vitamin B levels, high homocysteine,
and depression is not strong.

"It remains to be determined whether vitamin supplementation would be
an effective adjunctive antidepressant treatment for people with
severe depression, and if women would benefit more than men from this
therapeutic approach," they write.

The authors report no conflicts of interest.

J Clin Psychiatry. 2008;69:203-1209.

Patients with advanced Parkinson's disease (PD) who undergo
subthalamic nucleus deep-brain stimulation (STN DBS) have an usually
high rate of completed and attempted suicide.

Conducted by researchers at the CHU Henri Mondor, in Créteil, France,
with primary investigator Gilles Fénelon, MD, PhD, a retrospective
review of 200 PD patients who underwent STN DBS reveals a 1% rate of
completed suicide and a 2% rate of attempted suicide, despite clear
improvements in motor function.

In comparison, the prevalence rate of suicide in the French
population of the same age (between 45 and 74 years) is approximately
0.00016% for women and 0.0005% for men.

"Suicidal behavior is a serious potential hazard of STN, calling for
careful preoperative assessment and close postoperative psychiatric
and behavioral follow-up," the investigators write.

The study is published in the August issue of the Journal of
Neurology, Neurosurgery, and Psychiatry.

Low Suicide Rate

According to the study, despite a high frequency of depression in PD
patients, the incidence of suicide is lower than or similar to that
recorded in the general population. However, concerns have been
raised recently about a higher-than-expected frequency of suicide
among patients undergoing STN DBS for advanced PD.

To examine the prevalence and characteristics of completed and
attempted suicides in this patient group, the researchers reviewed
the files of 127 men and 73 women with advanced PD.

The study cohort had a mean age of 61.8 years and mean disease
duration of 14.8 years. All subjects underwent bilateral STN DBS at a
single center between 1997 and 2006.

During the study period, 24 patients died. There were 2 suicides, 2
deaths in undetermined circumstances, 4 attempted suicides, and 1
death by falling out of a window 3 days after surgery. However, this
death was considered accidental and attributed to postoperative
confusion.

Patients who attempted or committed suicide did so an average of 12
months following surgery, despite fair to excellent motor
improvement.

According to the authors, the characteristics of the suicidal
patients did not differ significantly from their nonsuicidal
counterparts with respect to age, disease duration, or scores on the
Mattis Dementia Rating Scale or the Montgomery-Asberg Depression
Scale. In addition, no link was found between suicide and recent
changes in stimulator settings.

Unlikely Culprit

Of the 6 suicidal patients in the cohort, 4 were depressed. According
to the authors, transient depression following STN DBS is relatively
common and reported to affect up to 25% of patients.

While the origin of postoperative depression in PD patients is
unclear, the investigators speculate that it is likely multifactorial
and could include risk factors such as a history of mood disorders,
disappointment with the results of the surgery, or difficulty
adjusting to social, family, or work life.

It is also possible that the reduction in dopaminergic treatment
following surgery is a contributor to postoperative depression,
suggesting that, at least in patients with preexisting mood
disorders, dopaminergic treatment should not be stopped abruptly.

However, rather than depression, the researchers speculate that
altered impulse regulation following STN DBS is more likely to play a
role in the observed suicide rate.

They point out that impulsive aggressive behaviors have been reported
following STN DBS. In addition, suicides have also been reported
following pallidal or thalamic DBS in PD patients and those with
other conditions, including dystonia.

"This further suggests that an induced disturbance of the basal
ganglia circuitry, presumably in the limbic component, may induce
mood disorders and/or suicidal ideas," they write.

In an accompanying editorial, Dr. John Moriarty, from King's College
Hospital, in London, UK, said the study emphasizes the need for
preoperative screening, not to exclude patients from the therapy but
to ensure that they and their family members are aware of the risks.

In addition, Dr. Moriarty called for further research. "There is a
need for us to collect good-quality data prospectively on patients in
order to try to identify those most at risk, and we also need to
collect information on suicides across centers to better understand
this rare but catastrophic outcome," he writes.

The authors report no relevant disclosures.

J Neurol Neurosurg Psychiatry. 2008;79:952-954 Abstract, 851. Abstract

Fenofibrate in combination with coenzyme Q10 (CoQ) appears to have a
number of beneficial hemodynamic effects in type 2 diabetic subjects
with mild left ventricular (LV) diastolic dysfunction, researchers
report in the August issue of Diabetes Care.

"The results of this pilot study suggest that combined use of
fenofibrate and CoQ could improve risk of cardiovascular disease in
diabetic patients," investigator Dr. Gerald F. Watts of the
University of Western Australia, Perth told Reuters Health.

Dr. Watts and colleagues came to this conclusion after a double-
blind study of 74 subjects who were randomized to receive either a
combination of fenofibrate 160 mg and CoQ 200 mg daily, or either
agent alone, or placebo.

None of the treatments had a significant effect on LV function.
Combination therapy, however, prompted a significant reduction in 24-
hour systolic blood pressure, with a prominent nocturnal effect.
Both agents alone also led to a significant drop in 24 hour
diastolic pressure.

In addition, fenofibrate reduced 24-hour heart rate by a significant
3.3 beats per minute. CoQ had no effect on heart rate.

The researchers point out that the approach did not improve
diastolic function, but "we observed beneficial hemodynamic effects
with no significant adverse cardiovascular sequelae."

However, concluded Dr. Watts, "this notion, based on favorable
changes in blood pressure, heart rate and endothelial function, will
need confirmation in a large clinical endpoint trial."

Diabetes Care 2008;31:1502-1509.

A new review by three renowned experts in cardiology suggests that
efforts to treat elevated cholesterol levels are not exploiting the
full potential of cholesterol-lowering strategies, and current
approaches to treatment are simply doing "too little, too late. [1]"
The evidence, say these experts, is strong enough to support even
more aggressive use of lipid-lowering therapies and to intervene at
earlier stages in the development of atherosclerosis.

Writing in the August 5, 2008 issue of Circulation, Drs Daniel
Steinberg, Christopher Glass, and Joseph Witztum (all from the
University of California, San Diego [UCSD]) point out that the
National Institutes of Health (NIH) now recognizes that for
individuals at high risk, treatment to LDL-cholesterol levels <70
mg/dL is better than previously recommended targets of <100 mg/dL.
The researchers suggest, however, that treating to LDL-cholesterol
levels to between 40 and 60 mg/dL confers even more benefit.

"With combination therapy, it is now possible to reach these low LDL
goals; they are not unrealistic," write Steinberg, Glass, and
Witztum. "Yet, most patients outside specialty clinics are not
reaching those goals, in part because of poor compliance but also in
part because practitioners are still hesitant to be more aggressive.
There continue to be concerns about safety and side effects, despite
the wealth of evidence that they are not serious problems in the
vast majority of patients."

In terms of clinical management, adults with existing coronary heart
disease or multiple risk factors should strive to lower their LDL-
cholesterol levels to <50 mg/dL. In fact, the authors write that on
the basis of the accumulated evidence, it "would be reasonable to
recommend that an 'ideal' LDL-cholesterol level should be defined as
<50 mg/dL."

Can You do Better Than Simply Lowering LDL Cholesterol?

Commenting on the proposals of the UCSD researchers, Dr Prediman
Shah (Cedars-Sinai Health Center, Los Angeles, CA) told heartwire
that he agrees with many of their arguments, especially that earlier
and more aggressive treatment in childhood and adolescence,
specifically through lifestyle modifications, might be the way to
further reduce cardiovascular events from atherosclerosis.

"The problem with that approach, however, is a practical one," said
Shah. "We won't be around to see the benefits of those interventions
begun in childhood. It will take 30 or 40 or 50 years to establish
the usefulness of those strategies, even though such benefits seem
reasonable and plausible. While it is still a worthwhile goal, what
do we do with the millions of people who have disease and need
something done now?"

In their paper, Steinberg, Glass, and Witztum point out that
atherosclerosis is often well under way by the time an individual is
30 years old, with fatty-streak lesions evident but asymptomatic and
clinically nonthreatening. They argue, however, that intervention
should not be deferred until later years--with treatment catching up
to the disease--but rather started early because atherosclerosis is
a single disease entity that evolves over time. If the disease is a
continuum, then treating these fatty streaks will prevent or slow
the progression of later, clinically significant lesions.

"Why not slow things down early in the game?" they ask. By
eliminating age from risk-prediction models, this would be one way
to encourage earlier intervention in patients with high-risk
profiles, they add.

Although a long-range plan focusing on prevention at a very early
age is appropriate, Shah said there exists a sizable challenge in
the current patient population where statin therapy alone is only
modestly effective in reducing cardiovascular events. Researchers
need to look to other paradigms of management that are applicable
now or those next-generation therapies on the horizon within the
next five or seven years, such as HDL-based or immunomodulation
therapies. Steinberg, Glass, and Witztum agree that these therapies
might one day be used alongside cholesterol-lowering agents, but
there are ample existing data that show statins and other agents
have not been utilized to their full potential and can be put to
work to further decrease the risks of hypercholesterolemia.

What About apoB and Other Markers of Risk?

On the proposed push toward an ideal LDL-cholesterol target of <50
mg/dL, Dr Allan Sniderman (McGill University, Montreal, QC) told
heartwire that this is an extreme and overly simplistic approach to
managing elevated cholesterol levels and the risk of coronary heart
disease. Clinicians simply are unable to get patients to such a low
treatment target, and in trying to do so, will be prescribing too
much medication for too many people. Instead, said Sniderman, the
focus should be on using technology to more precisely identify at-
risk individuals who would benefit from lower LDL-treatment targets.

Sniderman is a proponent of measuring apolipoprotein B (apoB), as it
is a surrogate of the number of atherogenic particles, including
very low-density cholesterol (VLDL) and LDL cholesterol, rather than
LDL cholesterol, which is a surrogate for the cholesterol
concentration of the LDL particle. He believes that Steinberg,
Glass, and Witztum are wrong in declaring war on LDL cholesterol and
the existing treatment targets.

"I think we would end up using all of the resources in healthcare in
a frantic way," said Sniderman. "I think we should try to identify
ways in which to make society healthier, but in medical terms, I
think we need better ways to identify high-risk people. They don't
mention apoB, which is unfortunate, because I don't think there is
much doubt that apoB identifies high-risk people more precisely than
LDL cholesterol. That's not really debatable at this point. Why
wouldn't we use better technology to identify fewer people to treat?"

The American Diabetes Association (ADA) and American College of
Cardiology (ACC), said Sniderman, have begun to recognize the value
of apoB as a marker of cardiovascular risk, and with the price of
the assay coming down, it should start to be used more frequently as
a means of identifying high-risk patients. "It's the same biology,
just more precise," he said. "So why wouldn't we want to do better,
target the patients better? The real benefit comes from making sure
you are treating the high-risk patient and get them down to a low
level."

Like Steinberg, Glass, and Witztum, Sniderman agrees that at
present, short-term strategies based on 10-year risk models result
in treating people too late. "Because of the effects of exposure, if
we can identify the high-risk person earlier, then we can make very
substantial changes in outcome by intervening moderately earlier in
life," he said.

Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and
more aggressive treatment of hypercholesterolemia. Circulation 2008;
118: 672-677. Abstract

There has been a consistent push in the management of LDL
cholesterol toward lower and lower levels, but there remains a
significant gap in overall lipid control, especially among
individuals with cardiovascular comorbidities, a new study has shown
[1]. Investigators observed that less than one in five individuals
with cardiovascular comorbidities are at recommended targets for all
lipids, including LDL cholesterol, HDL cholesterol, and
triglycerides.

"The clinical trials show that statins are definitely an indicated
therapy for people with cardiovascular disease," senior investigator
Dr Nathan Wong (University of California, Irvine) told
heartwire. "This is about trying to educate the public about that,
but also making sure the public and the physicians, who tend to be
very focused on LDL-cholesterol management, also improve HDL-
cholesterol and triglyceride levels among their patient population."

The study--a report examining the status of all lipid fractions
separately among US persons with a wide range of cardiovascular
comorbidities--is published in the July 2008 issue of the American
Heart Journal. Investigators evaluated the proportion of patients
with and without cardiovascular disease and related comorbidities
who achieved the recommended LDL-, HDL-, non-HDL-cholesterol, and
triglyceride targets of the National Cholesterol Education Program
(NCEP) guidelines by analyzing data from 2883 adults 20 years of age
and older who participated in the National Health and Nutrition
Examination Survey in 2003-2004.

Overall, just 37% of US adults with cardiovascular disease were at
the recommended LDL-cholesterol target levels, and only 17% were at
the recommended levels for all lipids. Among those without
cardiovascular disease, 85% were at their LDL-cholesterol goals and
67% met the recommended targets for all lipids.

"Frequently what a physician will do, because it's simplest and
takes the least amount of time, is put the patient on a statin, but
a statin has relatively little effect on HDL cholesterol and
triglycerides," said Wong. "Patients need to be better advised and
given the necessary support, whether it is dietary counseling or
counseling from an exercise physiologist, to achieve their ideal
body weight. Doing that is one of the single most important ways to
achieve improved HDL-cholesterol and triglyceride levels."

Achieving an ideal body weight also improves insulin resistance,
which is very closely associated with low HDL and triglyceride
levels, he added. In addition to statin therapy, as well as
lifestyle and dietary changes, clinicians should think about
initiating combination therapy to improve the entire lipid profile
in individuals with multiple lipid disorders, especially among those
with cardiovascular and related high-risk comorbidities, said Wong.

New Partnership Announced

Last week, it was announced that Abbott will begin to copromote
AstraZeneca's rosuvastatin (Crestor). According to financial
reports, this will lead to a 2010 launch of the fixed combination
TriLipix, the next-generation TriCor, with rosuvastatin. Abbott has
said it plans to submit a new drug application to the Food and Drug
Administration for the fenofibrate/rosuvastatin combination in 2009.
The combination has been shown to improve LDL-cholesterol, HDL-
cholesterol, and triglyceride levels in patients with mixed
dyslipidemia.

Ghandehari H, Kamal-Bahl S, Wong ND. Prevalence and extent of
dyslipidemia and recommended lipid levels in US adults with and
without cardiovascular comorbidities: the National Health and
Nutrition Examination Survey 2003-2004. Am Heart J 2008; 156:112-
119. Abstract

It's well appreciated that air pollution can worsen lung diseases
and, probably through a generalized inflammatory response,
cardiovascular disease as well; but that apparently isn't all there
is to what dirty air can do to the heart and blood vessels.

Some laboratory evidence suggests that ultrafine particles (UFP), a
component of air pollution that comes primarily from motor vehicles,
can cross into the circulation from the alveoli and have direct
toxic effects outside the lungs, observed Dr Robert A Kloner (Good
Samaritan Hospital, Los Angeles, CA).

Elaborating for heartwire on a "state-of-the-art paper" published in
the August 26, 2008 issue of the Journal of the American College of
Cardiology [1], of which he is a coauthor, Kloner said "the previous
thinking was that these ultrafine particles went to the lungs, and
the lungs got inflamed, then they generated toxic cytokines, and it
was the toxic cytokines that caused the cardiac damage. Our
experiments suggest that there actually may be a more direct effect
of the particles on the vasculature and the heart."

The article, with lead author Dr Boris Z Simkhovich (Good Samaritan
Hospital), is in large part a selective review of key, often
epidemiologic evidence for acute and chronic damaging effects from
exposure to air pollutants. Sometimes the effects are measured in
terms of hospital admissions for pulmonary or cardiovascular
disorders. Other studies have directly tied increased air-particle
concentrations to adverse changes in heart rate and HR variability,
blood pressure, endothelial function, and blood coagulability.

Notably, according to Kloner, one study with about 4500 participants
found an inverse relationship between the distance of a person's
residence from a main road (and car emissions) and degree of
coronary artery calcification at noninvasive imaging. "I think
that's a very sobering finding."

Less covered in the literature, however, is evidence that pollution
particles can directly affect the heart and vessels, independent of
any mechanism involving the lungs.

Research by Kloner's group and other teams, including experiments
conducted on isolated, perfused rat hearts, have suggested that
direct injection of UFPs into the circulation, without any lung
involvement, "can decrease coronary blood flow and decrease
contractility of the ventricles, and we've also seen when you give
these acutely you get an increase in arrhythmias," Kloner said.

Other work by various teams suggests that air pollution can provoke
an inflammatory response in the lungs through the generation of
reactive oxygen species (ROS), which have long been shown to have
different acute and chronic effects on the heart in various clinical
settings, the review from Simkhovich et al notes. They theorize that
if UFPs do enter the circulation from the lungs, they may affect
cardiovascular function by promoting ROS directly in the vessels and
heart.

"We think that oxygen radical production by these particles might be
important, and certainly that they could worsen inflammation and
cause damage in the blood vessels and stimulate atherosclerosis,"
according to Kloner. The idea was supported by work from his group,
reported as a poster at the American College of Cardiology 2008
Scientific Sessions [2], in which infusions of an antioxidant agent
reversed or attenuated impairments in coronary flow and contractile
function induced by the direct administration of UFP in isolated,
perfused rat hearts.

That observation, according to Kloner, raises at least the
theoretical possibility of some kind of antioxidant therapy against
the cardiovascular effects of air pollution. Currently the most
important "therapy" for susceptible individuals, especially patients
with coronary or pulmonary disease, consists of minimizing exposure.
That, he said, might include avoiding outdoor exercise on days when
air pollution is especially bad and staying indoors altogether when
it's most severe.

But could there be other therapies? "Is it possible, for example,
that patients with coronary disease should take antioxidants on days
when there are high levels of pollution? I don't know the answer,
but I know that experimentally, at least, we have preliminary data
suggesting that antioxidants might at least reduce the effect the
particles have on coronary flow."

Simkhovich BZ, Kleinman MT, Kloner RA. Air pollution and
cardiovascular injury. Epidemiology, toxicology, and mechanisms. J
Am Coll Cardiol 2008; 52:719-726.
Hwang H, Simkhovich BZ, Kleinman MT, Kloner RA. The direct toxic
effect of ultrafine particles in coronary flow: the importance of
the hydroxyl radical. J Am Coll Cardiol 2008; 51 (suppl A):A303.

I
guess this story about a court ruling about our profesison as medical
professionals whether as doctors or as clerks would sum it all up. what
are your reactions...I attached the excerpt....if you want the full
story...its here http://medicalstreamline.blogspot.com/

By a unanimous vote on Monday, the California Supreme Court affirmed
the right of a lesbian woman to be inseminated by doctors over their
religious and moral objections. That ruling is being harshly criticized
by faith-based groups that have fought to preserve physicians' right to
practice their faith as part of their professional ethics.

   The
justices ruled that California's anti-discrimination laws extend to
even medical treatment of homosexuals, and wrote that doctors at the
North Coast Women's Medical Group, a private fertility clinic, had
neither "a free-speech right nor a religious exemption" from the laws. ...

Sincerely,
P Allen Smith, M.D.
Neuroscience Coordinator
VAD Department, NY





[Non-text portions of this message have been removed]

The addition of "high-bolus-dose" tirofiban (Aggrastat, Merck) to
dual antiplatelet therapy in the prehospital setting significantly
improved ST-segment resolution both before and after primary PCI in
patients with acute ST-elevation MI (STEMI), in the placebo-
controlled second Ongoing Tirofiban in Myocardial Evaluation (ON-
TIME 2) trial [1]. Such triple antiplatelet therapy, given with
unfractionated heparin before PCI, didn't seem to increase the risk
of major bleeding.

There was a statistically significant reduction in a composite
clinical end point with added tirofiban, but the trial wasn't
powered for clinical outcomes, according to ON-TIME 2 investigators;
ST-segment resolution is an indirect marker for myocardial
reperfusion.

The findings, published in the August 16, 2008 issue of the Lancet,
with first author Arnoud WJ van't Hof (Isala Klinieken, Zwolle, the
Netherlands), had been preliminarily presented at the American
College of Cardiology 2008 Scientific Sessions and were covered then
by heartwire.

"The routine administration of glycoprotein [GP] IIb/IIIa blockers
in patients with STEMI is a class 2a indication according to [US and
European guidelines]," observe the authors, yet "large registry
studies show that in real-world practice, GP IIb/IIIa blockers are
given to only 25% to 30% of patients with STEMI, often for bailout
situations." The current trial, they write, suggests that the
drugs "should not be restricted to patients with complications after
PCI, even in a setting in which high-dose clopidogrel is given well
in advance of PCI."

Studies of prehospital GP IIb/IIIa inhibition in STEMI, usually with
abciximab (ReoPro, Centocor/Eli Lilly), have been conducted
primarily in Europe, where ambulances are often staffed by
physicians. In ON-TIME 2, van't Hof et al write, "patients were
diagnosed and immediately treated in the ambulance by either a
physician or a dedicated well-trained paramedic. Diagnosis was
correct in 94% of patients with computerized ECG algorithms only,
without the need for transmission of the ECG to the hospital."

The trial randomized 491 patients in the Netherlands, Germany, and
Belgium to receive the GP IIb/IIIa inhibitor as a 25-µg/kg bolus
followed by a 0.15-µg/kg/min infusion for 18 hours--493 patients
instead received placebo--on top of 600-mg oral clopidogrel and 500-
mg IV aspirin along with 5000-IU heparin, all administered in-
transit to a PCI center.

The entry criteria included MI symptoms for >30 minutes but <24
hours and ST-segment elevation >1 mV in two adjacent ECG leads.
Patients with severe renal impairment or in shock were excluded.

After the prehospital STEMI diagnosis, randomization took place a
median of 75 minutes after symptom onset; it was a median of 55
minutes from the start of prehospital antithrombotic therapy to
angiography.

"ON-TIME 2 tells us more than the benefit of high-dose tirofiban in
primary PCI. The study reveals that high-dose clopidogrel is not
effective enough and confirms the need for fast and strong platelet
inhibition," according to Dr Gilles Montalescot (Universitaire Pitié-
Salpêtrière, Paris, France) in an accompanying editorial [2]. The
trial, he writes, "reminds us also that the first contact with the
patient must be rapid and medical. Until now, only well-organized
prehospital systems have been able to provide such a service."

The trial was funded by Merck. Disclosures for its coauthors are in
the report. Montalescot reports that his center "has received
research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli
Lilly, and Centocor," and he has consulted for Sanofi-Aventis, Eli
Lilly, Bristol-Myers Squibb, Merck, GlaxoSmithKline, The Medicines
Company, and Schering-Plough and received lecture fees from Sanofi-
Aventis, Eli Lilly, Bristol-Myers Squibb, and GlaxoSmithKline.

van't Hof AWJ, ten Berg J, Heestermans T, et al. Prehospital
initiation of tirofiban in patients with ST-elevation myocardial
infarction undergoing primary angioplasty (ON-TIME 2): a
multicentre, double-blind, randomised controlled trial. Lancet 2008;
372:537–546.
Montalescot G. Mechanical reperfusion: treat well, treat on time
too. Lancet 2008; 372: 509-510.

A new study has found that retinopathy is associated with an
increased risk of coronary heart disease (CHD) regardless of whether
or not the person also has diabetes [1]. Dr Gerald Liew (University
of Sydney, Australia) and colleagues report their findings online
August 12, 2008 in Heart.

The researchers explain that diabetes is a known risk factor for CHD
and that previous studies have reported consistent association of
retinopathy with increased CHD risk in people with diabetes. "But
our study may be the first to report a similar association in people
without diabetes," they note.

Ophthalmologist and senior author Dr Jie Jin Wang (University of
Sydney) told heartwire: "Interestingly, the risk magnitude from
retinopathy is similar to the risk from diabetes alone. And if a
person has both diabetes and retinopathy, the risk is double
compared to those with neither."

One-Third Increase in CHD With Retinopathy

In their study, the Australian researchers looked at those
participating in the Blue Mountains Eye Study, in which 2768
participants did not have diabetes and 199 did. The presence and
severity of retinopathy was assessed from retinal photographs.
Twelve-year cumulative CHD deaths were ascertained from Australian
National Death Index records.

Over the 12 years, 353 participants (11.9%) died from incident CHD.
Retinopathy was present in 28.6% of those with diabetes and in 9.7%
of people without diabetes. The presence of retinopathy increased
the CHD mortality rate per person¡Vyear by an amount (0.005)
equivalent to diabetes itself.

After adjustment for risk factors, retinopathy remained an
independent predictor of CHD death, both in people with diabetes
(hazard ratio 2.21) and in those without diabetes (HR 1.33). More
severe (known as moderate) retinopathy was associated with adjusted
HR of 6.68 in those with diabetes and 2.29 in those without.

Wang told heartwire that the link between retinopathy and CHD is as
yet unclear, but "there is increasing recognition that coronary
microvascular dysfunction also plays an important role in CHD,
particularly in women and in persons with diabetes."

Retinopathy May Indicate Underlying Subclinical Vascular Disease

The researchers say, "These findings suggest that the presence of
retinopathy, regardless of a person's diabetes status, may indicate
underlying subclinical vascular disease."

Wang says: "We speculate that retinopathy may mirror similar changes
in small vessels of other organs of the body including the heart. If
this is proven, the small-vessel condition in the retina may be used
as a window to the small-vessel condition of the body, and
assessment of retinal condition using retinal imaging may help to
identify those at high risk of cardiovascular disease."

As retinopathy lesions, particularly moderate retinopathy, can
readily be identified in emergency departments and doctors' clinics,
the findings support a role for direct ophthalmoscopy to help
identify such people, she says

They "may benefit from a thorough CV risk assessment, lifestyle
changes, better management of risk factors, and closer monitoring
for CHD events," she and her colleagues conclude.

Liew G, Wong TY, Mitchell P, et al. Retinopathy predicts coronary
heart disease mortality. Heart 2008; DOI: 10.1136/hrt.2008.146670.
Available at: heart.bmj.com.

Debate is ongoing on whether use of the nucleoside reverse
transcriptase inhibitors (NRTIs) abacavir (ABC) and didanosine (ddI)
heightens the risk for cardiovascular disease (CVD). It came to the
fore in April in a paper published in The Lancet that analyzed data
from the observational D:A:D cohort study, and it continued here at
the XVII International AIDS Conference.

Jens Lundgren, MD, from the University of Copenhagen, Denmark, and
colleagues wanted to know whether the association of excess risk for
myocardial infarction (MI) that they found in analysis of
D:A:D "could be reproduced in another data set where utilization of
various NRTIs differed from that of D:A:D."

They turned to the SMART study, a randomized trial comparing
continuous and guided interruption of antiretroviral therapy. The
researchers stratified 4544 patients into 3 categories according to
use of NRTIs: ABC but not ddI, ddI with and without ABC, and use of
other NRTIs. Baseline characteristics of the groups were similar,
including risk factors for cardiovascular disease, diabetes, current
smoking, and use of hypertension and lipid-lowering medications.

The analysis evaluated 4 strata of CVD: CVD major; MI; CVD,
expanded; and CVD minor. The study found an almost exact overlap of
the adjusted and unadjusted hazard ratio in every category that
favored "other" more than ABC: 1.8, 4.3, 1.9, and 2.7 in each of the
4 categories of CVD, respectively. Similar patterns of association
were seen when use of ABC was compared with use of tenofovir.

Evaluation of a subset of patients with biomarker data available at
baseline found high-sensitivity C-reactive protein (hs-CRP) and
interleukin 6 (IL-6) levels to be 27% (P = .02) and 16% (P = .02)
higher for patients receiving ABC (n = 175) compared with other
NRTIs (n = 500). Use of ddI was not associated with altered risk for
CVD, nor with altered levels of biomarkers.

Dr. Lundgren concluded, "Consistent with D:A:D, current use of
abacavir during follow-up in SMART was associated with an excess
risk of CVD. And furthermore, abacavir use at study entry was
associated with increased levels of IL-6 and hs-CRP.

"The drug dose does not appear to affect the underlying
atherosclerotic process per se but may cause coronary arthritis that
leads to instability of plaques. This appears to be only clinically
relevant to consider among patients with elevated underlying
cardiovascular risk."

Responding to a question, Dr. Lundgren said this excess risk is seen
in patients who have been receiving ABC for an extended period of
time, so it is unlikely that it is linked to the HLA 5701 phenotype.
He encouraged researchers to look for other haplotypes that might
contribute to "ongoing, maybe subclinical inflammatory elevation."

Dr. Lundgren said that there appeared to be no relationship between
the use of protease inhibitors and increased cardiovascular risk in
either the D:A:D or SMART studies.

A clinician from Florida said that he has many patients on ABC who
by all accounts seem to be doing well. He was concerned as to
whether he should switch them to a different regimen.

Dr. Lundgren noted that the clinical relevance of these studies is
likely to apply only to a subset of patients, "namely, those who
have several underlying cardiovascular risk factors. For most
patients, this is not an issue."

GlaxoSmithKline's Response

GlaxoSmithKline, reacting to the earlier publication of the D:A:D
analysis, drew upon its HIV Data Repository to review and conduct a
composite analysis of data from the 14,683 participants who had been
in 54 clinical trials for 24 weeks or more, and who had been exposed
to abacavir. Earlier in the week, Jaime Hernandez, MD, from
GlaxoSmithKline, presented that analysis.

The data showed no difference between those who had and those who
had not been exposed to ABC. Baseline patient characteristics were
similar, as were treatment experience, lipids, and glucose values.
Indices of CVD were low and comparable, with the ABC-exposed
patients having a 0.249% frequency of coronary artery disorders and
those who were not exposed having a 0.416% frequency. The rates of
coronary artery disease per 1000 patient-years were 3.447 and 5.817,
respectively (P = .055). The rates of MI were 2.039 vs 2.2363 (P
= .706).

Dr. Hernandez acknowledged the limitations of the initial drug
development studies in possibly capturing long-term and low-
incidence events such as enhanced risk for cardiovascular disease.
Given the transition of HIV disease management from that of an acute
to a chronic condition, he said, "In future studies we need to
incorporate cardiovascular risk factors and other biomarker
collections of all non-AIDS risk factors."

Potential Reasons for Different Trial Results

During discussion, Cornell University researcher Roy Gulick, MD,
noted that "there are inherent differences between clinical trials
data and human cohort data," particularly with regard to
exclusionary criteria for the trials. This might help to explain the
discordance between the clinical trials and cohort analysis.

Another researcher commented that participants in the drug
development trials were, on average, younger than those in the
cohort studies, and that risk for CVD increases with age. She asked
whether the company had done a subset analysis of older trial
participants. Dr. Hernandez said it has not.

Kenneth Mayer, MD, a researcher at Brown University, Providence,
Rhode Island, and Fenway Community Health, Boston, Massachusetts,
told Medscape HIV/AIDS that this information reinforces the need to
monitor patients for cardiovascular risk factors: "If you work on
those, you can minimize any potential risk from abacavir, if it
really does exist." He called abacavir "a good drug" and said that
he would hate to see an overreaction on the part of clinicians who
would be afraid to use it where appropriate.

The D:A:D and SMART studies were funded by government health
agencies in the United States and Europe. The GlaxoSmithKline
analysis was conducted by that company. Dr. Hernandez is an employee
of GlaxoSmithKline. Dr. Lundgren, Dr. Gulick, and Dr. Mayer have
disclosed no relevant financial relationships.

XVII International AIDS Conference: Abstract THAB0305, presented
August 7, 2008; abstract WEAB0106, presented August 6, 2008.

US doctors have reported the first experiences of heart transplant
in three infants after cardiocirculatory death, rather than brain
death, in the donors [1]. Lead author Dr Mark M Boucek (Joe DiMaggio
Children's Hospital, Hollywood, FL) told heartwire this was, to his
knowledge, the first published account of heart transplant in
children after donor cardiac death, although organs other than
hearts are transplanted after cardiac death.

Boucek et al report their investigational findings in the August 14,
2007 issue of the New England Journal of Medicine; the transplants
were conducted at Denver Children's Hospital, in Colorado. The paper
is accompanied by three perspectives [2,3,4] and an editorial [5],
as well as a round-table discussion on the New England Journal of
Medicine website [6], all of which ponder the many scientific,
medical, legal, and ethical questions arising as a result of this
work.

In one perspective [2], medical ethicist Dr Robert M Veatch
(Georgetown University, Washington DC) says: "The results appear to
open the door to heart transplantation after cardiac death."

And in the editorial [5], New England Journal of Medicine editors
Drs Gregory D Curfman, Stephen Morrissey, and Jeffrey M Drazen say
that despite the many controversial and differing opinions of the
perspective authors and the ensuing debate--which they welcome--"one
conclusion is clear. As a result of their investigational protocol,
three babies are now alive; had the procedures not been performed,
it is virtually certain that all six babies would be dead."

Heart Transplant After Cardiac Death Feasible, Especially in Kids

The practice of donating organs after cardiac death, rather than
brain death, has gained acceptance in recent years, but only for
organs other than the heart. There has been one report of a
successful heart transplantation in an adult that involved a donor
who died from cardiocirculatory causes, but concerns about the
vulnerability of the heart to ischemic injury has limited further
cardiac transplantation in adults from donors who have died from
cardiac causes, Boucek et al explain.

But in children, heart transplant has been performed after prolonged
ischemic injury in a donor, and the results were similar to those
for donors without ischemic cardiac injury, they note. And the need
for more pediatric donors is pressing, Boucek stresses.

"There are a significant number of kids who have congenital heart
disease or develop disease of the heart muscle that prevent them
from surviving, and their only chance is a heart transplant," he
explains. And "the worst age for donation is in those under one, not
because there are not a large number of children who die at this
age," but because doctors feel a little less comfortable with
declaring even brain death in such infants, he says, "so many of
these children are not offered the option."

However, the parents of dying children are amenable to organ
donation, he says, stressing the positive feelings that arise for
the donor's family from giving the potential for life to another
child.

Three Children Still Alive Three Years Later

When kidneys, lungs, livers, and other organs are transplanted after
cardiac death, there are a number of differing opinions as to the
length of asystole required before pronouncement of death, with
times ranging from two to five minutes routinely used. But
autoresuscitation of the heart has never occurred any later than 60
seconds after asystole, so this two- to five-minute period is a
somewhat arbitrary concept, Boucek explained to heartwire.

And when the discussion moves from transplanting other organs to
transplanting the heart, this time period is vital, he notes,
because "the heart is the most vulnerable organ, and it needs to
work at its optimum right after transplantation." The longer the
period of time following asystole that is required before
pronouncement of death, the more likely the heart to be transplanted
will become damaged, jeopardizing the recipient.

Hence, in their protocol, Boucek et al started with a period of
three minutes after asystole for the first transplant they
performed, but thereafter "the feeling from the entire team was that
we should shorten this, as we may have jeopardized the recipient."
So, following extensive discussions including the hospital ethics
committee and the data and safety monitoring board, they adopted a
period of 75 seconds for the next two transplants.

"The outcomes after transplantation of hearts from donors who died
from cardiac causes were similar to those associated with
traditional organ donation," Boucek and colleagues note in their
paper. "All three recipients survived despite being at high risk for
death," and the six-month survival was 100%, compared with 84% for
17 control infants who received transplants procured through
standard organ donation. And the three children are still alive
three and a half years later, they note.

Distant Sharing of Hearts After Cardiac Death Would Have Great Impact

The legal and ethical issues surrounding this investigation that are
debated in the perspectives and editorials are welcomed by Boucek,
who told heartwire, "Discussion is healthy. There are a number of
angles that are taken that are relatively extreme, and that's
excellent, as the discussion should be full and uninhibited, and
these are rational people with differing opinions. The whole thing
should be done as transparently as possible. My hope is that this
leads to more opportunities for transplantation."

He added that there is no reason why the protocol developed by his
team, with perhaps certain adjustments to take into account local
conditions, could not be performed anywhere in the world.

The one great limitation of this procedure, said Boucek, "is that
you have to have a donor and a recipient at about the same time."
If, however, the concept of heart transplantation after cardiac
death could become mainstream and a donor heart procured following
cardiac death could be flown anywhere within reason--as is the case
currently for hearts donated after brain death--"this would have a
huge impact," he stressed.

"For pediatric heart donation and transplantation involving patients
who die from cardiocirculatory causes to become a more frequent
option for end-of-life care and to affect significantly the
nationwide risk of dying while waiting, the concept of distant
sharing of donated organs from these donors should be considered,"
he and his colleagues conclude.

Boucek MM, Mashburn C, Dunn SM, et al. Pediatric heart transplant
after declaration of cardiocirculatory death. New Engl J Med 2008;
359:709-714.
Veatch RM. Donating hearts after cardiac death--reversing the
irreversible. New Engl J Med 2008; 359:672-673.
Truog RD and Miller FD. The dead donor rule and organ
transplantation. New Engl J Med 2008; 359:674-675.
Bernat JL. The boundaries of organ donation after circulatory death.
New Engl J Med 2008; 359:669-671.
Curfman GD, Morrissey S, and Drazen JM. Cardiac transplantation in
infants. New Engl J Med 2008; 359:749-750.
Perspective roundtable. New Engl J Med. Available at:
http://media.nejm.org/Data/DataSupplements/NEJMp0804161/664/ds.aspx?
DSID=664.

The combination of amlodipine and valsartan lowered blood pressure
in blacks more effectively than did amlodipine monotherapy both
before and after the optional addition of hydrochlorothiazide,
according to the results of the Ex-STAND Study presented at the
National Medical Association meeting on July 26 in Atlanta, Georgia.
Contrary to conventional wisdom that the combination of calcium
channel blockers with angiotensin-converting enzyme (ACE) inhibitors
may cause severe adverse events ¡X including angioedema and cough ¡X
in blacks, combination therapy was well tolerated in this study of
more than 500 black patients.

The meeting highlighted multiple areas of disparities in healthcare
among different racial and ethnic groups, as well as medical and
public policy interventions that may improve quality of care for
all. To learn more about specific strategies that may reduce racial
and ethnic disparities in cardiovascular healthcare among groups, as
well as the overall implications of the Ex-STAND Study, Medscape's
Laurie Barclay, MD, interviewed presenter and lead investigator John
M. Flack, MD, MPH, FAHA, FACP, professor of medicine and physiology,
chair of the Department of Medicine, and chief of the Division of
Translational Research and Clinical Epidemiology at Wayne State
University in Detroit, Michigan.

Medscape: What genetic and/or cultural factors increase the risk for
cardiovascular disease among different racial and ethnic groups in
the United States?

Dr. Flack: Clearly, cardiovascular diseases are influenced by
genetic and environmental factors [and] their interactions with each
other, as well as interactions within each domain ¡X complex gene
interactions and the combined interplay between environmental
exposures. Nevertheless, for common cardiovascular diseases that are
likely attributable to the small effects of multiple genes, there is
no consistent pattern of genetic differences that accounts for the
cardiovascular disease excess observed in many minority groups
relative to whites or between the minority groups themselves.
Furthermore, race and/or ethnic groups do not represent discrete
gene pools, and typically there is much more genetic variation
within a racial group than between [the groups].

Cultural factors such as diet ¡X potassium, calcium, and sodium
intakes ¡X along with long-term habits such smoking[,] habitual
activity, and obesity appear to significantly increase the risk of
some cardiovascular diseases that occur to excess in nonwhite
populations and also parallel cardiovascular disease gradients
within racial groups.

Medscape: How can these factors be addressed to minimize risk?

Dr. Flack: The most accessible determinants of cardiovascular
disease are environmental exposures ¡X diet and possibly air
quality ¡X habitual physical activity, smoking (including passive),
and the important balance between caloric intake and energy
expenditure that, when imbalanced in favor of the former, leads to
obesity. One mistake is to believe that the sole avenue toward
favorably influencing these exposures depends entirely on individual
choices. Though important, the built environment in a community and
the relative education attainment and affluence of communities, [as
well as] the availability of high-quality, less energy-dense food,
are all important factors and even influence the individual choices
made by individuals that affect cardiovascular disease risk.

As physicians we focus on the individual. And, for sure, the
individual is important; however, so are these other factors.

Medscape: What differences in treatment response to cardiovascular
drugs and regimens exist among different racial and ethnic groups in
the United States?

Dr. Flack: At the group level, differences have been noted across
racial groups in their response to certain drugs. Most notably, in
the cardiovascular arena, [there are] lesser average blood pressure
responses in blacks prescribed ACE inhibitors and angiotensin
receptor blockers than in whites. This is mostly observed when
dietary intake of sodium is unrestricted or physiologically high.
Nevertheless, the range of blood pressure responses is much broader
and more variable within racial groups than between them.

There is no drug, to my knowledge, that works only in 1 racial or
ethnic group. This includes the drug isosorbide
dinitrate/hydralazine that putatively works only in blacks. This
drug has never been tested on top of contemporary heart failure
treatments in whites and [was] never tested in white women under any
circumstances. Thus, utilization of modest shifts in average
responses for groups to determine the suitability of a drug for an
entire race of people ignores the wide and overlapping responses
within these groups.

Medscape: What was the take-home message from the trial you
presented on amlodipine and valsartan?

Dr. Flack: The take-home message from the 2402 trial with
amlodipine/valsartan in blacks with stage 2 systolic hypertension is
that significant numbers [of patients], approximately one half, can
obtain blood pressure control to less than 140/90 mm Hg with a
single pill. The combination of an angiotensin receptor blocker or
an [ACE] inhibitor lowers blood pressure very efficiently in all
populations including blacks. However, the substitution of the
angiotensin receptor blocker for the [ACE] inhibitor removes the
risk of ACE-inhibitor angioedema (~4-fold higher in blacks than
whites) and ACE inhibitor cough. Thus, the tolerability should be
greater.

Medscape: Have medical education and continuing medical education
adequately addressed cardiovascular risk and disease management
based on these differences, and if not, what can be done to improve
physician awareness and implementation of specific strategies?

Dr. Flack: Medical education has probably overemphasized racial
differences in response to cardiovascular drugs such as ACE
inhibitors, and while group differences exist in response, there is
no accurate way to extrapolate these differences to an individual of
either race since the blood pressure response distributions mostly
overlap, and differences in response are much greater within racial
groups than between them. We have to do a better job in medical
education of highlighting the hazards of blanket application of
modest shifts in response between racial groups to all individuals
in these groups. This is not individualizing treatment, as it has
erroneously been called.

Medscape: What initiatives and strategies have the National Medical
Association and/or other groups begun to try to address identified
deficiencies in cardiovascular healthcare?

Dr. Flack: Organizations such as the National Medical Association
and the International Society on Hypertension in Blacks have worked
to highlight the need to individualize treatment of blacks and to
avoid the mistake of making blanket assumptions that a drug always
works or never works based on shifts in the response distributions
to a given drug given to different races. One indirect approach to
accomplishing this is to focus on the quality of care rendered to
patients.

[F]or example, in hypertension treatment, the blood-pressure-
lowering effect of a single drug is not totally unimportant, but in
the overall scheme of things, [it] has been grossly overemphasized,
given that the overwhelming majority of hypertensive patients will
not ever be controlled to their goal blood pressure and lower with a
single antihypertensive agent. In hypertension treatment, the
addition of a diuretic or a calcium antagonist to either an ACE
inhibitor or angiotensin receptor blocker eliminates racial
disparities in blood pressure response.

Medscape: How successful have these strategies been, and what are
the largest obstacles to their implementation?

Dr. Flack: The largest obstacle to implementation of a more
individualized approach to hypertension treatment in blacks has been
the entrenched attitude that somehow or another, for all the years
that the use of ACE inhibitors was avoided in blacks, somehow...this
approach could not be wrong.

A similar mindset exists for favoring the use of diuretics and
calcium and calcium antagonists in blacks to the exclusion of other
monotherapies in blacks with hypertension. In reality, this paradigm
is significantly flawed during antihypertensive monotherapy when
applied to individuals of either race and is irrelevant for the
majority of hypertensives requiring combination antihypertensive
drug therapy to attain and maintain blood pressure levels at or
below goal levels.

Medscape: What do you recommend in terms of current cardiovascular
healthcare policy and in terms of future research?

Dr. Flack: In terms of future cardiovascular healthcare policy,
there should be a greater emphasis on quality. This will help
eliminate racial and ethnic disparities...in the processes of care
measured and [in] relevant outcomes while, at the same time, raising
the quality of care for all patients.

Future research should focus on the role of ancestry more than
phenotypically determined race. Hopefully, our ability to more
accurately phenotype individual patients with noninvasive vascular
measures, determination of levels of proteinuria, ancestry and other
genetic variation, and diet and lifestyle habits will allow greater
individualization of therapeutic choices that will maximize the
desired therapeutic responses while minimizing adverse effects.

Dr. Flack reports having consulting contracts, having received
lecture fees, and/or having grant research funding from Novartis,
Pfizer, Mannkind, the National Institutes of Health, the US Centers
for Disease Control and Prevention, Takeda, Daichii-Sankyo,
Boehringer Ingleheim, and Gilead.

National Medical Association 2008 Annual Convention and Scientific
Assembly. July 26

The US FDA has approved the first combination of an angiotensin
receptor blocker (ARB)--valsartan--with a calcium-channel blocker
(CCB)--amlodipine--for the initial treatment of hypertension. The
product, known as Exforge, was given the additional indication along
with another combination containing valsartan and
hydrochlorothiazide, Diovan HCT [1]. Both are marketed by Novartis.

The products were already available for the second-line treatment of
high blood pressure--Exforge having first been approved just last
year. Hypertension expert Dr Franz Messerli (St Luke's Roosevelt
Hospital, New York) told heartwire that the new indication for
Exforge "is by far the more important of the two, because valsartan
and amlodipine are the most commonly prescribed ARB/CCB combination,
and this is the first time such a combination has been approved for
initial therapy."

Messerli welcomes the approval--"I think this is a major progress"--
but cautions that "patient selection is crucial when it comes to
using fixed-dose combinations, because they are not for every
patient. A decade ago the pharmaceutical companies were taking out
full-page ads stating that 80% of patients can be controlled on drug
X monotherapy, and now they are saying that more than 80% of
patients need combination therapy. I suspect the truth is somewhere
in between, with around 50% to 65% of patients needing
combinations."

Approval sanctions off-label use, allows companies to market as
first-line

Messerli says the FDA has "been fairly trigger-happy to approve
diuretic-based combinations" but slightly more reluctant to grant
approvals of other fixed-dose combinations, particularly for initial
therapy, for the simple reason that it fears that some patients will
be exposed unnecessarily to combination treatment.

But he believes that physicians have been erring on the side of
caution in this regard, "as they are a bit reluctant to be too
aggressive in lowering blood pressure too fast." However, "the
ACCOMPLISH study really has put fixed combinations on the map, and
therefore physicians have been using them, which is not surprising,"
and some doctors have been using Exforge off-label for the initial
treatment of hypertension, "so in some ways the FDA is belatedly
blessing what many physicians have been doing for quite some time."

Another expert, Dr Elizabeth Ofili (Morehouse School of Medicine,
Atlanta, GA), agrees, adding that "it is important to get the first-
line approval for a number of reasons, one of which is managed care.
The FDA is moving toward this area and recognizing that high blood
pressure is a complex process." Messerli says such approvals also
allow the companies to market their products as first-line therapy,
something they have previously been unable to do.

"There are two main advantages of fixed-dose combinations for the
patient," he says. "First, the pill burden is reduced, and second,
the patient only has one copayment instead of two."

Both Messerli and Ofili said that there would not be too much
competition from generics for the new Exforge product or for other
similar combinations at the present time. Although amlodipine has
recently become available generically in the US, it is not that
cheap, they point out.

"Once amlodipine becomes a Wal-Mart $4 drug, it's obvious that cost
will become an issue," says Messerli. None of the ARBs are yet
available generically in the US, he adds, although losartan will be
available next year.

Novartis. Single-pill combinations Diovan HCT and Exforge approved
in US as first-line treatments for high blood pressure press
release]. August 4, 2008. Available at:
http://www.novartis.com/newsroom/media-
releases/en/2008/1239786.shtml.

Many patients with heart failure would prefer to be on chronic
medical therapy, which is likely to prolong survival at the cost of
some quality of life, while others would rather be on a treatment
that makes them feel better but perhaps die sooner, such as oral
inotropic agents--that much is well known. But the path a patient
would choose appears unrelated to LV ejection fraction, NYHA
functional class, quality-of-life scores, or other measures of
symptom status and overall health, according to a small study of
adults with heart failure published online July 28, 2008 in the
Journal of Heart & Lung Transplantation [1], with Jane MacIver
(Toronto General Hospital, ON) as the first author.

"There is no easy way to determine who falls into which group,"
observe the authors. "Talking to patients about their treatment
options, before they are in the terminal stages of heart failure, is
still the best way to understand treatment preferences."

Their analysis included 91 patients with heart failure of either
NYHA class 2 or 4 who were interviewed on management preferences and
completed the Minnesota Living with Heart Failure Questionnaire and
other subjective tests.

The 43 patients in NYHA class 4 had significantly poorer quality-of-
life and dyspnea scores and poorer health overall compared with the
48 in NYHA class 2, to be sure, but the latter group with less
severe disease and the sicker patients didn't differ much in how
often they preferred quality over quantity of life or the reverse.

"One thing we had thought going into the study was that patients who
had suffered extensively from advanced heart failure might feel
differently than those who had never had severe heart failure. But
in fact, that wasn't the case," primary author Dr Heather J Ross
(Toronto General Hospital) told heartwire.

"The reality we've learned, by and large as doctors, is that we're
probably not the best at assuming what they will or won't want," she
said. "I think actually us showing that the patients are making
these decisions early in the course of their illness is an important
thing that the study found."

As part of the interview process, the patients were informed about
the "outcome, treatment burden, and mode of death" for three
treatment options: standard medical therapy, oral inotropic therapy,
and implantation with a left ventricular assist device (LVAD). They
also expressed preferences in hypothetical treatment situations that
accounted for what each option offered with respect to symptom
relief vs survival.

Asked to choose between two of the treatment options, on average the
patients preferred oral inotropes over optimal standard medical
therapy (p<0.01), "indicating a strong preference for the symptom
relief afforded by inotropes" over the better survival promise of
standard meds; optimal medical therapy over an LVAD (p<0.01); and
inotropic drugs over an LVAD (p<0.05).

More patients ranked inotropic therapy as their first choice among
the three options (42%) than an LVAD (32%) or optimal medical
therapy (26%).

The findings support the idea, familiar in the heart-failure
community, that oral inotropic drugs should be available for
palliative care to patients who aren't candidates for heart
transplantation or destination LVAD therapy and want to sacrifice
some survival time in order to feel better, Ross and her colleagues
write.

"In patients who understand, recognize, and are competent enough to
appreciate that distinction, given how horrible death from advanced
heart failure can be," Ross said, "I think [oral inotropic agents]
should be a potential treatment option in the palliative care
setting."

MacIver J, Rao V, Delgado DH, et al. Choices: a study of preferences
for end-of-life treatments in patients with advanced heart failure.
J Heart Lung Transpl 2008; DOI:10.1016/j.healun.2008.06.002 .
Available at: http://www.jhltonline.org.

FDA has approved its intravenous antihypertensive clevidipine
(Cleviprex), which is the first new IV drug for high blood pressure
in 10 years [1].

Clevidipine is a new calcium-channel blocker, which has shown
promise in several studies, including in severe acute hypertension
in the emergency department and in the setting of perioperative
blood-pressure management. Doctors presenting these trials, as
previously reported by heartwire, said the advantages of clevidipine
over current drugs used for acute hypertension--such as sodium
nitroprusside, labetalol, and nicardipine--are that it is easy to
titrate and has an ultrashort half-life of less than one minute.

Rocky path to approval

The path to approval has not been clear of obstacles for
clevidipine, however. In 2005, the company had to halt patient
enrollment in a series of trials in the perioperative setting--known
as ECLIPSE--after patients randomized to the drug showed more
frequent atrial fibrillation (AF) following surgery compared with
patients randomized to comparative treatments.

But the ECLIPSE trials were restarted, and when the results were
presented at ACC 2007 meeting, the lead investigator said that the
AF seen did not appear related to clevidipine. And there was no AF
seen in the VELOCITY study with clevidipine, the very first study
ever to deal with acute hypertension in the emergency department,
according to the lead investigator of that trial, Dr Joseph Varon
(University of Texas Health Science Center, Houston).

Reporting the findings of VELOCITY last year, he told heartwire: "If
I were to put it in a simple way, I would say that clevidipine
is 'supernicardipine.' The beauty of clevidipine is in the short on-
off, and the way we performed the study meant that if we overdid it,
we just stopped the infusion and then the blood pressure came back
to normal. It was an amazing finding. Most of our patients were able
to have their blood pressure controlled within 10 minutes. When you
are dealing with a situation such as emergency care, that's a big
advantage."

The Medicines Company. The Medicines Company's Cleviprex receives
FDA approval [press release]. August 4, 2008. Available at:
http://www.themedicinescompany.com.

A new study shows that in patients with early Alzheimer's disease
(AD), better cardiorespiratory fitness is associated with less
atrophy in regions of the brain associated with memory; no such
relation was seen in nondemented patients.

"The summary of these results is that fitness is associated with
hippocampal and parahippocampal volumes in early Alzheimer's disease
patients but not in nondemented subjects," Robyn A. Honea, PhD, a
postdoctoral fellow in the alzheimer's and memory program at the
University of Kansas Medical Center, in Kansas City, told attendees
here. "This suggests that maintaining cardiorespiratory fitness may
modify Alzheimer's-disease-related atrophy."

The findings were presented here at ICAD 2008: Alzheimer's
Association International Conference on Alzheimer's Disease.

Separate presentations reported that AD patients who did caregiver-
directed exercise had a reduction in falls and an increase in
quality-of-life measures.

Whole- and Regional-Brain Atrophy

The study by Dr. Honea and colleagues follows a paper published by
their group in the July 15 issue of Neurology (2008;71:210-216),
showing an association between cardiorespiratory fitness in early AD
patients and whole-brain volume, after controlling for factors such
as age, sex, and dementia severity; no such relation was seen in
healthy elderly subjects without dementia.

In this follow-up investigation, the researchers looked at the
association between cardiorespiratory fitness and regional-brain
volumes using an MRI-based analysis technique called voxel-based
morphometry.

A total of 63 early-stage AD patients and 56 nondemented subjects
underwent MRI and treadmill testing to assess peak oxygen
consumption (VO2 peak), a standard measure of cardiorespiratory
fitness. MRI images were then processed and segmented into gray
matter, white matter, and cerebrospinal fluid.

"Basically, what we're doing is trying to correlate a measure of
aerobic fitness (VO2 peak) across the whole brain, on a voxel-by-
voxel basis, to look for significant relations between that measure
and smaller regional changes in gray- and white-matter volumes," Dr.
Honea said.

They found that in patients with early AD, there was a significant
relation between higher VO2 peak and higher hippocampal and
parahippocampal volumes. These regions are associated with memory
and, in the precentral gyrus, are associated with motor
functions, "both of which we hypothesize might be related to
cardiorespiratory fitness," she told Medscape Neurology &
Neurosurgery. "But what was interesting is that it was just in the
Alzheimer's group, and not in the nondemented group, that it was
significant."

Dr. Honea pointed out that this is a cross-sectional study, which
limits us from making recommendations about the effects of exercise
in AD patients, but she noted that they are planning to begin a
randomized trial of exercise in AD patients to look more closely at
whether this relation is actually one of cause and effect. They also
plan to follow this cohort to see if better cardiorespiratory
fitness modifies the progression of AD over time.

During the discussion here, Dr. Honea was asked whether they plan to
look at the number of white-matter lesions in these patients, where
most of the changes were. She answered that they do plan to assess
whether better cardiorespiratory fitness is associated with fewer
white-matter lesions, using scans that are already available.

They will also be reporting on the effect of the apolipoprotein E
genotype on the relation between cardiorespiratory fitness and
atrophy in the brain.

Exercise Program for AD Patients

In 2 other studies presented here, researchers, led by Megan J
Wraith, PhD, and R. Arthur Criddle, MD, both from Western Medicine,
in Nedlands, Western Australia, found that a home-based exercise
program for demented patients delivered by caregivers resulted in
fewer falls and a better quality of life for both patients and their
caregivers.

One third of older people living in the community fall each year,
and those with dementia fall up to 3 times more than those who have
no cognitive impairment, the authors note. In these studies, they
assessed a caregiver-directed home-exercise program to see whether
it would improve balance and reduce falls in people with dementia
and whether it would affect the daily activities and quality of life
of people with dementia.

A total of 33 pairs of patients and caregivers were randomized to an
exercise program (n = 42) or usual care (n = 24). Caregivers in the
exercise group were taught to guide the patients through a series of
exercises at home.

Pairs in the exercise group were visited by investigators 8 times in
the first 6 months of the study to ensure that exercises were being
done correctly and safely. In the second 6 months, the caregivers
were left to carry out the program independently, keeping track of
exercise sessions, other physical activities, and falls on a daily
basis. This information was submitted each month to investigators.
Those in the usual-care group also received 8 home visits and also
recorded falls and any physical activity.

At 6 months, they found a significant difference in the rate of
falling between the exercise and usual-care groups (P = .047).
Scores on the Berg Balance Scale significantly improved in the
exercise group over the 12 months of the study, whereas scores in
the usual-care group deteriorated, they note.

Quality of life (QoL-AD) was measured at baseline and at 6 and 12
months; activities of daily living were assessed using the Falls
Efficacy Scale (FES), the Frenchay Activities Score, and the
Modified Barthel Index.

Results showed that AD patients in the exercise group had no
deterioration in quality of life over 12 months, nor did their
caregivers, the authors report, whereas those in the usual-care
group showed a reduction in quality-of-life scores. Caregivers in
the usual-care group also reported changes in quality of life, they
note.

Patients in the usual-care group also showed significant
deteriorations on the FES, the Frenchay score, and the Barthel Index
over 12 months; in the exercise group, these measures remained
stable.

"This study is small and is just a beginning, but maintaining
quality of life at the same level in the context of deteriorating
cognitive abilities is an achievement," Dr. Wraith said in a release
from the Alzheimer's Association. "The results are sufficiently
encouraging to pursue this approach and develop a caregiver-focused
home-based exercise program on a larger scale."

In the same statement, William Thies, PhD, vice president of medical
and scientific relations for the Alzheimer's Association, said that
these studies "reinforce the need for increased awareness and
education about the importance of living a brain-healthy lifestyle,
including staying physically active. Growing evidence shows that
physical exercise does not have to be strenuous or require a major
time commitment. It is most effective when done regularly, and in
combination with a brain-healthy diet, mental activity, and social
interaction."

A new study has found that renal transplants in black patients
appear to be more successful if the donor is black and has died of
cardiac causes rather than brain death [1]. The findings are
somewhat unexpected, because white patients seem to do better if
they receive a kidney from a brain-dead rather than cardiac-death
donor. Dr Jayme E Locke (Johns Hopkins University, Baltimore, MD)
and colleagues report their findings online July 23, 2008 in the
Journal of the American Society of Nephrology.

Coauthor Dr Daniel S Warren (Johns Hopkins University) told
heartwire: "This highlights how little we know about the molecular
consequences of cardiac and brain death as it pertains to
transplantation. It's fairly interesting that seemingly the best
organ for a white recipient is a white brain-dead donor and the best
organ for a black recipient is from a black cardiac-death donor."

Locke added, "Using cardiac-death donors is a relatively new thing.
Initially people were concerned that kidneys from cardiac-death
donors wouldn't be ideal. But multiple studies have now shown you
can achieve outcomes with cardiac-death donor kidneys that are
essentially the same as outcomes with organs from brain-dead donors,
as long as certain criteria are adhered to. People are beginning to
realize that, particularly with young donors who die of cardiac
death, you can achieve pretty excellent results."

"Optimization of this untapped donor source could dramatically
increase the number of kidneys available for transplantation each
year," the researchers conclude.

Blacks Getting Kidneys From Black Cardiac-Death Donors Has 70%
Reduction in Graft Loss

Locke and colleagues explain that black patients, despite making up
almost 35% of the transplant waiting list, are currently two times
less likely to receive a kidney transplant than their white
counterparts.

And many studies have shown that black recipients are more likely to
experience graft failure than whites; this disparity in outcome
exists even after socioeconomic factors are controlled for. In
addition, kidneys from black deceased donors have a 1.64-fold higher
risk for graft loss compared with those from white donors.

In their new study, Locke et al looked at the outcomes of more than
100 000 adults who received a deceased-donor transplant between 1993
and 2006 and were included in the United Network for Organ Sharing
(UNOS) database.

They identified 142 black recipients of kidneys from black cardiac-
death donors. Compared with standard-criteria kidneys from white
donors after brain death, kidneys from black donors after cardiac
death conferred a 70% reduction in the risk for graft loss (adjusted
hazard ratio 0.30, 95% CI 0.14¡V0.65; p=0.002), and a 59% reduction
in risk for death (adjusted HR 0.41; p=0.02).

"There are two main messages," Locke told heartwire. "One is that
outcome with cardiac-death donors appears to be less racially
disparate than outcomes with brain-death donation. Second, and more
specifically, black recipients achieve the best long-term kidney
graft survival when they receive a kidney from a black donor who had
a cardiac death."

Hope That This Will Encourage More Donation

She added: "In 2005, the Institute of Medicine found that, in the
US, there were 22 000 potential cardiac-death donors, yet if you
look at kidney transplants, we performed less than 600, so these
results provide more evidence demonstrating that cardiac-death
kidneys can perform as well as, and in some cases slightly better
than, brain-death organs. What I'm hoping is that this will
encourage more organ donation."

"Increased recovery of organs donated after cardiac death from black
donors may . . . mitigate existing racial disparities and improve
outcomes for black renal-transplant recipients," the researchers say.

But they also warn that their data are preliminary. Warren
notes, "We have a sentence in the paper where we specifically argue
against using this information to direct patient-level decisions or
to alter current allocation algorithms, simply because of how few
black recipients have ever received a black cardiac-death organ."

"In the current environment, there is still an organ-shortage
crisis," Locke explains. "So if we were to say, based on this data,
black recipients should wait for a kidney that comes from a black
donor who died of cardiac death, the black recipient would be
disadvantaged by that. We all know that getting a kidney transplant
is much better than staying on dialysis, no matter what donor."

Locke JE, Warren DS, Dominici F, et al. Donor ethnicity influences
outcomes following deceased-donor kidney transplantation in black
recipients. J Am Soc Nephrol 2008; DOI: 10.1681/ASN.2008010078.
Available at: jasn.asnjournals.org. Abstract

If the US News & World Report rankings for cardiovascular care were
Wimbledon, this year it would be the Cleveland Clinic in the role of
Rafael Nadal--or Venus Williams, depending on one's point of view
[1].

The magazine's 2008 rankings for best hospitals for "heart and heart
surgery" are out, with probably few surprises among the top 10
centers on the list. The Mayo Clinic trails in second place, with
Johns Hopkins Hospital a distant third, as they might say on ESPN.

The publication's annual list is closely watched by both the public
and hospital marketing departments but, as reported by heartwire in
previous years, has drawn criticism for, some say, taking outcomes
numbers out of context, considering criteria of questionable
importance, and using methodology that excludes some worthy centers.
But it also earns praise in some quarters for helping patients take
control of their own healthcare.

The heart and heart-surgery category, as often occurs in the public
media, combines two separate disciplines the public often has
trouble distinguishing. Still, probably few would deny that the
list's top-ranked centers provide excellent cardiovascular and
surgical care.

In fact, the rankings were to a large extent determined by centers'
reputations among a sample of 200 cardiologists and cardiac
surgeons, who were asked "to list five hospitals they consider among
the best in their specialty for difficult cases, without taking into
account cost or location." Centers were scored, with 100 as the
maximum, with equal weight given to "reputation, death rate, and
care-related factors such as nursing and patient services,"
according to the magazine.

US News & World Report. Best hospitals: Heart and heart surgery.
July 11, 2008. Available at http://www.usnews.com.

Extremely obese patients are posing logistical and safety challenges
for interventionalists, and many hospitals don't know what to do
when it comes to treating patients who exceed the designated weight
restrictions on angiography tables, a new study has shown [1].

"It is a paradox," said lead investigator Dr Thomas Vanhecke
(William Beaumont Hospital, Royal Oak, MI). "New research is showing
us that patients are dying younger with more cardiovascular disease,
and yet there are no cath lab guidelines for how to treat those who
are morbidly or massively obese."

In a telephone survey of 100 hospitals that perform the most PCI
procedures in the United States, 22% of nurse managers in the
cardiovascular catheterization laboratories said they referred
patients to other institutions if they were too heavy, but 70% of
respondents didn't have a solution to the problem. The average
weight restriction on the angiography table, with its complex
assortment of machinery, mechanisms, and controls, is 437 lbs,
although ten hospitals limit access to those weighing less than 350
lbs. The highest limit was 550 lbs. Roughly five patients per year
were turned away for being above the lab's designated weight limit.

Speaking with heartwire, Vanhecke said that when faced with obese
patients, they are typically told to exercise and diet before they
can undergo the procedure. Unconventional means include cutting
weight through dehydration or surgical means. Going the surgical
route is often not effective, though, because most surgeons want to
see a full risk profile, including stress tests and angiogram,
before operating. Other methods include "offloading" some of the
weight to supporting structures, such as a stretcher, to reduce the
load on the angiography table, and even treating patients at
veterinary hospitals, said Vanhecke.

Obese patients pose other challenges, he added, noting that adipose
tissue impairs x-ray image quality. In addition, it is harder to
control bleeding in heavier patients and femoral access is often
more difficult to obtain. Moreover, moving the patient from the
stretcher to the table is challenging, requiring between six and ten
people, he said.

Vanhecke TE, Berman AD, McCullough PA. Body weight limitations of
United States cardiac catheterization laboratories including
restricted access for the morbidly obese. Am J Cardiol 2008; 102:285-
286. Abstract

Doctors are doing a good job identifying patients with evolving MI
presenting to the emergency department with chest pain but without
ST segment elevation or an initial positive troponin test, a new
study suggests [1].

The study, published in the August 1, 2008 issue of Emergency
Medicine Journal, was conducted by a group led by Dr Chadwick Miller
(Wake Forest University Baptist Medical Center, Winston Salem, NC).

He explained to heartwire that some patients who are having an MI
might not always show a positive troponin when first presenting
because it can take six to eight hours for troponins to rise after
the start of an MI. And there is concern that, among patients
without ST elevation or a positive initial troponin test, those with
evolving MI might not be identified and therefore might not be
treated as aggressively as they should be.

To look at this further, the researchers conducted an observational
study using data from the Internet Tracking Registry for Acute
Coronary Syndromes, a registry of patients presenting with
undifferentiated chest pain. This analysis included patients without
ST segment elevation with at least two troponin assay results less
than 12 hours apart. Patients were stratified into three groups:
those with an initial negative but a second positive troponin assay
(classified as evolving MI); those with an initial positive troponin
assays (NSTEMI); and those with two negative troponin assays (no
MI). Miller explained that the first two groups had similar
conditions but different time frames; the first group was at an
earlier stage in the course of their MI than the second group.

Of the 4136 patients studied, 5% were found to be having an evolving
MI, 8% had NSTEMI, and 87% had no MI. Patients with evolving MI were
more similar, with respect to demographic characteristics,
presentation, admission patterns, and revascularization, to those
with NSTEMI than to those with no MI, and 76% of the time,
physicians' initial impressions suggested heightened concern for
cardiac risk in the evolving MI patients.

"Our results show that, on the whole, emergency physicians are doing
a good job in picking up the patients with evolving MI before
conclusive troponin tests are in," Miller commented to
heartwire. "It was hard to tell from this study which factors are
the most important in identifying these patients. It was a
combination of findings from the patient's history, clinical
examination, and ECG. But what we have shown is that the emergency's
doctor best guess is usually right in finding these patients."

One of the symptoms of interest was chest pain described as
burning. "We showed a strong association between burning chest pain
and evolving MI. Burning chest pain is often taken as a symptom of
GI reflux, but I think one message from our study is that we should
not be discounting burning pain as reflux, as actually there is
quite a high likelihood that it could be an ACS," Miller commented
to heartwire.

He added that these results have implications for how a chest pain
triage system is managed. "There are places where the triage system
could be improved. But on the whole, I am happy with what we saw
here. It is reassuring to see that the admission patterns among the
evolving MI patients were more aggressive than with the patients
found not to be having an MI, even though in both these groups the
initial troponin results were not elevated. This suggests that
clinicians are not allowing the initial negative troponin results to
overshadow their clinical impression,¡¨ he said.

Miller explained that one of the issues is that chest pain patients
thought not to be having an MI are sometimes sent for stress tests
to rule out further cardiac causes before the second troponin test
is back, but this would not be advisable for a patient who is having
an evolving MI because it could induce ventricular arrhythmias. "If
patients with evolving MI are lumped in with this group, then we
could have a problem. But our results suggest that this is
relatively unlikely to happen. In our study, of 4136 patients, just
187 were found to be having an evolving MI on the basis of the
second troponin test. Because 76% of these were initially thought to
be having an MI, unstable angina, or high-risk chest pain, only
about 40 of these patients were not flagged after the initial
examination," he noted.

Miller CD, Fermann GJ, Lindsell CJ, et al. Initial risk
stratification and presenting characteristics of patients with
evolving myocardial infarctions. Emerg Med J 2008; 25:492-497.
Available at emj.bmj.com.

If 100 patients referred for a primary-prevention implantable
cardioverter defibrillator (ICD) based on a low LVEF, determined by
any accepted method, had cardiac function measured using a gold
standard such as radionuclide ventriculography, almost a third would
then show LVEFs high enough to render them ineligible for an ICD.
Avoiding that many device implantations would save the healthcare
system enough to recoup the added cost of the nuclear scans many
times over.

That's the upshot of an analysis of just such a cohort treated in
Canada from 2005 to 2006, published online July 14, 2008 in the
American Journal of Cardiology [1]. Adding the scan increased
preimplantation costs by about $400 per patient, but excluding some
ICD candidates based on its results cut overall postimplantation
costs by an average of about $6000.

"The cost saving was substantive, suggesting that verification of
ejection fraction should be performed in all patients considered for
a primary-prevention ICD," write the authors, led by Dr Andrew D
Krahn (University of Western Ontario, London).

The analysis has implications beyond the dollars, observed Krahn for
heartwire. One obvious interpretation, according to Krahn, "is that
we are putting in a lot of unnecessary ICDs because the [referred]
patients probably have better heart function than we think."

But another way of looking at it, he said, is that primary-prevention
ICDs may be more efficacious and cost-effective if recipients can be
selected more precisely. "If ICDs are the most useful in patients who
have poor heart function, ICDs may be even more useful than we think
if we can do a better job of selecting who needs them," such as by
using a standardized, relatively objective method for the follow-up
LVEF assessment.

However, "this doesn't prove that we're necessarily doing a better
job of picking candidates by doing that. What this proves is that the
[initial] assessment of heart function isn't necessarily accurate
when we repeat it systematically," Krahn said. The initial
evaluations aren't typically performed at hospitals with referral-
center experience and so may be less accurate. But, he observed, it's
also common for a patient's medical therapy to intensify following an
initial finding of low LVEF and, as a result, for the referral LVEF
assessment to reflect some improvement in cardiac function.

"There are enough reasons to believe that over time, with repetition,
the heart-function assessment will change and should be verified
before proceeding to an ICD implant," Krahn said.

In the current analysis, 67 patients with ischemic and 33 with
nonischemic cardiomyopathy, three-fourths of whom were male, were
referred for ICDs based on cardiac function measured by
echocardiography (mean LVEF 21.5%), catheter-based quantitative
ventriculography (mean LVEF 20.0%), or multiple-gated acquisition
(MUGA) scanning (mean LVEF 21.2%).

Cardiac function was higher, on average, on echocardiography and MUGA
scanning performed consistently in all patients after referral (23.2%
and 28.9%, respectively). Of the 100 patients, 31 had a MUGA-verified
LVEF exceeding 30%, making them ineligible for an ICD according to
joint guidelines from the Canadian Heart Rhythm Society and Canadian
Cardiovascular Society, according to Krahn et al.

"One of the reasons we chose MUGA [for the referral assessment] is
that it's primarily a quantitative technique," he said, as opposed to
echocardiography, in which images are more open to
interpretation. "It's an objective way to measure this, it's reliable
and reasonably reproducible, so we used it as a gold standard," he
said, acknowledging that not all will agree with the choice.

Verifying LVEF with MUGA scanning increased the preimplantation cost
from $130 to $536 per patient but reduced the cohort's total mean
postimplantation cost from $20 914 to $14 877 and overall saved $603
722. (The cost data reported in US dollars had been collected in and
converted from Canadian dollars at May 2007 rates.)

The cost analysis used 30% as a strict cutoff for determining whether
a patient received an ICD, but the real-world cohort's management
went a bit differently: the 69% of patients with MUGA findings
qualifying them for an ICD wasn't the same 69% that ultimately
received devices. Of the latter group, 56 were below and 13 were
above the 30% threshold by the referral MUGA. Of the 31 patients who
didn't receive an ICD, 11 had MUGA-determined LVEF <30%.

The discrepancy between MUGA-defined and real-world ICD eligibility
derived in part from patients who were offered but declined device
therapy or from its inappropriateness due to excessive patient
comorbidities, Krahn observed, as well as from changes in US-European
recommendations during the years covered by the analysis. The 2006
joint American College of Cardiology, American Heart Association, and
European Society of Cardiology guidelines extended the LVEF threshold
up to 40% in some cases.

Krahn AD, Hoch JS, Rockx MA, et al. Cost of preimplantation cardiac
imaging in patients referred for a primary-prevention implantable
cardioverter-defibrillator. Am J Cardiol 2008;
DOI:10.1016/j.amjcard.2008.04.067. Available at: www.ajconline.org.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, a
randomized, multicenter, placebo-controlled study evaluating the
effects of combination ezetimibe and simvastatin (Vytorin, Merck and
Schering-Plough) on clinical outcomes in patients with aortic
stenosis, was presented this week, and while some experts say the
results provide little new information and won't alter clinical
practice, some see the results as positive for Vytorin, especially
when placed in the context of other LDL-lowering studies.

The study, presented by Dr Terje Pedersen (Ulleval University
Hospital, Oslo, Norway) this week during an unusual press conference,
showed that the cholesterol-lowering combination was no better than
placebo in reducing the primary composite end point of aortic valve
and cardiovascular events. Vytorin was significantly more effective
than placebo in reducing the risk of ischemic events, a secondary
composite end point of nonfatal MI, CABG surgery, PCI,
hospitalization for unstable angina, nonhemorrhagic stroke, and
cardiovascular death.

With this 22% reduction in ischemic events, however, concerns were
raised when SEAS investigators also showed a significantly increased
risk of cancer. A group independent of researchers, however, says
this finding is likely due to chance.

Asked about the results and how they fit into the context of existing
Vytorin data, Dr Harlan Krumholz (Yale University School of Medicine,
New Haven, CT) told heartwire that SEAS reinforces the message from
March when the Effect of Combination Ezetimibe and High-Dose
Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in
Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE)
trial was presented.

"This drug does not have sufficient evidence for it to be used as a
front-line agent," he said. "Statins are the drugs of choice. The
evidence is not even strong enough to say that people who cannot
tolerate statins should go on it. It is an option. Right now using it
is based on an assumption that you know what IMPROVE-IT will find."

IMPROVE-IT is Still a Long Way Off

IMPROVE-IT is the clinical outcomes study chaired by Dr Eugene
Braunwald of the TIMI Study Group and cochaired by Dr Robert Califf
(Duke Clinical Research Institute, Durham, NC). The study will
compare simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg
alone in 18 000 patients with a recent acute coronary syndrome. Those
results will be available in 2012, nearly a decade after the US Food
and Drug Administration approval of ezetimibe as an adjunct to
statins for cholesterol lowering.

Commenting on the SEAS study, Dr Richard Karas (Tufts University
School of Medicine, Boston, MA) took issue with the tone of media
coverage surrounding the results, including heartwire's coverage. He
said many in the media portrayed the study as another failure for
Vytorin, something he did not believe to be the case.

"There are people saying that there is no clinical-trial evidence
showing that Vytorin does anything on atherosclerotic events," said
Karas. "Now we have a secondary end point, which is important to
recognize, but it's a prespecified end point, and the drug has a
statistically significant benefit on ischemic events. That's really
the story, in my opinion."

Still, despite the statistical significance of benefit in this
secondary end point, others are not impressed with the results. Dr
Allen Taylor (Walter Reed Army Medical Center, Washington, DC) told
heartwire that although there was a dramatic 61% reduction in LDL
cholesterol, the relative reduction in ischemic events was just 22%
compared with placebo in a high-risk population. "That's actually
less relative risk protection than was seen in 4S and the Heart
Protection Study, studies using similar doses of simvastatin but with
less LDL reduction," said Taylor. "It falls beneath one's
expectations."

There are difficulties making cross-trial comparisons because the
populations are not the same and the end points are not uniform, said
Taylor, but the overall benefit observed in SEAS does not provide any
useful information about the additive benefit of the combination over
simvastatin alone.

Dr Rory Collins (Clinical Trials Service Unit, Oxford, UK), the lead
investigator of the Study of the Heart and Renal Protection (SHARP)
trial, a randomized placebo-controlled study of simvastatin and
ezetimibe in 9400 patients with chronic kidney disease, told
heartwire, however, that he does see these findings as benefiting a
difficult-to-treat patient population.

"Although the study didn't provide evidence of benefit on the aortic
valve, I think it does provide good evidence that you get quite a
worthwhile absolute reduction in ischemic events--almost 5%--in a
population that is currently not being treated with statins," he said.

Media Saturation and the Stock Market

Speaking with heartwire, Karas said too much emphasis in the media
was placed on the motives for designing the trial, including
speculation that positive findings could rehabilitate Vytorin in the
eyes of cardiologists. The purpose of the study, he said, was to
determine whether medical therapy might be successful in the
treatment of a condition in which surgery is the only existing
option. Karas acknowledged that Merck and Schering-Plough have
successfully marketed Vytorin, but many other drugs, including
atorvastatin (Lipitor, Pfizer) when it first came on the market, were
prescribed because of the LDL-lowering capabilities.

"In this area, the evidence is so strong that successfully altering
lipids produces benefit," said Karas. "My perspective is not so black
and white, but medicine is an art, and we have to practice medicine
on the basis of the best evidence we have. Would you rather leave a
patient's LDL cholesterol above the national guideline targets
because there aren't clinical end-point data?"

Collins added there is always a need to be cautious interpreting
secondary end points. However, placing the SEAS findings in the
context of other LDL-cholesterol-lowering studies makes the reduction
in ischemic events a strong finding of benefit in this population. To
make this point, Collins notes that the Incremental Decrease in
Events through Aggressive Lipid Lowering (IDEAL) study wasn't
statistically significant, but in the context of other aggressive vs
conventional LDL-lowering studies, it was very consistent with
efficacy.

"LDL lowering decreases the risk of cardiovascular events, and that
has been shown consistently when you look at the totality of
evidence," said Collins. "It is important not to look at trials in
isolation."

Speaking last March at the American College of Cardiology (ACC) 2008
Scientific Sessions, Krumholz urged clinicians to return to first
principles: maximizing statins to the highest tolerated dose before
adding other agents. He said the ENHANCE trial gave pause to many
assumptions and reminded researchers how many lipid-lowering drugs
have not come to fruition when subjected to the scrutiny of a
clinical trial.

"The fact that some of the leading cardiologists are involved in
IMPROVE-IT tells you that they are comfortable in saying that we
truly do not know the effect of this drug on patient outcomes, and
the only way to find out is to monitor risk and benefit in a trial,"
Krumholz told heartwire this week. "Any patient using the drug should
understand where we stand with respect to the evidence and the
uncertainty about the drug."

Taylor stressed the results should not alter clinical practice and
that the community must still wait for the findings from IMPROVE-IT.
Nothing changed this week, he said, except there is now a little more
uncertainty about the drug, with the unexpected adverse-event
signal. "It might be due to chance, but it still needs due
consideration," he added.

Statins for Aortic Stenosis Unlikely

The SEAS study was designed to answer the question about whether or
not lipid-altering therapy altered the course of aortic valve
disease. Its failure to yield a significant effect on the primary
outcome--a large composite end point that included aortic and
cardiovascular events--should not be interpreted as a failure of the
drug, Karas told heartwire.

"This is a whole different kettle of fish than what are the effects
of lipid lowering on atherosclerosis," said Karas. "Investigators
came up with the question asking whether there might be a
relationship between lipid-altering interventions and slowing the
progression of aortic valve disease, and the answer to that is no."

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) told
heartwire that initial hopes for statins to halt the progression of
calcified aortic valve disease were based on retrospective data and
open-label studies, but SEAS and an investigation of atorvastatin 80
mg in SALTIRE have now failed to show any benefit of LDL lowering for
this condition. Although the ASTRONOMER trial with rosuvastatin
(Crestor, AstraZeneca) is ongoing, "the time is ripe for the lipid-
lowering hypothesis for [halting] progression of calcific aortic
valve stenoses to be abandoned," said Kaul.

Regarding the reduction in ischemic events, Kaul was careful in his
interpretation.

"As a general rule, when primary outcomes fail to meet statistical
verdicts, analyses of secondary outcomes should be interpreted with
caution," said Kaul. "This applies equally to the ischemic composite
end point, which showed a 20% reduction with Vytorin, and to the 50%
increased cancer risk associated with Vytorin. Nonetheless, the
signal for increased cancer rate is 'concerning' and merits careful
scrutiny. Interim analyses of ongoing studies to refute or
corroborate findings observed in other clinical trials are a slippery
slope."

The cancer findings were concerning enough for investigators that an
independent analysis of the two large ongoing studies, the IMPROVE-IT
and SHARP trials, was performed by Sir Richard Peto (Clinical Trials
Service Unit, Oxford, UK), an expert in clinical-trial meta-analyses
and cancer epidemiology, to determine whether the cancer risk was
real or chance. His analysis showed "no credible evidence" that
Vytorin posed a cancer risk and should not be a reason to divert
patients from the drug.

Live Blogging the Press Conference and Cancer Risks

In keeping with the media scrutiny of Vytorin, as well as the two
companies that market the cholesterol-lowering agent, coverage of the
SEAS trial was extensive, much like the coverage of the controversial
ENHANCE trial when it was first presented last January and later at
the ACC meeting. Some newspapers, including the New York Times,
played up the safety angle of the trial by emphasizing the cancer
findings.

"In a clinical trial, the cholesterol-lowering drug Vytorin did not
help people with heart-valve disease avoid further heart problems but
did appear to increase their risk of cancer," writes reporter Alex
Berenson in the July 22, 2008 New York Times.

While the Times notes that researchers urged caution and that
additional analyses of other trials did not show a similar cancer
risk, Berenson notes the cardiologists and epidemiologists share
concerns over the findings.

The Associated Press and Reuters beamed stories around the world
about SEAS missing its primary end point, while many influential
business publications, including Forbes and the Wall Street Journal,
reported extensively on the findings. Not surprisingly, financial
coverage of Merck and Schering-Plough dealt primarily with plunging
stock prices.

In an interesting twist on the presentation of medical data, Jacob
Goldstein of the Journal's Health Blog live-blogged the results of
SEAS, updating readers every couple of minutes with new data and
commentary from the conference participants.

SEAS investigator Pedersen said he would have preferred to hold the
findings and present them at a major medical meeting and publish them
in a peer-reviewed journal, but interest in the study made it
difficult to keep the results secret. Merck and Schering-Plough have
been in hot water with the US Congress over the 18-month delay
between when ENHANCE was completed and the presentation of the
results in January 2008.

Regarding the cancer findings, Krumholz said he was surprised by it,
and while "it is never good to see a drug associated with a 50%
increased risk of cancer," he has doubts about whether it truly
represents an adverse effect. Although he has not had time to fully
read the analysis by Peto and colleagues, he said he was glad to hear
the analysis did not show similar findings.

Karas, who also conducts research on cancer risks, lipid-lowering
interventions, and LDL-cholesterol levels, as well as Collins, told
heartwire they believe the safety conclusions reached by Peto are
correct. PROSPER and CARE also turned up a statistically significant
increased risk of cancer, but two large meta-analyses later showed
that statins do not increase the risk. In SEAS, the timing and the
type of cancers involved make little sense and are likely a chance
finding, they both said.

Adding both more clarity and more confusion to a field already
peppered with conflicting data, a new study has found that people
who have migraine with aura are more likely to experience migraine
relief following patent foramen ovale (PFO) closure than people who
get migraines without aura [1]. But, more puzzlingly, migraine
relief can occur even if residual shunting occurs after the PFO is
closed. The counterintuitive findings come from a retrospective
analysis of 77 patients treated at the Swedish Medical Center, in
Seattle, WA, between April 2001 and June 2005.

"This retrospective study included a group of patients with ischemic
stroke, who also had a history of active migraine at the time of PFO
closure," Dr Jill Jesurum (Swedish Medical Center, Seattle, WA) told
heartwire. "In this sample of patients, we found that those who had
migrainous aura had an odds ratio of 3.5 that they would more likely
experience migraine relief following PFO closure than those who did
not have aura."

Jesurum notes that while the MIST trial--the only completed
randomized study to date addressing this question--enrolled only
patients with migraine with aura, other trials still ongoing, ESCAPE
and PREMIER, are enrolling migraineurs with and without aura. "The
jury is still out, basically, as to the migraine profile most likely
to benefit from PFO closure and whether PFO closure is efficacious
in reducing migraine frequency," Jesurum said.

But the more perplexing finding in Jesurum et al's analysis was that
full closure of the PFO was not a prerequisite for migraine
reduction. "That was very surprising for us as well, and I think
that has not been previously reported, at least in long-term follow-
up," she said. "A possible explanation is that migraineurs have
increased cortical hypersensitivity, and a large right-to-left shunt
permits a greater volume of vasoactive chemicals and
microaggregates, such as activated platelets, to cross the PFO and
trigger migraine. It is speculation that that a significant
reduction of shunt and transmission of these chemicals and
microaggregates may reduce the threshold of cortical
hypersensitivity and therefore reduce migraine frequency."

The Migraine-PFO Hypothesis

The notion that migraine might be linked to PFO stems from
observations that people who had undergone PFO closure for
decompression illness or secondary prevention of cryptogenic stroke
reported fewer or no migraines postprocedure. Investigators have
speculated that some migraines might be caused by microemboli or
chemicals normally filtered out in the lungs, traveling via the PFO
to the brain. The disappointing MIST trial results indicated that
PFO closure had no significant impact on migraine cure or on
reducing migraine frequency despite a low rate of residual shunting
postprocedure. As reported by heartwire, however, one of the
investigators for the MIST study has disputed the residual shunt
data and is currently in the middle of a legal imbroglio with the
study sponsor, NMT Medical.

In Jesurum et al's study, investigators reviewed late follow-up
data, including transcranial Doppler (TCD) imaging results six and
12 months after PFO closure and migraine questionnaires from 77
patients who had received PFO-closure devices and who reported
migraines at baseline. In all, 71% of patients had migraine with
aura, while the remainder reported experiencing migraine without
aura at the start of the study.

Of the 67 patients in whom both PFO follow-up and migraine
information was available, 54% of patients reported complete
migraine relief and an additional 25% experienced "substantial"
relief (more than a 50% reduction in migraines per month). Overall,
more than one-third had residual right-to-left shunts, defined as 30
embolic tracks on TCD at a median of 366 days postprocedure.
Strikingly, there were no significant differences in migraine relief
between people who experienced no residual shunting vs some residual
shunting.

Where differences in migraine relief were seen, however, was
according to type of migraine at baseline: 86% of subjects with
migraine with aura at baseline experienced migraine relief at follow-
up, compared with only 59% of subjects reporting migraine without
aura. Of note, residual shunt rates were similar between the two
groups. Overall, say the authors, "Migraineurs with aura were 4.6
times more likely than migraineurs without aura to experience relief
after PFO closure."

Hypothesis-Generating Results

To heartwire, Jesurum emphasized that the analysis was underpowered,
retrospective, and not designed with migraine reduction as a primary
end point. "This needs to be repeated prospectively and with an
adequate sample size before any definitive conclusions can be made,"
she said.

She also pointed out that TCD measures embolic tracks in the
cerebral vasculature from contrast that's been in injected into an
antecubital vein, but it is not specific to contrast passing through
the PFO. "Most of the time, a positive TCD is indicative of a PFO,
but this is not absolute," she explained. "A positive TCD can also
be due to a pulmonary arteriovenous malformation. So there can be
other sources of shunt, although the most probable source is a PFO.
That is another limitation of this study. We assumed the residual
shunt was related to incomplete PFO closure, but that was not
confirmed in all cases."

As such, even a patient with successful PFO closure could continue
to have right-to-left shunting via another source. Indeed, in other
research that Jesurum and colleagues are in the process of preparing
for publication, they have found that almost one-third of patients
referred to the cath lab for PFOs also have a secondary source of
right-to-left shunt.

Jesurum, for the time being, says she can't even speculate on
whether PFO closure will ever prove to be a solution for migraine
sufferers. "I definitely do not believe that all migraine or even
all migraine with aura can be attributed to PFO. We do know from
epidemiology studies that migraineurs who have aura have a higher
prevalence of large PFOs than the general population. But I don't
believe we can say that this is the be-all and end-all treatment for
all migraineurs. There may be a subpopulation of migraineurs for
whom there is some potential causal mechanism between PFO and
migraine and who may benefit from PFO closure, but the mechanism has
yet to be determined, as does the efficacy of PFO closure."

Getting Answers

Commenting on the study for heartwire, Dr Jonathan Tobis (University
of California, Los Angeles [UCLA]) acknowledged that the theory of
a "threshold" effect based on shunt size is a plausible hypothesis
to pursue. "If a little bit of chemical goes through, you don't get
a migraine, but if a lot goes through, you do get a migraine: I
think that's a reasonable theory," he said.

But emphasizing a point also made by Jesurum, Tobis highlighted the
fact that the randomized, controlled trials of PFO closure for
migraine are not necessarily enrolling the same kinds of patients as
the ones studied in Jesurum et al's study or, for that matter, most
of the studies that first led to the migraine-PFO hypothesis
evolving in the first place.

"The population that seems to respond to PFO closure is those people
with episodic migraine, who came in with cryptogenic stroke or some
neurologic symptoms, their PFOs were closed, and their migraines got
better," Tobis explained. "The problem is the FDA won't let us treat
these kinds of patients with a permanent device." Instead, the FDA
is asking for companies to study people who are severely disabled by
migraine, meaning six or more days per month, Tobis said.

"Because of the risk/benefit ratio associated with permanent
implants, they want us to study only the most disabled patients,
which is reasonable. The problem is we don't know if that will
actually work or not, particularly with the results of MIST weighing
on everybody's minds."

He notes that while the PREMIER and ESCAPE trials are still ongoing,
the study sponsors have gone back to the FDA to explain why they are
having difficulty recruiting patients and to ask whether adjustments
can be made to the eligibility criteria. "So hopefully things will
be a little bit liberalized, and they will be able to increase
enrollment," Tobis said.

The authors have no conflicts of interest. Tobis has previously
disclosed serving on the steering committee for AGA's PREMIER trial
of PFO closure for migraine, being a consultant for AGA, and also an
implanting physician at UCLA for AGA's RESPECT trial, examining PFO
closure for stroke.

Jesurum JT, Fuller CJ, Kim CJ, et al. Frequency of migraine headache
relief following patent foramen ovale "closure" despite residual
right-to-left shunt. Am J Cardiol 2008;
DOI:10.1016/j.amjcard.2008.05.035. Available at: www.ajconline.org.

Patients with coronary heart disease are more likely to show reduced
cognitive function in late middle age than those without heart
disease, a new study has found [1]. And cognitive function was worst
in patients with the earliest diagnosis of CHD.

"Although our results do not prove that coronary heart disease
causes reduced cognitive function, we have shown a strong link, and
it is likely that the risk factors for heart disease are also risk
factors for cognitive function," lead author Dr Archana Singh-Manoux
(INSERM, Villejuif Cedex, France) commented to heartwire. "Our
results should be an added incentive for controlling these risk
factors, such as bad diet, sedentary lifestyle, smoking, blood
pressure, and lipids. We know these things contribute to heart
disease, and now we suspect they also contribute to cognitive
decline," she added.

The latest findings, published online July 23, 2008 in the European
Heart Journal, come from the Whitehall II study, which followed 10
308 civil servants based in London, UK, with an average age of
around 40 at the start in 1985. Baseline screening involved a
clinical examination, including biochemical measurements, and a
questionnaire on demographic characteristics, health, lifestyle
factors, work characteristics, social support, and life events. Six
subsequent data collections have taken place involving either
questionnaires alone or questionnaire plus a clinical examination.
In the most recent evaluation (2002¡V2004), 5837 participants
undertook six cognitive tests: reasoning, vocabulary, phonemic and
semantic fluency, memory, and the Mini-Mental State Examination
(MMSE).

For the purpose of this study, the authors recorded the time of the
first CHD event, defined as nonfatal MI or definite angina (found
from data from questionnaires and corroborated by medical records),
and examined whether this correlated with cognitive function at the
2002-2004 screening, when the participants had an average age of
about 60. The analyses adjusted for age, education, marital status,
and medication for cardiovascular disease.

Results showed that among men, CHD history was associated with lower
scores for reasoning, vocabulary, and the MMSE. And in women, these
effects were also evident for phonemic and semantic fluency. Among
men, the trend within CHD cases suggested progressively lower scores
on reasoning, vocabulary, and semantic fluency among those with
longer duration of CHD.

Important to Focus on Middle Age

The authors note that while dementia occurs late in life, it is
increasingly recognized that there is a long preclinical phase
characterized by progressive neuropathological changes that then
become clinically detectable as cognitive deficit or dementia and
that this "lifelong" view of dementia stresses the importance of
risk factors in midlife. "Our core hypothesis is that cognitive
decline starts earlier in life than widely accepted, so identifying
risk factors for this cognitive decline is vitally important," Singh-
Manoux commented to heartwire. "We have shown that if you get CHD
you are more likely to suffer reduced cognitive function. We don't
know that this will definitely translate into dementia, but we
believe it is likely that this would be the case."

Singh-Manoux said that this was the first large study to examine the
association between coronary heart disease and cognition. "Until
now, research on the link between cardiovascular disease and
dementia has focused more on cerebrovascular disease than CHD.
However, it is CHD and not cerebrovascular disease that makes up the
bulk of cardiovascular disease and is a major health problem in the
developed world," she commented. "Our results should give an added
incentive to reduce the risk factors for CHD, as by so doing we
could also be reducing the chances of cognitive decline," she noted.

Singh-Manoux said she and her fellow researchers are continuing to
follow the study participants, and they plan to conduct further
cognitive function testing to look for further cognitive decline and
dementia. "This is always problematic, as people with the poorest
cognition are the most difficult to keep track of, and they tend to
be the ones who drop out. As a result, these associations are always
underestimated, but we are doing our best to try and pick these
people up," she added.

Singh-Manoux A, Sabia S, Lajnef M, et al. History of coronary heart
disease and cognitive performance in midlife: the Whitehall II
study. Eur Heart J 2008; DOI:10.1093/eurheartj/ehn298. Available at:
eurheartj.oxfordjournals.org.

Merck and Schering-Plough presented interim results of the
Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study today, a
randomized, multicenter, placebo-controlled study evaluating the
effects of combination ezetimibe/simvastatin (Vytorin) on clinical
outcomes in roughly 1800 patients with aortic stenosis, and the
results showed that the controversial cholesterol-lowering
medication was no better than placebo in reducing the primary
composite end point of aortic-valve and cardiovascular events.

The combination was significantly more effective than placebo in
reducing the risk of ischemic events, a secondary composite end
point of nonfatal MI, coronary artery bypass graft (CABG) surgery,
PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and
cardiovascular death. Vytorin failed to meet a secondary goal of
improving aortic-valve disease events, which included valve-
replacement surgery, hospitalization because of heart failure, and
cardiovascular mortality.

"The SEAS study has given a clear-cut answer to the question of
whether intensive lipid lowering will influence the course of aortic-
stenosis disease. I think we can conclude that it does not,"
announced Dr Terje Pedersen (Ulleval University Hospital, Oslo,
Norway), chair of the steering committee, during a conference call
today with the media. "We have also shown there is benefit in
treating such patients with the study drug combination, as we saw a
reduction in the risk of coronary artery disease."

Cancer Findings

The results, however, raised anxiety among the SEAS researchers
after a safety signal grabbed everybody's attention. Despite the 20%
reduction in ischemic events, concerns were raised by the
significant increase in the risk of cancer, a finding that triggered
a quickly performed analysis of ongoing studies with ezetimibe and
simvastatin. Overall, Pedersen said there was a significantly higher
incidence of cancer--102 patients taking ezetimibe/simvastatin
compared with 67 taking placebo--and more patients died of cancer
with the combination, a finding of borderline significance.

The cancer findings were concerning enough that an independent
analysis of the two large ongoing studies, the IMPROVE-IT and SHARP
trials, was performed to determine whether the cancer risk was real
or chance. Sir Richard Peto (Clinical Trials Service Unit, Oxford,
UK), an expert in clinical-trial meta-analyses and cancer
epidemiology, said the data warranted further attention and have
been reported to all the proper regulatory agencies.

In an analysis of IMPROVE-IT and SHARP, two studies that allowed for
the testing of the hypothesis generated in SEAS, four times the
number of cancers were observed than in the SEAS trial, but there
was no overall risk of developing cancer with ezetimibe/simvastatin,
said Peto. The cancer pattern observed in SEAS, occurring so quickly
and without any one dominant type of cancer, as well as not
increasing over time, is likely due to chance and should not divert
anybody from taking the drug.

"The studies do not confirm the hypothesis that treatment with this
combination increases the overall risk of developing cancer," said
Peto.

Pedersen said he feels reassured by the Oxford analysis that the
combination is well tolerated and safe. Dr Rory Collins (Clinical
Trials Service Unit, Oxford, UK), chair of the SHARP steering
committee, who was present during the conference call, said the data
safety monitoring board (DSMB) endorsed Peto's conclusions, while
the IMPROVE-IT DSMB is scheduled to meet in September. Dr Eugene
Braunwald (Harvard Medical School, Boston, MA), cochair of the
IMPROVE-IT steering committee, who phoned into the media event, said
the group had been informed of the SEAS findings, but no changes to
the study are planned, a recommendation that was made without Peto's
analysis. The DSMB will be given the full results of Peto's
investigation as soon as possible, said Braunwald.

What Do the SEAS Results Mean?

There was speculation that the trial could help rehabilitate Vytorin
after the Effect of Combination Ezetimibe and High-Dose Simvastatin
vs Simvastatin Alone on the Atherosclerotic Process in Patients with
Heterozygous Familial Hypercholesterolemia (ENHANCE) trial was
published in March, but the placebo-controlled trial design, as well
as the patient population, were likely to limit the clinical impact.

The presentation of the SEAS results today came as a surprise to
investors, financial analysts, and the media, as the full data were
not expected until later this year at the American Heart Association
2008 Scientific Sessions, in New Orleans, LA. Pedersen said he would
have preferred to present the findings at an upcoming meeting and
then publish them in a major medical journal, but interest in the
study and difficulties maintaining secrecy about the findings made
that problematic.

The SEAS results are the first clinical results for Vytorin since
ENHANCE was published. In that study, investigators tested the
effectiveness of combined ezetimibe/simvastatin therapy in patients
with familial hypercholesterolemia and found that the combination
did no better than simvastatin monotherapy on several surrogate end
points. The combination did not result in a significant difference
in changes in intima-media thickness compared with simvastatin
alone, despite significantly greater reductions in LDL cholesterol
and C-reactive protein.

Many experts used the ENHANCE findings to criticize the explosion in
prescriptions for Vytorin since its approval, an explosion that
occurred without hard clinical end-point results. With the benefit
of Vytorin unproven and full results of IMPROVE-IT, the clinical
outcomes study, not expected until 2012, nearly a decade after the
US Food and Drug Administration approval of ezetimibe as an adjunct
to statins for cholesterol lowering, it had been thought the SEAS
study could help persuade doctors to use Vytorin and ezetimibe alone
(Zetia, Merck/Schering-Plough) again. Since ENHANCE, prescriptions
of both drugs are down as much as 40%.

Pedersen said that the results of SEAS are unlikely to change
clinical practice, and it was pointed out repeatedly that the trial
was designed only to test whether aggressive LDL-cholesterol
lowering with Vytorin was effective in treating patients with aortic
stenosis. In this study, treatment with ezetimibe and simvastatin
reduced LDL-cholesterol levels from 140 mg/dL to 52 mg/dL.
Investigators stressed the trial was not designed to test whether
the addition of ezetimibe to statin therapy provides additional
benefit in reducing clinical events, something that will have to
wait to be answered by the IMPROVE-IT trial.

"I'm very pleased with the fact that intense cholesterol lowering
reduces coronary events in patients with aortic stenosis, a group of
patients in whom I've had a longstanding interest," said
Braunwald. "We have a green light to continue the [IMPROVE-IT]
trial. We think that's a really important trial, sort of the center
of a bull's-eye of coronary disease."

Also speaking on the conference call, IMPROVE-IT cochair Dr Robert
Califf (Duke Clinical Research Institute, Durham, NC) said it is
important not to overreact, either positively or negatively, to the
SEAS findings. He called it an important contribution to the
literature, but that a single, isolated study is unable to tell a
complete story.

Using enoxaparin or heparin to bridge long-term anticoagulation
therapy with warfarin for secondary stroke prevention has been
associated with a high risk for serious bleeding in patients with
cardioembolic stroke (CES).

A retrospective study of 204 CES patients showed that only those who
received bridging with enoxaparin went on to have symptomatic
intracranial bleeding. Similarly, all CES cases with systemic
bleeding were treated with intravenous heparin.

"Our study suggests doctors should think twice before using
enoxaparin, or intravenous heparin for that matter, to bridge
anticoagulation therapy with warfarin in patients with cardioembolic
stroke," principal investigator Hen Hallevi, MD, from the University
of Texas Health Science Center at Houston, told Medscape Neurology &
Neurosurgery.

The study is published online July 14 in Archives of Neurology.

Clinical Dilemma

While it is widely acknowledged that CES patients require long-term
anticoagulation, the issue of when and how to initiate it remains a
clinical dilemma, said Dr. Hallevi.

Routinely bridging CES patients in the acute phase with enoxaparin
or heparin until warfarin therapy begins to work is a widespread
practice, but one that is not supported by the literature or current
guidelines, he said.

He added that the current study was initiated based on anecdotal
observations that CES patients tend to have more intracranial and
systemic bleeding, also described as hemorrhagic transformation,
than other types of stroke patients.

To examine possible explanations for this phenomenon, the
researchers looked at the type of treatment administered to CES
patients who were admitted to a single stroke center between April
1, 2004 and June 30, 2006 and who were not treated with tissue
plasminogen activator.

Patients were categorized into one of 5 possible treatment groups.
These included no treatment, aspirin only, aspirin followed by
warfarin, intravenous heparin in the acute phase followed by
warfarin, and full-dose enoxaparin combined with warfarin.

The study's primary outcomes included serious bleeding (defined as a
parenchymal hematoma, grade 2, or systemic bleeding) and stroke
recurrence during hospital stay.

Secondary end points included discharge with a favorable outcome
(modified Rankin Scale score of 0 to 3), stroke progression, and in-
hospital mortality.

All Intracranial Hemorrhage Occurred in a Single Group

Of the total study group, 8 subjects received no anticoagulation, 88
received aspirin alone, 35 were treated with aspirin followed by
warfarin, 44 received intravenous heparin followed by warfarin, and
29 received full-dose enoxaparin combined with warfarin.

Hemorrhagic transformation occurred in 23 (11%) patients. Of these
cases, 3 were symptomatic. Systemic bleeding occurred in 2 patients,
who were both taking heparin.

"We found that all of the hemorrhage cases were in 1 group ¡X those
who were bridged with enoxaparin," said Dr. Hallevi. "When you think
about it, this is really not surprising, because the good thing, as
well as the bad thing, about this drug is that it does exactly what
it is supposed to do, it fully anticoagulates," he said.

"We believe the infarct damages the small and medium-sized vessels,
which are later reperfused and tend to leak blood. But the
difference between this patient group and patients with other types
of stroke is that those with cardioembolic stroke get anticoagulated
really quickly, which promotes bleeding," he added.

Stroke progression occurred in 11 (5%) of patients and was
significantly associated with poor outcome. All except 1 of these
cases occurred in the aspirin-only group. In fact, the analysis
revealed that patients receiving aspirin alone were 12.5 times more
likely to experience progressive stroke compared with individuals on
other types of anticoagulation. This finding, said Dr. Hallevi,
suggests aspirin may not be as potent as other forms of
anticoagulation therapies.

Despite these findings, Dr. Hallevi, cautioned that the
retrospective nature of the study cannot prove causality.
Nevertheless, he added, clinicians treating CES patients may want to
consider these findings before opting for anticoagulation with
enoxaparin or heparin.

Arch Neurol. Published online July 14, 2008. Abstract

Results of a meta-analysis indicate that the antiepileptic agent
pregabalin is safe and effective for relieving pain in diabetic
peripheral neuropathy (DPN).

The analysis of pooled data from seven randomized, placebo-
controlled trials of pregabalin, with dosages ranging from 150 mg
daily to 600 mg daily and from 5 to 13 weeks in duration, are
published in the July issue of Diabetes Care.

Dr. Roy Freeman of Harvard Medical School in Boston and colleagues
report that "pregabalin significantly reduced pain and pain-related
sleep interference" with 150 mg/day, 300 mg/day and 600 mg/day given
in three divided doses.

"Only the 600 mg/day dosage showed efficacy when administered BID,"
the investigators report.

The greatest effect on pain and sleep interference was seen with the
highest dose.

The median time to onset of a sustained improvement in pain, defined
as a reduction in pain of 30% or greater by the end of the study
period, was four days with 600 mg/day, five days in patients treated
with 300 mg/day, 13 days in patients treated with 150 mg/day and 60
days in patients receiving placebo.

"The dose-related increase in efficacy was accompanied by a dose-
related increase in incidence of most adverse events," the team
notes.

No differences between BID and TID dosing on the rate of adverse
events were observed. The most common treatment-related adverse
events were dizziness, somnolence, and peripheral edema.

Peripheral edema was dose-related. Weight gain was also related to
the dose and to the duration of treatment.

"The underlying cause of the weight gain is not known and does not
appear to be related to the presence of peripheral edema. There was
no evidence that the weight increase compromised glycemic control,"
the authors write.

Diabetes Care 2008;31:1448-1454.