Danish researchers have identified a link between type 2 diabetes in
adults and gestational or type 1 diabetes in their mothers.

In the February issue of Diabetes Care, Dr. Tine Dalsgaard Clausen
of Copenhagen University Hospital and colleagues there and elsewhere
report on 597 adults who were born between 1978 and 1985, when
pregnant women in Denmark with risk factors for gestational diabetes
were routinely screened for the condition.

The subjects were divided into four groups based on maternal status
during pregnancy. The prevalence of type 2 diabetes, impaired
glucose tolerance, or impaired fasting glucose was 21% in subjects
born to mothers with diet-treated gestational diabetes, 12% in those
whose mothers had a genetic predisposition for diabetes but a normal
glucose tolerance test, 11% when the mothers had type 1 diabetes,
and 4% in subjects born to controls with no history of gestational
or other diabetes.

"Our findings support the hypothesis that a hyperglycemic
intrauterine environment plays a role in the pathogenesis of type 2
diabetes," the authors said. "Identification of risk groups gives
unique opportunities for lifestyle interventions; furthermore,
aiming at a normoglycemic intrauterine environment in pregnant women
may reduce the risk of type 2 diabetes in future generations."

Diabetes Care 2008;31:340-346.

Vitamin E supplementation reduces cardiovascular events in middle-
aged patients with type 2 diabetes and the haptoglobin (Hp) 2-2
genotype, Israeli researchers report in the February issue of
Arteriosclerosis, Thrombosis, and Vascular Biology.

Dr. Andrew P. Levy of Technion-Israel Institute of Technology, Haifa
and colleagues note that Hp is a determinant of cardiovascular
events in patients with diabetes. The common alleles are Hp 1 and Hp
2. The Hp 2 allele protein product, they observe, provides inferior
antioxidant protection.

According to the authors, 2-3% of the general population are
diabetics who carry the Hp 2-2 genotype. In a randomized trial in
1,434 such individuals aged 55 or older, the researchers
investigated the value of vitamin E supplementation in reducing the
risk of cardiovascular events. Subjects received vitamin E, 400 U
per day, or placebo.

At 18 months, 2.2% of vitamin-E treated patients had experienced the
composite endpoint of MI, stroke and cardiovascular death, compared
to 4.7% of subjects in the placebo group. This finding led to early
termination of the study, the authors report.

In comments to Reuters Health, Dr. Levy stressed, "It is critically
important that this study be repeated before any treatment
recommendations can be made."

He added that he and his colleagues "are working to get another
study initiated in the US and Europe." If their findings are
confirmed, Dr. Levy concluded, "Hp genotyping to determine if you
should get vitamin E could become part of the routine management of
the individual with diabetes."

Arterioscler Thromb Vasc Biol 2008;28:341-347.

Unintentional regular daytime dozing can more than quadruple stroke
risk in elderly patients and significantly increase their risk for
other vascular events.


Presented here at the American Stroke Association's International
Stroke Conference 2008, these latest findings from the Northern
Manhattan Study (NOMAS), a prospective study of stroke and stroke
risk factors in a multiethnic population, showed individuals with
excessive daytime sleepiness had a 4.5-fold increased risk for
stroke compared with their counterparts who did not doze off during
the day.

According to study investigator Bernadette Boden-Albala, PhD, from
Columbia University, in New York, this is the first large
prospective study to show that daytime sleepiness is an independent
risk factor for stroke and all vascular events.

"At this point it is fair to say doctors don't fully appreciate the
impact of sleep disturbance on vascular disease. However, these
results clearly indicate it is very important," Dr. Boden-Albala
told Medscape Neurology & Neurosurgery.

Previous research has linked poor or diminished quality of sleep to
an increased risk for vascular events, including stroke. However,
prospective studies are limited and have included only populations
diagnosed with a sleep disorder such as sleep apnea.

The researchers used the Epworth Sleepiness Scale (ESS), which
measures daytime sleepiness, and 2 nighttime sleep questions about
snoring and choking as a marker of sleep disturbance. They then
examined the risk for stroke and other vascular events.

In 2004 investigators began collecting daytime dozing data using the
ESS as part of the annual NOMAS follow-up. Subjects, who were stroke-
free at study entry, were divided into 3 groups: no dozing, some
dozing, and significant dozing.

A total of 2153 subjects were included in the final analysis. Of
these, 44% reported no dozing, 47% reported some dozing, and 9%
reported significant dozing. At 2-year follow-up investigators found
there had been 40 strokes and 127 vascular events.

Unexpectedly High Risk

After adjusting for age, race/ethnicity, sex, education, systolic
blood pressure, diabetes, obesity, and physical activity,
investigators found unexpectedly high risk the among "some dozing"
and "significant-dozing" groups.

"At 2 years of follow-up we really didn't expect to see any effect,
but, boy, did we see something. I think it is really significant
that in this very short period of time we saw this strong an
effect," said Dr. Boden-Albala.

Compared with those who reported "no dozing," individuals
reporting "significant dozing" had a 4.5-fold increased risk for
stroke and those who reported "some dozing" had a 2.6-fold increased
stroke risk.

Further adjusted analyses revealed daytime sleepiness also markedly
increased the risk for all vascular events, with a 60% increased
risk among those who reported some dozing and a 2.6-fold increased
risk in the "significant dozing" group.

One of the "troubling" aspects of these findings, said Dr. Boden-
Albala, is the fact that more than half of the study population
(56%) had sleep disturbance. At this point, she said, it is not
clear whether sleep apnea is driving the observed risk, but what is
clear is the importance of sleep on vascular health.

"People need to speak to their physician about sleep, and physicians
need to screen for sleep disturbances. An initial assessment can be
something as simple as the Epworth scale. If patients are moderately
or significantly dozing, physicians need to think about sending them
for further evaluation," she said.

Commenting on the study for Medscape Neurology & Neurosurgery,
George Howard, DrPH, from the University of Alabama at Birmingham,
also said the findings reinforce the need for physicians to assess
patients' sleep quality.

"You can't tell whether a patient has a fever if you don't take
their temperature, and the same principal applies to sleep
disturbance. Physicians need to ask their patients about sleep, and
patients need to be made aware of the importance of sleep on their
health and understand that if they have a problem with sleep they
should raise the issue with their doctor," he said.

The study was funded by the National Institute of Neurological
Disorders and Stroke.

American Stroke Association International Stroke Conference 2008:
Abstract 94. Presented February 21, 2008.

A survey in 14 US states has found that less than a third of adults
are aware of all five warning signs and symptoms of MI and would
call 911 first in the event of an MI [1]. There were variations in
awareness between races and between the sexes and also by geographic
region and education, say Dr J Fang (US Centers for Disease Control
and Prevention, Atlanta, GA) and colleagues in their report
published online February 22, 2008 in Morbidity and Mortality Weekly
Report.

"The disparities observed in this report by race/ethnicity, sex, and
education level, with higher levels of awareness among whites,
women, and persons with a college education, suggest that public-
health measures should target blacks, Hispanics, men, and persons
with less education," they say.

In addition, the state and local departments of health in states
with lower awareness should collaborate to implement general public-
awareness campaigns to increase the percentage of people who are
both aware of all five signs and symptoms and who know to call 911
immediately if a person is having a heart attack or stroke, they
stress.

Awareness high for some signs but not others

Fang et al explain that around 50% of all cardiac deaths occur
within one hour of symptom onset, before patients reach a hospital,
so timely access to emergency cardiac care is imperative. This in
turn depends upon early recognition of the warning signs and
symptoms of a heart attack both by those experiencing the attack and
bystanders and immediately calling 911.

For the current study, they accessed the Behavioral Risk Factor
Surveillance System (BRFSS), a state-based, random-digit-dialed
telephone survey of the US population from 2005 and included self-
reported data from almost 72 000 respondents in 14 states that
included questions on signs and symptoms of a heart attack. An
incorrect symptom--sudden trouble seeing in one eye--was included in
the survey to assess the possibility that people would answer "yes"
to all the items in a series of closed-ended questions.

Respondents were also asked to choose the one action that they would
take first, from the following, if they thought that a person was
having a heart attack or stroke: take the person to the hospital,
advise the person to call a doctor, call 911, call a spouse or
family member, or do something else.

Although respondent awareness of some of the five major signs and
symptoms of MI was quite high, it was lower for others: pain or
discomfort in the jaw, neck, or back (48%); feeling weak,
lightheaded, or faint (62%); chest pain or discomfort (92%); pain or
discomfort in the arms or shoulder (85%); and shortness of breath
(93%). A total of 86% of respondents reported that they would call
911 if they thought someone were having a heart attack or stroke.

Awareness of each of the five major heart-attack warning signs and
symptoms varied by race/ethnicity, sex, level of education, and by
state. Awareness was highest in West Virginia (35.5%) and lowest in
DC (16.0%). The other states surveyed were: Alabama, Florida, Iowa,
Louisiana, Maine, Minnesota, Mississippi, Missouri, Oklahoma,
Tennessee, and Virginia.

Knowledge of all signs pretty poor

When it came to awareness of all five signs and symptoms of MI,
results were poorer, however, with only 31% of respondents knowing
all five signs and just 27% recognizing all signs and saying their
initial impulse would be to call 911. Furthermore, only 16% of
people were aware of all five signs plus the one incorrect sign
inserted into the survey and said they would call 911 first.

"Mortality from heart attack would decrease if patients received
medical assistance more quickly, [and] research suggests that
patient delays in seeking help are a major factor related to delay
in care," say Fang et al.

"Because only approximately one third of the surveyed population
knew all five correct heart-attack signs and symptoms, state and
local public-health measures should be developed to improve public
awareness of heart-attack warning signs and symptoms," they conclude.

Fang J, Keenan N, Dai S, et al. Disparities in adult awareness of
heart attack warning signs and symptoms--14 states, 2005. MMWR Morb
Mortal Wkly Rep. February 20, 2008. Available at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5707a3.htm?
s_cid=mm5707a3_e.

New research linking the effects of nighttime noise on blood
pressure has found that people living near airports experience both
chronic and acute blood-pressure increases in response to aircraft
sounds, even during sleep [1]. A new analysis from the Hypertension
and Exposure to Noise Near Airports (HYENA) study, published online
February 12, 2008 in the European Heart Journal, suggests that blood
pressure spikes not only in response to aircraft sounds, but also
traffic or indoor sounds of the same intensity.

Earlier findings from the HYENA study found that risk of
hypertension was increased with long-term noise exposure, with
higher blood-pressure values corresponding to higher-intensity and
more frequent noise events. This analysis included a larger sample
of nearly 5000 subjects living near one of the six major European
airports and appears online in Environmental Health Perspectives [2].

In the European Heart Journal paper this week, Dr Alexandros S.
Haralabidis (National and Kapodistrian University of Athens, Greece)
and colleagues looked specifically at nighttime blood-pressure
increases in response to discrete noise events in a smaller group of
volunteers.

Blood pressure lifts off, with flight sounds

For the study, 140 volunteers living near the airports of Athens
(Greece), Malpensa (Italy), Arlanda (Sweden), and Heathrow (UK) wore
blood-pressure monitors that checked their blood pressure at 15-
minute intervals throughout the night. Noise levels were recorded by
specialized devices, with a noise event defined as LAmax>35 dB. MP3
recorders were used to identify the source of the noises throughout
the night, enabling researchers to link specific noises to blood-
pressure increases.

The authors report that systolic blood pressure increased by a mean
of 6.2 mm Hg and diastolic by a mean of 7.4 mm Hg within 15 minutes
of an "aircraft event," but that other sources of noise, including
traffic sounds and indoor noise--mostly snoring--also produced blood-
pressure spikes. Of note, the noise levels studied in this analysis
are below levels that tend to actually wake people from sleep,
meaning that the noises were affecting blood pressure at a
subconscious level. Earlier studies in animals had suggested that
blood-pressure responses could occur during sleep or anesthesia, but
this has not been previously shown in humans, senior author on the
study, Dr Lars Järup (Imperial College London, UK), told heartwire.

Järup emphasized that the study is just one of a growing body of
literature assessing the impact of noise and other stressors on
cardiovascular health and public health generally. The World Health
Organization, he noted, is currently evaluating all the literature
on aircraft noise and health and is planning to publish the results
of its analysis later this year. The HYENA investigators have also
collected stress hormones, found in saliva samples, from their study
volunteers and are planning to examine the link between
physiological stress markers and blood pressure.

Järup adds that clinicians should be aware that nighttime noise
might be yet another culprit in driving up blood-pressure
levels. "Clinicians, and cardiologists in particular, are already
very aware that there are many different risk factors for
hypertension and this is just one. It's probably fair to say that
other risk factors may be more important; however, it's critical for
us to pinpoint what proportion of risk this conveys. From my point
of view, the more risk factors you can eliminate, the better, and
this is one of them."

From a health-policy level, he added, "it would make sense to have
more restrictions on nighttime flights, when blood-pressure
responses to aircraft noise are greatest." Some of the airports in
Europe have already limited their night flights, he pointed out.

Haralabidis AS, Dimakopoulou K, Vigna-Taglianti F, et al. Acute
effects of night-time noise exposure on blood pressure in
populations living near airports. Eur Heart J 2008;
DOI:10.1093/eurheartj/ehn013. Available at:
http://eurheartj.oxfordjournals.org. Abstract
Järup L, Babisch W, Houthuijs D, et al. Hypertension and exposure to
noise near airports: the HYENA study. Environ Health Perspect 2008;
116:329–333. DOI:10.1289/ehp.10775. Available at:
http://www.ehponline.org/docs/2007/10775/abstract.html.

A study published this week provides a little more evidence that the
benefit of statins extends beyond their ability to lower LDL-
cholesterol levels [1]. In a new meta-analysis, investigators showed
that the use of statins was significantly associated with a
decreased risk of incidence or recurrence of atrial fibrillation
(AF) in patients in sinus rhythm with a history of previous AF,
those undergoing cardiac surgery, or those prescribed the drugs
after an acute coronary syndrome (ACS).

In a paper published in the February 18, 2008 issue of the Journal
of the American College of Cardiology, a special issue focusing on
AF, Dr Laurent Fauchier (Centre Hospitalier Universitaire Trousseau,
Tours, France) and colleagues note that the "beneficial effect
seemed more marked in the prevention of AF recurrence than in
primary prevention of AF" but cautioned against making too much of
this finding as there was only a trend of benefit in these patients.

The meta-analysis included six studies with approximately 3500
patients in sinus rhythm. Three studies investigated the use of
statins in patients with a history of paroxysmal AF or persistent AF
undergoing electrical cardioversion, while the others investigated
the use of statins in primary prevention of AF in patients
undergoing cardiac surgery or following ACS. The follow-up in the
six trials ranged from three to 26 weeks, and in five of the six
studies, atorvastatin was the statin prescribed.

Treatment with a statin reduced the incidence and recurrence of AF
61% compared with placebo. While there were trends toward
significance in primary- and secondary-prevention subset analyses,
none of these reductions were statistically significant. The overall
results were similar when investigators excluded the Myocardial
Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)
study, which was published only in abstract form. They note that the
protective benefit of statins did not appear to be related to dose,
as individual odds ratios were similar in the studies that used
atorvastatin 40 mg and 80 mg to studies that used lower doses.

While the mechanisms of benefit are still unknown, Fauchier and
colleagues note that statins reduce inflammation and that
inflammation is involved in the "development, recurrence, and
persistence of AF." They also note that some evidence suggests an
association between AF and enhanced renin angiotensin system (RAS)
activity. Other studies have also suggested a link between
dyslipidemia and the RAS, and with statins reducing cholesterol
levels, the drugs might downregulate the RAS and possibly explain
the antiarrhythmic effects observed.

Still, large-scale, prospective, randomized clinical trials are
needed to establish whether statins bring a similar benefit to those
not part of the patient population in this meta-analysis and to
explore whether the drugs might be an appropriate therapeutic option
in all subgroups of patients for the management of AF, conclude the
authors.

The authors report no conflicts of interest related to this study.

Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect
of statin therapy and atrial fibrillation. J Am Coll Cardiol 2008;
51:828-35.

The US Food and Drug Administration has approved a fixed-dose
combination of extended-release niacin (Niaspan, Abbot) and
simvastatin for use in patients with complex lipid abnormalities
where treatment with niacin or simvastatin alone is not sufficient.

The drug, known as Simcor (Abbott, Abbott Park, IL), is approved to
lower total- and LDL-cholesterol levels and triglycerides and to
raise HDL-cholesterol levels. The approval is based on safety and
efficacy data from 640 patients with mixed dyslipidemia and type 2
dyslipidemia, a study in which patients treated with Simcor 1000/20
mg achieved significantly better improvements in cholesterol end
points than simvastatin 20 mg. Also, compared with simvastatin 20
mg, the fixed-dose combination reduced triglyceride levels an
additional 27%.

The drug was generally well tolerated, with flushing the most
commonly reported side effect.

The US National Institutes of Health (NIH) is also sponsoring a
trial that is evaluating the merits of simultaneously lowering LDL
and raising HDL. The trial, known as Atherothrombosis Intervention
in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on
Global Health Outcomes (AIM-HIGH), will compare the incidence of
major cardiovascular events in patients randomized to niacin plus
simvastatin or simvastatin alone.

The trial, which will enroll 3300 patients with established vascular
disease, is run by Drs William Boden (Hartford Hospital, CT) and
Greg Brown (University of Washington School of Medicine, Seattle),
but full results are not expected until 2011. In addition to the
NIH, Abbott is a cosponsor of the AIM-HIGH study.

The Clinical Trials Service Unit (CTSU) of Oxford University is also
in on the HDL-cholesterol show. That group is running a study, known
as Heart Protection Study 2 Treatment of HDL to Reduce the Incidence
of Vascular Events (HPS2-THRIVE), that will assess whether a new
combination tablet, containing extended-release niacin and a
specific blocker of prostaglandin D2 to prevent flushing, prevents
MI, stroke, or revascularization procedures in patients with
existing vascular disease.

US Medicare patients recovering from an MI would live longer, without
costing society more money, if Medicare covered all of their
secondary-prevention drugs over the long term, rather than providing
the partial coverage in place now, new research suggests [1]. Writing
in an early online publication in Circulation, Dr Niteesh Choudhry
and colleagues (Harvard Medical School, Boston, MA) note that, even
from a Medicare perspective, full drug coverage would be highly cost
effective, although not actually cost saving.

"Our analysis suggests that providing full coverage for combination
therapy to post-MI Medicare beneficiaries would save both lives and
money from the societal perspective," they write.

For their analysis, Choudhry et al considered the incremental cost
effectiveness of aspirin, beta-blockers, ACE inhibitors or
angiotensin receptor blockers, and statins. They conducted their cost-
efficacy analysis first from a society perspective, then from
Medicare's perspective. As Choudhry explained to heartwire. "It's
most fair to do this kind of analysis if you consider all costs to
everybody from a new policy, that's the 'society perspective.' So
from that perspective, what it means is that, for the purposes of the
analysis, I'm going to care about costs to patients, to hospitals, to
insurers, to care-givers--everybody."

In this analysis, they report, Medicare beneficiaries aged 65 years
and older would live an average of 8.56 quality-adjusted life-years
(QALYs) after their initial MI if the cost of their drugs were fully
covered, at a cost of US$111 600. Under the existing Medicare Part D
program, in which approximately 37% of drug costs are covered, post-
MI Medicare patients would live an average of 8.21 QALYs, at a
societal cost of $114 000.

When the analysis was performed again, from the perspective of
Medicare, full drug coverage would be highly cost effective, at a
cost of $7182 per QALY, but not cost saving, the authors note.

"What we found is that you can get more health and save money from a
societal perspective by covering these drugs in full," Choudhry
commented. "From a Medicare perspective, we found that you do have to
spend more money, on average $2500 dollars more per beneficiary, but
you get more health. When you look at that ratio, it's about $7200
per QALY, and that's a low number."

He emphasized that his study is just an economic model at this
stage. "It seems to make sense and is a good idea, but we don't know
if this will actually work in real life and we don't exactly know how
many more people will begin to use medications when they eliminate
their costs. . . . We don't know whether this will exactly translate
into better quality of life or longer life, so it really needs
testing."

Choudhry said that he and others have started a large randomized
trial, the Post-MI-FREEE trial, comparing outcomes in patients who
received full cardiovascular drug coverage with those in patients
receiving partial coverage by a private insurer. He also believes
that Medicare could be testing this approach, even in a nonrandomized
fashion. Choudhry points out that it's too early to know if the Part
D program has helped save lives and money, but predicts that it
probably has. Of note, the Part D program was not tested in trials
before implementation.

Choudhry NK, Patrick AR, Antman EM, et al. Cost-effectiveness of
providing full drug coverage to increase medication adherence in
post¡Vmyocardial infarction Medicare beneficiaries. Circulation 2008;
DOI: 10.1161/CIRCULATIONAHA.107.735605. Available at:
http://circ.ahajournals.org.

Preliminary findings from the ADVANCE trial provide no evidence that
intensive treatment to lower blood-glucose levels in type 2
diabetics increases mortality risk.

The ADVANCE study is similar to the blood-glucose-lowering part of
the ACCORD trial, which was stopped last week because of a higher
number of deaths in patients allocated to intensive glucose lowering
rather than standard treatment.

In a press release released by the ADVANCE group, principal
investigator Prof Stephen MacMahon (The George Institute, Sydney,
Australia) stated that "Due to the unexpected report from the ACCORD
trial, we felt it was in the public interest for us to ask our data
monitoring and safety committee to make a statement as to whether
the available data from ADVANCE provide any support for the
suggestion that intensive blood-glucose lowering may increase
mortality."

"Reassured"

ADVANCE management committee chair Prof John Chalmers (The George
Institute) commented: "Doctors and patients should feel reassured
that the mortality trend reported by the ACCORD study has not been
found in the interim results from ADVANCE. However, we need to await
more definitive analyses and reports from both studies before
drawing final conclusions."

ADVANCE involves 11 140 high-risk patients with type 2 diabetes who
were randomized to intensive or standard glucose-lowering
treatments. The study is just coming to an end, but the database is
still locked and the investigators still blinded while the data are
checked and cleaned up, study director Dr Anushka Patel (The George
Institute) told heartwire. The database will be unlocked in March
and the analysis will begin at that point. She added that the data
were now "more than 99% complete and so we are confident that the
interim findings communicated here are a reliable guide to the final
results."

Twice as much data as in ACCORD

In the press release, data safety and monitoring board (DSMB) chair,
Prof Rory Collins (University of Oxford, UK), said the data
provided "no confirmation" of the adverse mortality trend reported
from the ACCORD study. He also noted that the ADVANCE interim
results were based on more than twice as many data and similar
levels of glucose control as in ACCORD.

Patel told heartwire that only the DSMB has seen the data and the
ADVANCE investigators have not had access to the study results. "We
do not know if the mortality results show a benefit for intensive
glucose lowering or a neutral effect. But we understand that there
is no indication of harm," she said. She added that no information
on any other outcome, other than mortality, was yet available.

Same A1C level as ACCORD in intensive arms

She noted that the intensive arm was aiming for HbA1C levels of 6.5%
or below, and they actually achieved 6.4%--exactly the same level as
the intensive arm in ACCORD. The standard-treatment arm achieved an
A1C level of 7%, slightly below the 7.5% reached in ACCORD.

Patel said she "couldn't even begin to speculate" on reasons why the
mortality results were different between the two trials. "It's far
too early. We haven't even seen the data yet. We don't know enough
information. The ACCORD investigators have done some analyses, but
we haven't even started our analyses yet."

Differences between the trials

While ACCORD and ADVANCE are similar in that they both investigated
intensive vs standard glucose lowering in type 2 diabetes, there are
many differences between the two trials. ACCORD allowed any
treatment whatsoever to reach target glucose levels, whereas in
ADVANCE, all patients in the intensive group started treatment with
the sulfonylurea drug modified-release gliclazide. But Patel noted
that the vast majority of patients could not reach target levels on
this one drug alone, and so other treatments were added and, like
ACCORD, many therapies were used. "There was probably a similar
range of treatments used in the two studies, but there will be some
differences. For example, ACCORD applied more stringent drug therapy
to reach targets than we did, and there was probably more use of
thiazolidinediones in ACCORD than in ADVANCE."

She said the patient population was "broadly similar" in the two
studies, with around one-third of patients in both studies having a
prior history of cardiovascular disease, but the average age in
ADVANCE was slightly higher (66 vs 62 years in ACCORD), and patients
had had diabetes for a shorter time in ADVANCE (eight years vs 10
years in ACCORD). In addition, A1C levels were a bit lower at
baseline in ADVANCE patients, but their blood pressure was a little
higher than those in ACCORD.

Less intensive intervention in ADVANCE?

ACCORD steering committee member Dr John Buse (University of North
Carolina, Chapel Hill) pointed out some other differences between
the two trials to heartwire. "ADVANCE included a population with
milder diabetes that I suspect required a less intensive effort to
get the A1C to 6.4%. They were aiming only for 6.5%, while we were
aiming for <6.0%," he said. While the two populations arguably had
similar cardiovascular risk, none of the ADVANCE patients are in the
US and thus will be socially and culturally quite different, he
added.

"I think ADVANCE supports the notion that it is the intensity of the
medical intervention and not the A1C level achieved on average that
is the problem, but we'll know for sure in a few weeks," Buse
commented.

Asked whether the ACCORD investigators considered asking for ADVANCE
data before stopping the study, Buse replied: "The decision to stop
the study was made by the [National Heart, Lung, and Blood
Institute] NHLBI. As an investigator, they did not discuss it with
me before the decision was final." He noted that the ACCORD and
ADVANCE investigators had met from time to time during the past five
years and have some joint analyses planned.

Buse, who is also president of medicine and science at the American
Diabetes Association (ADA), said he did not feel patients should be
confused by the differing results of the two studies. "We have
really tried to encourage people not to read between the lines. We
tried as hard as we could to make the point that the study was
stopped due to a safety concern but that it should in no way affect
current ADA guidelines. The only cautionary note we sounded was
using very intensive programs of glucose lowering in patients at
very high risk of CVD. From what I know about ADVANCE, they did not
use a very intensive glucose-lowering program," he told heartwire.

The NHLBI told heartwire that the ADVANCE and ACCORD studies have
agreed to share data and that although there may be several
differences between the studies that need to be examined, hopefully
a consensus can be reached on the conclusions.

ADA statement

In a statement, the ADA said it "believes that the information from
ADVANCE is very important and further magnifies the uncertainty over
whether intensive glucose control may harm some people with
diabetes." The association notes that results of a third trial, the
VA Diabetes Trial, which also examined the relationship between
intensive glycemic control and cardiovascular outcomes in type 2
diabetes, are due out soon. "The ADA plans to critically examine the
final data from these studies once they are publicly available later
this year and will issue further recommendations at that time. In
the meantime, the ADA continues to advise most people with diabetes
to strive for an A1C of less than 7% but as always stresses
individualization of treatment goals. People with type 2 diabetes
who have existing CVD or multiple CVD risk factors should consult
with their healthcare team about their treatment goals," it adds.

Oncologists should be paying attention to noncancer-related medical
problems in addition to focusing on the cancer, particularly those
who treat breast cancer patients. This is the message in an
editorial accompanying a study showing that older breast cancer
patients are more likely to die from causes other than breast
cancer. Both the paper and the editorial appear in the February 20
issue of the Journal of the National Cancer Institute.

"As deaths from breast cancer fall and the population ages, breast
cancer patients are increasingly likely to die of other illnesses.
Thus, appropriate treatment of medical conditions other than breast
cancer is critical for our patients' overall health," write
editorialists Sharon H. Giordano, MD, MPH, and Gabriel N.
Hortobagyi, MD, FACP, both from the department of breast medical
oncology at University of Texas M.D. Anderson Cancer Center, in
Houston. Although the study did not provide information on specific
causes of death, it showed that cardiovascular disease at baseline
significantly increased the risk for death from other causes, and
that osteoporosis at baseline increased the risk for death from
other malignancies.

The editorialists focus on cardiovascular disease because, as the
leading cause of death in the United States, it is likely to have
been a contributing factor in the deaths of many of these patients,
they say. "Cardiovascular disease is of particular concern to breast
cancer patients because of its prevalence and the fact that many
therapies for breast cancer can cause cardiac dysfunction," they
write. "Breast cancer survivors should have regular assessment of
cardiovascular risk, as should all women, but the extent to which
cancer survivors are receiving this care is uncertain."

The study is reported by Judith-Anne Chapman, PhD, from Queen's
University, in Kingston, Ontario, and colleagues on behalf of the
National Cancer Institute of Canada Clinical Trials Group. They
report data from the group's MA.17 trial, which involved 5170 breast
cancer patients who were disease-free after approximately 5 years of
adjuvant tamoxifen therapy, and who were then randomized to receive
either the aromatase inhibitor (AI) letrozole (Femara, Novartis) or
placebo. During a median follow-up of 3.9 years, 256 deaths were
reported ¡X 102 from breast cancer, 50 from other malignancies, 100
from other causes, and 4 from unknown causes.

Nonbreast cancer deaths were more common than deaths from breast
cancer, the researchers point out, accounting for 60% of deaths
overall. This figure was even higher (72%) among women who were 70
years of age or older, but fell to 48% among women 70 years and
younger.

"The results of this study point out that medical attention to the
potential of death from other causes becomes increasingly important
in older populations of patients with breast cancer," Dr. Chapman
and colleagues conclude. "It becomes important at a general societal
level to consider relative survival from breast cancer, which takes
into account other risks of mortality in the population at large."

The editorialists point out that results from a similar study with
the AI anastrozole (Arimidex, AstraZeneca), the Arimidex Tamoxifen
Alone or in Combination (ATAC) trial, show a similar pattern, in
that 60% of all the reported deaths were from causes other than
breast cancer. This high risk for death from other causes might
explain why it has been difficult to show overall survival benefits
in the AI trials, they comment.

They also point out that the population of patients in these AI
trials is not representative of all breast cancer patients. The
patients in these trials had estrogen-receptor-positive or unknown
tumors and were still disease-free after 5 years on tamoxifen, so
they had a good prognosis. Dr. Chapman and colleagues add that
younger women, who tend to have hormone-receptor-negative disease
and shorter survival, were excluded from their trial.

One coauthor of the study, James N. Ingle, MD, from the department
of oncology at the Mayo Clinic in Rochester Minnesota, has received
honoraria from Novartis, and another coauthor, Paul E. Goss, MD,
PhD, from the department of hematology and oncology at Massachusetts
General Hospital Cancer Center, Harvard Medical School, in Boston,
has received consulting honoraria from Novartis, AstraZeneca, and
Pfizer. The editorialists have disclosed no relevant financial
relationships.

J Natl Cancer Inst. 2008; 100:252-260.

Patients taking sunitinib (Sutent, Pfizer) will require close
cardiac monitoring, a new study suggests. The drug, which is used to
treat renal cell carcinoma and gastrointestinal stromal tumor
(GIST), has been linked to more heart failure than previously
reported. The findings are scheduled to be presented on February 16
at the 2008 Genitourinary Cancers Symposium.

Speaking to reporters in advance of the meeting, lead author Melinda
Telli, MD, from the Stanford University School of Medicine in Palo
Alto, California, reported that 15% of patients taking sunitinib
developed heart failure ¡X more than the previously reported 8%.

The researchers also emphasize that, contrary to previous findings,
the effects were irreversible even after stopping therapy.

Sunitinib is an oral small-molecule multitargeted receptor tyrosine
kinase inhibitor. It works by inhibiting the growth of blood vessels
that tumors need to grow and spread. The drug might also slow the
growth and division of cancer cells. Sunitinib is currently being
tested for the treatment of a variety of other cancers, both in
early and advanced stages.

During an interview with Medscape Oncology, press-conference
moderator Howard Sandler, MD, from the University of Michigan Health
System in Ann Arbor, pointed out that the study of just 48 patients
was small and questions remain about how reliable the observation is.

"But the findings certainly support the routine cardiac monitoring
of patients taking sunitinib," Dr. Sandler said. "The researchers
were also looking at an unselected patient population from Stanford,
and this may have important implications for the general
population," he added.

The current study is the first to evaluate adverse cardiovascular
effects in patients who were taking sunitinib outside of the context
of a clinical trial. Patients with pre-existing cardiac conditions,
for example, would not have been excluded from this study.

Patients on Sunitinib Will Require Close Cardiac Monitoring

Dr. Telli said that although larger studies will need to be
conducted, she wonders whether the true incidence of heart failure
is even greater than what her group saw.

Sunitinib has also been linked to hypertension. Animal studies have
shown that the drug can be toxic to cardiac cells and that this
effect might be exacerbated by high blood pressure.

In the current analysis, researchers studied the occurrence of
symptomatic heart failure in 48 patients on sunitinib from the
Stanford University Comprehensive Cancer Center.

A total of 7 patients experienced symptomatic left ventricular
dysfunction during treatment. These effects were observed as early
as 22 days and as late as 435 days after the start of therapy.
Symptoms persisted in 3 patients despite the discontinuation of
sunitinib and the initiation of heart failure treatment.

The mean age of those experiencing cardiotoxicity was 65 years.
Investigators found that patients with a history of heart failure, a
history of coronary artery disease, or a low body-mass index were
more likely to experience heart failure.

"Cardiac adverse effects need to be carefully examined in future
trials of sunitinib to determine the factors that place patients at
risk for this complication," Dr. Telli told reporters. "That
information will allow us to administer this medication more safely
to patients for whom the benefits of treatment clearly outweigh the
risks."

Such trials are urgently needed, she noted, because plans are
underway to expand the oncologic indications for this drug.

Study investigators report having received honoraria and funding
from Pfizer, the maker of sunitinib.

American Society of Clinical Oncology 2008 Genitourinary Cancers
Symposium (GCS): Abstract 351.

Results of a new prospective study suggest that the composition of
plaques removed during carotid endarterectomy (CEA) can help predict
the risk of subsequent restenosis. In this study, less target vessel
restenosis was seen in patients whose excised plaque showed
significant macrophage infiltration and a large lipid core.

"The dissection of a lipid-rich, inflammatory plaque is associated
with a reduced risk of restenosis," the researchers, with first
author Willem E. Hellings and corresponding author Gerard
Pasterkamp, both from the University Medical Center in Utrecht, the
Netherlands, conclude.

Their findings are published as a Preliminary Communication in the
February 6 issue of the Journal of the American Medical Association.

Assessing Restenosis Risk

Restenosis is a drawback of catheter-based and surgical
interventions in different vascular territories, the authors write.
Clinical predictors of restenosis in coronary and peripheral
vascular disease include diabetes, and after carotid intervention,
smoking, age, and female sex have been associated with increased
restenosis. In addition, angiographic predictors such as lesion
length and decreased vessel diameter have been associated with
increased risk of restenosis.

However, they note, plaque composition in the atherosclerotic plaque
taken from the carotid artery during the procedure has not been well
studied as a possible marker for restenosis.

In this project, called the Athero-Express Study, the researchers
investigated the relationship between atherosclerotic plaque
histology and the occurrence of restenosis after CEA. Athero-Express
is a longitudinal vascular biobank study including atherosclerotic
plaques of patients who underwent primary CEA. There were 500 of
these patients prospectively followed up between April 1, 2002 and
March 14, 2006 to assess carotid restenosis using duplex ultrasound
1 year after their intervention.

The researchers then looked at the risk for carotid restenosis in
relation to various predefined histologic characteristics, including
macrophage and smooth-muscle infiltration, collagen, calcifications,
intraplaque bleeding, luminal thrombus, and lipid core size,
adjusted for clinical characteristics using multivariate logistic
regression analysis.

At 1 year, 81 of the 500 patients, or 17%, developed a 50% or
greater restenosis, including 40 patients (8%) who developed a 70%
or greater restenosis in the target vessel.

They found that patients whose plaques showed marked macrophage
infiltration had a lower risk of developing both a 50% or greater
restenosis and a 70% or greater restenosis over 1 year.

Similarly, patients whose plaques had a large lipid core size (>
40%) had a lower risk than those with a lipid core of less than 10%
of developing either a 50% or greater or a 70% or greater
restenosis, independent of other clinical characteristics.

"This is the first study to our knowledge that provides prospective
evidence that the composition of the atherosclerotic plaque ¡X low
macrophage infiltration and small or absent lipid core ¡X is
associated with risk of restenosis after a vascular intervention,"
the authors conclude.

Theoretically, they add, assessment of the plaque using noninvasive
imaging may help to tailor treatment strategies ¡X whether carotid
endarterectomy, stenting, or medical treatment ¡X for patients with
carotid artery stenosis.

"Previously, it was shown that symptomatic clinical presentation is
related to plaques with a large lipid core size and strong
macrophage infiltration, and it was suggested that benefit of
carotid endarterectomy might be less in plaques without these
histopathological features," they note. "Our study shows that
vessels with these vulnerable plaques (low macrophage and lipid
content) are more prone to develop restenosis after endarterectomy."

Their findings, though, were based on a small group of patients, and
require confirmation in other populations at risk.

The study was funded by the University Medical Center, in Utrecht,
the Netherlands. The authors report no conflicts of interest.

JAMA 2008;299:547-554.

A new Danish study, Steno-2, has shown that in high-risk type 2
diabetes patients, early intensive intervention with multiple drug
combinations and behavior modification leads to reduced rates of
death and cardiovascular disorders [1]. Dr Peter Gaede (Steno
Diabetes Center, Copenhagen, Denmark) and colleagues report their
findings in the February 7, 2008 issue of the New England Journal of
Medicine.

"The most impressive finding is the 20% absolute risk reduction in
the primary end point--all-cause mortality--after a total of 13.3
years of follow-up. Similarly, the absolute risk reduction for
cardiovascular death was 13.0%. We show these risk reductions in
high-risk type 2 diabetes patients--defined by the presence of
microalbuminuria--who were originally treated in the intensive arm
of our study for close to eight years," principal investigator Dr
Oluf Pedersen (Steno Diabetes Center) told heartwire. He added that
this is the first time that such an absolute risk reduction has been
shown in any high-risk group of diabetics.

The results of Steno-2 at first glance appear to be in direct
contrast to those of a National Heart, Lung, and Blood Institute
(NHLBI) study, ACCORD, in which the blood-glucose-lowering arm has
just been prematurely halted, as reported by heartwire. This was due
to a higher mortality in patients in the intensive glucose-lowering
arm compared with patients in the standard arm.

But Pedersen is keen to point out that the study populations of the
two trials should not be confused, as "there is a huge difference
between Steno-2 and ACCORD." Patients in Steno-2 were younger, had
had diabetes on average six years, and were deemed high risk by the
presence of microalbuminuria rather than having heart disease or two
known risk factors for heart disease, as in ACCORD (just 25% of
Steno-2 patients had known cardiovascular disease on entry). Also,
because of treatment resistance, only 18% of patients in Steno-2
achieved the target HbA1c level of below 6.5%, he notes. "The impact
on mortality and micro- and macroangiopathy in Steno-2 is likely
related to the early and additive effects of treating dyslipidemia,
hypertension, hyperglycemia, and platelet aggregation in a
relatively intensive and structured way."

Follow-Up to Steno-2 Study

Pedersen explained that around a third of all type 2 diabetes
patients have microalbuminuria, "which is a marker of global
vascular damage. Not just a marker for developing nephropathy, it's
a risk marker for premature cardiovascular disease. So it's not a
trivial population."

The original results of the Steno-2 study were published five years
ago, as reported by heartwire, and showed that intensive
intervention against multiple risk factors in patients with type 2
diabetes reduced cardiovascular and microvascular events by about
50%. Although the number of deaths was lower in the intensive-
therapy group in this study, the relatively small number of patients
who reached that end point precluded a determination of whether the
approach affected mortality, the researchers explain.

In the study, 160 patients with type 2 diabetes and persistent
microalbuminuria, with a mean age of 55 years, were randomly
assigned to receive either intensive therapy--with tight glucose
regulation and the use of renin-angiotensin blockers, aspirin, and
lipid-lowering agents--or conventional multifactor therapy; the mean
treatment period was 7.8 years.

Original Intensive-Arm Patients Fared Best

The current paper looks at a mean follow-up period of 5.5 years
after the initial treatment period had ended; during this time, all
patients in the conventional-therapy arm were offered intensive
treatment. Despite this, patients who were originally in the
intensive arm did better, indicating the benefit of early
intervention as compared with late intervention, say the
researchers.

At the end of a total of 13.3 years, 24 patients in the intensive
group had died, compared with 40 in the original conventional-
treatment group (hazard ratio 0.54; p=0.02). Intensive therapy was
also associated with a lower risk of death from cardiovascular
causes (hazard ratio 0.43; p=0.04) and of cardiovascular events (HR
0.41; p<0.001).

One patient in the intensive-therapy group had progressed to end-
stage renal disease, as compared with six in the conventional-
treatment group (p=0.04). And fewer patients in the intensive group
required retinal photocoagulation (relative risk 0.45; p=0.02).

"In comparison with the results of trials involving treatment of
single risk factors in patients with type 2 diabetes, the achieved
risk reductions in our trial were considerable," Gaede et al note.

"We are dealing with the additive effects of multiple drugs on a
background of healthy-behavior coaching," Pedersen told
heartwire. "This study justifies widespread use of multiple
medications to achieve treatment targets in type 2 diabetes patients
at high risk."

In terms of glucose lowering, Pedersen explained to heartwire that
at the end of the 7.8 years of randomization in Steno-2, the mean
A1c was 7.9% in the intensive arm vs 9.0% in the conventional-
treatment arm. At the end of the observational follow-up at 13.3
years, these figures were 7.7% and 8.1%, respectively.

In the glycemic-control part of ACCORD, the median A1c level
achieved in the intensive-treatment group was 6.4%, vs 7.5% in the
standard group. The trial was stopped early because of an excess of
three deaths per 1000 participants per year in the intensive group
vs the standard group, over an average of four years of treatment.

The Hard Part: Translating the Effects From a Trial to the Real
World

The Steno-2 researchers point out the "shocking" 50% mortality rate
during the entire follow-up period in the patients originally
offered conventional treatment, emphasizing a very poor prognosis
for these patients, "comparable to many forms of cancer," unless
treated early and intensively.

The first important step is to identify type 2 patients with
microalbuminuria, which can be done with a simple urine albumin
measurement, Pedersen told heartwire.

"The results we obtained were because we began treatment at a very
early stage, as soon as we identified microalbuminuria, and that's
key. We need to develop the tools to assist patients to adhere to
multiple drugs, and that's not easy. Also, we need to figure out how
to translate these kinds of 'greenhouse experiments' in a clinical
trial to GPs and the primary-care community, where the majority of
patients are treated. This is an enormous challenge for healthcare
policy-makers."

Coauthor Dr Hans-Henrik Parving (University of Aarhus, Denmark) has
received consulting and lecture fees from Merck, Novartis, Bristol-
Myers Squibb, Pfizer, and Sanofi; grants from Merck, Novartis, and
Bristol-Myers Squibb; and has an equity interest in Novo-Nordisk and
Merck. Pedersen has an equity interest in Novo-Nordisk.

Gaede P, Lund-Anderson H, Parving HH, et al. Effect of a
multifactorial intervention on mortality in type 2 diabetes. New
Engl J Med 2008; 358:580-591.

After years of decline, rates of uncontrolled hypertension appear to
be reaching a plateau for men and have actually increased for women,
a new analysis suggests [1]. In Washington, DC and many southern
states, one in four women has high blood pressure, a finding that
researchers say is deplorable, given the well-established lifestyle
and low-cost, off-patent pharmaceutical options available for
controlling hypertension.

"There are a lot of things that affect human health, but this is
obviously one of the largest ones," lead author on the analysis, Dr
Majid Ezzati (Harvard University, Boston, MA), told heartwire. He
explained that while blood-pressure levels for both men and women
declined during the 1970s and 1980s, the rate of decline stated to
slow down for men in the 1990s and actually went up in women. "Here
we have something that is well-studied, with no uncertainty about
what to do about it, and yet hypertension rates are not going down."

AHA president Dr Dan Jones, commenting on the study in a press
statement, agreed: "Easily applied methods for prevention and
treatment are available," he said. "It is amazing that blood-
pressure control rates are not improving in our country. Public-
health officials, policy makers, health professionals, and the
American public need to respond."

The paper appears online February 11, 2008 in Circulation.

Ezzati et al's study used actual and self-reported data collected in
the National Health and Nutrition Examination Survey (NHANES), then
extrapolated from this to the Behavioral Risk Factor Surveillance
System (BRFSS) to estimate state-specific mean systolic blood
pressure and uncontrolled hypertension rates. From this they
determined that DC, South Carolina, Georgia, Texas, Louisiana, and
Mississippi had the highest prevalence of uncontrolled hypertension
in the US, ranging from 18% to 21% in men and 24% to 26% in women,
while the states of Vermont, Connecticut, New Hampshire, Iowa, and
Colorado had the lowest prevalence of uncontrolled hypertension (15%
to 16% for men and around 21% for women).

Reversible trends

To heartwire, Ezzati emphasized that while some states were doing
better than others at controlling blood-pressure levels, the overall
trends were the same, state by state: hypertension had stopped
declining in men and was increasing in women. While his study didn't
examine reasons for the phenomenon, Ezzati speculated to heartwire
that part of the problem may be the obesity epidemic, hitting women
harder than men, and also the fact that women are less likely to
access, or have access to, good medical care.

"Given that a big part of managing blood pressure is being told by
somebody that you have high blood pressure and being put on a
specific intervention--consuming less salt, taking antihypertensives
regularly--that might be part of the story," he said.

The authors also explored the link between hypertension and
mortality and found that between 2001 and 2003, deaths attributable
to uncontrolled hypertension were less frequent in the states where
hypertension prevalence was lower and more common in the states with
the highest rates of uncontrolled hypertension. For example, deaths
due to suboptimal blood-pressure control among women in Washington,
DC and Mississippi were 360 to 370 per 100 000, compared with 200 to
220 in Minnesota and Massachusetts. For men, deaths from high blood
pressure ranged from 210 per 100 000 in Utah and Colorado to 410 per
100 000 in Washington, DC.

Ezzati believes physicians and patients may have become somewhat
complacent about measuring blood pressure regularly or acting
aggressively to lower it. "Maybe physicians are being too
conservative in actually recommending both lifestyle and
pharmacological interventions," he suggested. "Salt is arguably one
of the largest drivers of blood pressure; perhaps physicians are
being too conservative about warning people about it."

He also believes physicians should play a bigger role not just with
individual patients, but on a broader population level. "Maybe in
the same way that physicians played a role in broad public advocacy
for reducing the use of tobacco, they may also need to be a part of
public advocacy for reducing salt intake and other factors that
affect blood pressure as a whole."

Ezzati M, Oza S, Danaei G, and Murray CJL. Trends and cardiovascular
mortality effects of state-level blood pressure and uncontrolled
hypertension in the United States. Circulation 2008;
DOI:10.1161/CIRCULATIONAHA.107. 732131. Available at:
http://circ.ahajournals.org.

Researchers studying the effects of beet juice on blood pressure say
they may have discovered a new mechanism by which green, leafy
vegetables and other nitrate-rich foods protect the heart. Dr Andrew
J Webb (Barts and the London School of Medicine and Dentistry, UK)
and colleagues, writing in the March 2008 issue of Hypertension,
propose that bacteria on the human tongue, interacting with saliva,
may convert the otherwise biologically inert nitrate (NO3) in
vegetables into bioactive nitrite (NO2), which can in turn reduce
blood pressure, platelet activation, and endothelial
ischemia/reperfusion injury [1].

"It's quite clear that fruits and vegetables are good for you, and
there have been some very large studies showing that when people
were put on a fruit-and-vegetable diet--particularly green, leafy
vegetables--that their cardiovascular function and cardiovascular
health improved," senior author on the study, Dr Amrita Ahluwalia
(Barts and the London School of Medicine and Dentistry), told
heartwire. "The vast amount of literature out there has suggested
that antioxidants underlie these beneficial effects, but this has
been a bit of problem, because large-scale clinical trials directly
addressing the question of whether antioxidant vitamins can improve
CV health have shown no benefit whatsoever, and in fact recent meta-
analyses have shown that they might in fact be damaging."

"Beeting" hypertension

To look for other possible mechanisms, Webb, Ahluwalia, and
colleagues set out to test whether inorganic nitrate--found in large
quantities in green leafy vegetables, as well as in beetroot, might
somehow play a role. Ahluwalia points to the explosion of research
in the past 15 years into the vasodilatory, antiatherosclerotic, and
antiplatelet effects of nitric oxide (NO), with nitrite and nitrate
believed to be inactive waste products indicative of nitric-oxide
activity. More recently, she notes, research has suggested that
nitrite may not, in fact, be inactive but rather can confer
protection against ischemia/reperfusion injury by being reduced from
nitrite to nitric oxide when needed. The question, Ahluwalia
explained to heartwire, was whether the high nitrate content of
certain vegetables might not just be excreted as a "rubbish" waste
product after consumption but might in fact be converted to nitrite
in the body.

"When we eat vegetables the NO3 enters the stomach and gets absorbed
and enters our circulation," she explained. "Most nitrate--about 75%-
-is excreted in the urine, but we know we also have the capacity to
concentrate nitrate in our saliva: after consuming nitrate, if you
spit out saliva, you can see that the nitrate concentration in the
saliva goes up."

While the human body can't do anything with the nitrate, bacteria
can, she adds. "We have bacteria on the back of our tongue that
cleverly do us a bit of a favor and convert nitrate into nitrite, so
they take an oxygen molecule off it."

In the study, healthy, normotensive volunteers who drank 500 mL of
beetroot juice had significant increases in plasma nitrate and
plasma nitrite--suggesting conversion was taking place--as compared
with volunteers who drank 500 mL of water; beet-juice drinkers also
showed significant decreases in blood pressure, beginning within one
hour of beet-juice ingestion, reaching a peak drop of 10.4 mm Hg
after 2.5 hours and remaining lower than that of the water drinkers
over 24 hours. Among volunteers who drank the beet juice, then
proceeded to spit out all their saliva over the next three hours,
plasma nitrate concentration was high, but plasma nitrite was not.
According to Ahluwalia, "the bacteria is still converting the
nitrate to nitrite, but the nitrite isn't entering the stomach, so
it doesn't get into the circulation." This would thus explain the
lack of an effect on blood-pressure levels in the group that spat
out their saliva--a phenomenon also seen in the study. Separate flow-
mediated dilation studies also showed that beet juice appeared to
protect against ischemia/reperfusion-induced endothelial
dysfunction.

Studies needed in hypertensives

The authors acknowledge that while the precise means by which
nitrite mediates blood-pressure reduction is unclear, it likely
occurs through the chemical reduction of nitrite to nitric oxide.
They propose that the nitrate-nitrite exchange taking place after
consumption of nitrate-rich vegetables may go a long way to
explaining the cardioprotective effects of these vegetables. To
heartwire, Ahluwalia cautioned that their hypothesis does not
exclude a role for antioxidants but may explain why some randomized
trials have failed to show a benefit of antioxidant supplementation.
And unlike antioxidants, she added, nitrate is not destroyed with
cooking, one of the problems with antioxidants.

That said, she added, "Eating tons and tons of nitrates and
forgetting everything else is a mistake, that's not what this
research is about. Antioxidants are, for sure, good for you. . . .
We're proposing that this is an additional strategy that one might
want to pursue to sustain good cardiovascular health but potentially
also to reduce raised blood pressure."

One caveat, she emphasized, is that this study was conducted in
healthy volunteers with normal blood pressure. Further research
needs to be done in hypertensive subjects, she noted, although she
has every reason to believe the effect will be seen in this group as
well. "If anything, some of the experimental studies looking at
vasodilators suggests that the blood-pressure effect that one sees
is much bigger in a hypertensive than it is in a normotensive. So if
beetroot juice is a vasodilator in a normotensive, which is what it
looks like, you'd bet that it would be as good in hypertensives, if
not better."

Webb AJ, Patel N, Loukogeorgakis S, et al. Acute blood pressure
lowering, vasoprotective, and antiplatelet properties of dietary
nitrate via bioconversion to nitrite. Hypertension 2008; DOI:
10.1161/HYPERTENSIONAHA.107.103523. Available at:
http://hyper.ahajournals.org. Abstract

Coronary events in the Italian capital, Rome, dropped significantly
in the year following a smoking ban in public places, a new study
shows [1]. Dr Giulia Cesaroni (Rome E Health Authority, Italy) and
colleagues report their findings online February 11, 2008 in
Circulation.

Cesaroni told heartwire that one of the unique aspects of the study
was that they adjusted for other factors that could affect coronary
events, such as temperature, air pollution, flu epidemics, and time
trends, "so we are pretty sure the drop we saw was due to the
smoking ban."

She and her colleagues compared acute coronary events in Rome--the
largest city in Italy--for five years preceding the public smoking
ban, which was instituted in January 2005, and for one year after.

They found an 11.2% reduction in acute coronary events in adults
aged 35 to 64 and a 7.9% reduction in those aged 65 to 74 in the
year following the ban. There was no drop, however, in events in
those aged 75 and over, which is likely due to the fact that people
of this age group spend more time at home rather than in public
places, Cesaroni says. "The smoking ban has a greater effect on
those of working age and those who spend a lot of their time in
public places."

Men and those of lower socioeconomic status benefited most

The Italian researchers found the greatest reduction in coronary
events among lower socioeconomic groups and among men.

"This implies that a disadvantaged person has a higher probability
of being surrounded by smokers at work and in public places unless a
smoking ban is in place," Cesaroni says.

She adds that some of the health benefits of this study likely
resulted from a significant reduction in exposure to passive
smoking. In addition, a smoke-free environment makes it easier for
people to quit. During the period of the study, frequency of smoking
decreased from 34.9% to 30.5% in men and from 20.6% to 20.4% in
women, and cigarette sales decreased 5.5%.

These results parallel and strengthen preliminary findings on
coronary events after smoking bans from the US and other European
countries, say the researchers.

"Since coronary disease is a leading cause of death in Italy, the
reduction observed has enormous public-health implications," says
second author Dr Francesco Forastiere (Rome E Health Authority).

"It will be interesting to see if the effect of the ban is stable
over time and if similar positive health effects can be detected in
other places. While the trend is to implement smoking bans, there
are still areas in the world . . . where smoking in public places is
an important public-health issue. Smoking bans should be extended to
all possible countries, and smoking bans in the workplace should be
strongly enforced," he concludes.

Cesaroni G, Forastiere F, Agabiti N, et al. Effect of the Italian
smoking ban on population rates of acute coronary events.
Circulation 2008; DOI: 10.1161/circulationaha.107.729889. Available
at: http://circ.ahajournals.org.

Doctors and regulators concerned about the spike in off-label patent
foramen ovale (PFO) closure procedures now have some numbers to fall
back on. A research letter appearing in the February 7, 2008 issue of
the Journal of the American Medical Association reports that the
number of adults undergoing PFO/atrial septal defect (ASD) closure
between 1998 and 2004 increased more than 50-fold, despite a lack of
randomized clinical-trial evidence proving that PFO closure prevents
stroke or transient ischemic attack (TIA) [1].

During this time period, the number of surgical closure procedures
has remained relatively stable, while percutaneous procedures
increased by at least 50% each year, from 14 in 1998, to 82 in 2001,
to 815 in 2004. Percutaneous procedures as of 2004 represented 92.5%
of all closure procedures, up from 18.5%.

In an interview with heartwire, lead author on the analysis,
cardiology fellow Dr Alexander Opotowsky (University of Pennsylvania,
Philadelphia), said that he and his coauthors were primarily
interested in PFO-closure procedures, which are "more controversial,"
but that these could not be differentiated from ASD closures, which
share the same ICD-9 code [ICD-9 35.52, "Repair of ASD with
prosthesis, closed technique"].

"While the population represented a combination of PFOs and ASDs, the
increase in volume is probably due mostly to PFO closure," he
said. "These are adults, making PFOs more likely; the lack of change
in surgical volume is also suggestive. There's no way to
differentiate, but the reason to think that the majority are PFOs is
that there has been no major change in indications for ASD closure.
The main change is that we now have a percutaneous option."

The big question, he continued, is whether there is any benefit to
closing PFOs at all. "No one really knows. There are good reasons to
close ASDs, and the two options are surgical or percutaneous. There's
no reason to think that the number of patients requiring closure of
an ASD would have increased 50-fold over seven years. Either people
are closing ASDs they wouldn't have closed before, or they are
closing PFOs percutaneously in people who wouldn¡¦t have been
referred for surgical closure."

Off-Label Use Hampers Trial Enrollment

In 2006, the FDA opted to withdraw humanitarian device exemption
(HDE) approval for the only two dedicated PFO-closure devices that
held it. HDE approval is intended to encourage the development of
therapies for rare conditions affecting less than 4000 patients. The
FDA maintained that the number of patients receiving PFO-closure
devices under the HDE had far outstripped this cutoff and was likely
stymieing attempts to reach enrollment targets in the PFO-
closure/stroke clinical trials.

Until now, says Opotowsky, "There are not a lot of data out there
looking at how often these procedures are being done, which is
somewhat surprising. The only hint, other than anecdotal experience,
that the numbers might be increasing was that the FDA¡¦s actions
suggested that there were greater than 4000 PFO closures being
performed per year, but beyond that I don¡¦t think this has been
looked at before."

Opotowsky et al's study does not encompass the time period after HDE
was withdrawn for PFO-closure devices, so it sheds no light on
whether the FDA's strategy will help boost the number of patients in
clinical trials. Opotowsky, however, has his doubts, especially since
physicians were using ASD-closure devices to close PFOs before
dedicated PFO devices were developed. "There were certain
institutions that were very good at encouraging patients to go into
trials, and others that would tend to do more off-label procedures,
and I don't know how much that has changed. The ASD devices are still
available, and so there are still ways around it. So I don't know if
the decision to revoke HDE has increased PFO-trial enrollment, and
these data can't give evidence to that."

Difficult Decisions

He points out that even if there were separate ICD-9 codes to help
track PFO- and ASD-closure procedures separately, it still would be
difficult to get an accurate idea of what devices are being used and
for what procedures. Some physicians using ASD-closure devices off
label have, for regulatory reasons or billing purposes, charted the
procedure as an ASD closure. Opotowsky downplayed the potential
financial motives for doing the off-label procedures and instead
insists that many physicians either are already persuaded that PFO
closure prevents strokes or at least believe that the minimal risks
of the procedure are worth taking if there is a potential for
benefit. And in some cases, he adds, it is patients who come in
asking for the procedure.

"It's difficult for clinicians to withhold a relatively safe
procedure when the other therapeutic options, namely antiplatelet
agents or anticoagulants, have a known, significant failure rate," he
explained. "These patients are often young healthy people who have
had a stroke and who are petrified of a recurrent event and its
potentially devastating consequences. It's difficult to withhold this
option, and it's difficult to convince a patient to enter a study
that may randomize him to medical therapy when this procedure is
available elsewhere. I think this is the main driver. It's not only
personal conviction regarding efficacy but also the relatively low
perceived downside of the intervention."

He continued: "It's a tough situation: these are patients who are
having real issues now and are living with the constant anxiety of a
possible devastating neurological event at any time. And then there's
a relatively safe device whose benefit is entirely unproven. It's a
very difficult decision for patients and doctors to make."

Off-Label Use

Asked to comment on the study for heartwire, Dr Ziyad Hijazi (Rush
University, Chicago, IL) agreed that the increasing number of
procedures likely reflects increased use of ASD-closure devices off
label. "ASD cases would not have increased in this time period," he
explained. "In fact, there has been a decrease in the number of ASD
closures, because prior to device approval we had thousands of
patients waiting for these devices. When they were approved in 2001,
we were doing two or three cases every day. Over the past three
years, the number of ASD cases started to go down, because there are
only a certain number of people born each year in the US with ASDs,
about 5000 cases a year. Essentially we've finished our stock of
patients, and we're waiting for new patients to be born with ASDs,
then get to about three or four years of age when they can be
treated."

If anything, he expects the number of ASD-closure procedures to
decline. "But since there are no approved indications for
percutaneously PFO closure outside the trials, everyone is using
these devices off label."

Opotowsky AR, Landzberg MJ, Kimmel SE, Webb GD. Trends in the use of
percutaneous closure of patent foramen ovale and atrial septal defect
in adults, 1998-2004 [research letter]. JAMA 2008; 299:521-522.
Abstract

The use of thrombus aspiration to prevent the embolization of
atherothrombotic debris during PCI results in better reperfusion and
clinical outcomes compared with conventional PCI, a new study has
shown [1]. Investigators say that manual aspiration can be performed
in a large majority of patients presenting with ST-segment-elevation
MI, irrespective of their clinical and angiographic features, such as
a visible thrombus on angiography.

Lead investigator Dr Tone Svilaas (University Medical Center
Groningen, the Netherlands) and colleagues also observed a
significant relationship between myocardial and electrocardiographic
variables or reperfusion and rates of death and major adverse cardiac
events, supporting "the validity of these reperfusion variables as
surrogate end points in patients who have myocardial infarction with
ST-segment elevation."

In an editorial accompanying the published study [2], Dr George
Vetrovec (Virginia Commonwealth University, Richmond) said that on
the basis of these data, thrombus extraction is "conceptually sound
and appears to reduce the risk among patients undergoing primary
PCI." He notes, however, that operators were from a single center,
and all were highly experienced interventionalists with low failure
rates, and it is unknown "whether more general use will demonstrate
similar safety and favorable outcomes."

The study, known as Thrombus Aspiration During Percutaneous Coronary
Intervention in Acute Myocardial Infarction Study (TAPAS), and the
editorial are published in the February 7, 2008 issue of the New
England Journal of Medicine.

Assessing Myocardial Reperfusion and Clinical Outcome

Microvascular obstruction, which is related to plaque embolization or
downstream thrombotic particles in the infarcted artery, results in
diminished myocardial perfusion, and this event, note the authors, is
associated with an increased infarct size and increased mortality.
This has led to the development of various devices to protect
microcirculation, some of which have been successful, while other
devices have not.

In this study, the operators used a 6-French compatible manual-
aspiration catheter, a device they say is "relatively flexible and
nontraumatic in use," to evaluate whether aspiration could improve
perfusion during PCI. In total, 1071 patients with ST-segment-
elevation MI were randomly assigned to treatment--thrombus aspiration
during PCI or conventional PCI--before coronary angiography was
performed, thus eliminating considerations of angiographic selection
criteria.

Results showed that aspiration before stenting resulted in improved
myocardial reperfusion, as documented by improvements in myocardial
blush grade, increased resolution of ST-segment elevation, and
reduced residual ST-segment deviation. The benefit, as noted, was
consistent across all patients, regardless of baseline clinical or
angiographic characteristics such as age, sex, the infarct-related
coronary artery, preprocedural TIMI flow, or visible thrombus on the
angiogram.

Clinical outcomes at 30 days, including major bleeding, death,
reinfarction, target-vessel revascularization, and major adverse
cardiac events (MACE), were not statistically different between the
two treatment arms. The rates of death and MACE, however, were both
significantly related to myocardial blush grade, resolution of ST-
segment elevation, and ST-segment deviation, an association that
confirms "the prognostic value of the myocardial blush grade and
degree of resolution of the ST-segment elevation after reperfusion,"
write the authors.

Of those who underwent aspiration during PCI, thrombus was retrieved
in 73% of patients, and histopathological study confirmed earlier
observations that thrombi are predominantly composed of platelets in
ST-segment-elevation MI patients, the authors add.

Balloon Angioplasty Followed by Stenting

In his editorial, Vetrovec notes that one of the concerns with
aspiration during PCI is that the catheters can damage or dissect the
artery, which results in the need for longer stents, something that
could increase the risk of late restenosis.

He also points out that patients undergoing conventional PCI in the
TAPAS study had balloon angioplasty followed by stenting. Some
operators, he writes, believe that direct stenting without multiple
balloon inflations can reduce the risk of distal emboli and that this
difference--those in the thrombus-aspiration group had stents placed
directly--could affect the results.

Vetrovec writes that the risk of death associated with early
reperfusion in acute MI is low and any refinements to PCI can be
expected to make only small, albeit clinical meaningful, improvements
in outcome. "Thrombus aspiration," he writes, "appears to be such a
favorable improvement."

No potential conflict of interest relevant to this study was reported.

Svilaas T, Vlaar PJ, van der Horst I, et al. Thrombus aspiration
during primary percutaneous coronary intervention. N Engl J Med 2008;
358: 557-567.

Vetrovec GW. Improving reperfusion in patients with myocardial
infarction. N Engl J Med 2008; 358:634-637.

Persistent depression is associated with worse physical health a
year after an acute coronary syndrome (ACS), according to a report
in the January 1st issue of the American Journal of Cardiology.

Previous research has linked depression after an ACS with worse
cardiac morbidity and mortality, the authors explain, but the
relation between depression and quality of life during recovery
remains unclear.

Dr. Brett D. Thombs from McGill University, Montreal, Quebec, Canada
and colleagues investigated whether symptoms of depression during
and after hospitalization for ACS predict physical health status 12
months after ACS in a prospective study of 425 patients.

Based on a Beck Depression Inventory (BDI) score of 10 or higher,
123 patients (28.9%) had at least mild symptoms of depression during
their hospitalization, the authors report, and 102 patients (24.0%)
had at least mild symptoms of depression a year later.

Patients with depressive symptoms in hospital had significantly
poorer physical health status 12 months after ACS compared with
patients having a BDI score below 10.

Persistent symptoms of depression significantly predicted worse
physical health at 12 months compared with physical health before
ACS, the report indicates, whereas new depressive symptoms showed
only a nonsignificant trend to predict worse physical health.

Patients with transient symptoms of depression did not face a higher
risk of poor physical health outcomes 12 months after ACS, the
investigators say.

"The findings of this study emphasize the importance of assessing
symptoms of depression, not only at the time of the acute ACS
hospitalization, but also subsequently during follow-up visits," the
researchers conclude.

Am J Cardiol 2008;101:15-19.

The blood-glucose-lowering part of the ACCORD trial in patients with
type 2 diabetes at especially high risk of heart disease has been
stopped prematurely because of a higher rate of mortality in the
patients in the intensive arm vs that in the standard arm [1].

Patients in the standard-treatment group will continue treatment
without changes, but patients in the intensive-treatment group will
now be transitioned to the standard treatment.

The trial was a study of strategy rather than specific drug therapy,
and many diabetes agents were used to reach glycemic targets. The
higher death rate in the intensive group was not due to episodes of
hypoglycemia or to any single drug, including rosiglitazone, or to a
combination of drugs, ACCORD investigators said.

ACCORD is an National Heart, Lung, and Blood Institute (NHLBI) study
of approximately 10 000 patients with type 2 diabetes and either
heart disease or two risk factors for heart disease. The trial has a
double 2X2 factorial design. All patients were participating in the
glycemic-control part of the trial, which was testing whether an
intensive strategy that targets a HbA1c level of <6.0% reduces the
rate of cardiovascular events more than a standard strategy that
targets an HbA1c of 7.0% to 7.9%.

Then, depending on their blood-pressure and cholesterol levels,
patients are assigned to two other parts of the trial. These are
testing the combination of a fibrate (to raise HDL and lower
triglycerides) and a statin (to lower LDL) vs a statin alone, and
lowering systolic blood pressure to a target of below 120 mm Hg vs a
target of 140 mm Hg. These blood-pressure and lipid arms of the
study will continue until the study ends as planned, in June 2009.

In the glycemic-control part of the study, the median A1c level
achieved in the intensive-treatment group was 6.4%, vs 7.5% in the
standard group. The trial was stopped because of an excess of three
deaths per 1000 participants per year in the intensive group vs the
standard group, over an average of four years of treatment.

In a conference call on February 6, Dr Elizabeth Nabel, director of
the NHLBI, pointed out that the death rate in both arms was lower
than that previously observed in individuals with type 2 diabetes at
especially high risk for heart disease, who generally have a risk of
death of approximately 50/1000 per year. She also reported that
there was a trend toward benefit in the intensive arm in terms of
nonfatal cardiovascular events, but that this was outweighed by the
increased mortality.

"This is an important finding that shows that if you have type 2
diabetes and are at especially high risk for heart disease, very
intensive glucose-lowering treatments aimed at normalizing blood
glucose to an A1c of less than 6% may be detrimental," Nabel stated.

She stressed that these results were applicable only to those
individuals who are similar to the ACCORD participants--who had had
type 2 diabetes on average for 10 years at the time of enrollment,
had higher HbA1c levels than most type 2 diabetes patients in the US
today (average of 8.2% at baseline), and had known heart disease or
at least two risk factors in addition to diabetes, including high
blood pressure, high cholesterol levels, obesity, and smoking.

She added that patients should not change their diabetes treatment
without consulting with their healthcare provider and that the NHLBI
concurs with the general recommendation of the American Diabetes
Association that patients with diabetes should aim for an A1c level
of less than 7%. "However, for this special group of individuals
with diabetes, as exemplified in the ACCORD population, who were
average age of 62, had diabetes for an average of 10 years, and had
known heart disease or were at high risk, less stringent A1c goals
are likely appropriate, with an aim for around 7%."

Reduction in Nonfatal Events?

Expanding on the study findings, chair of the ACCORD steering
committee, Dr William Friedewald (Columbia University, New York),
said the intensive group showed approximately 10% fewer nonfatal
cardiovascular events such as MIs compared with the standard-
treatment group, but that it appeared that, if an MI did occur, it
was more likely to be fatal. In addition, the intensive-treatment
group had more unexpected sudden deaths.

Not Linked to Rosiglitazone

Friedewald noted that because of recent concerns about
rosiglitazone, they had specifically analyzed the data to try to
determine whether there was any link between this particular
medication and the increased deaths in the intensive-treatment
group, but so far no link has been found, and the use of
rosiglitazone does not seem to explain the increased mortality.

Some Benefits Seen in Other Populations

Dr Hertzel Gerstein (McMaster University, Hamilton, ON), who led the
group that designed the glycemic-control approaches used in ACCORD,
gave some background to the study. He noted that a large body of
research has shown that higher glucose levels predict a higher
likelihood of fatal and nonfatal cardiovascular events and that
studies have shown that lowering blood glucose levels can
significantly lower the risk of certain complications of diabetes,
such as eye, nerve, and kidney diseases. In addition, a major study
in people with type 1 diabetes has suggested that intensive blood-
sugar-lowering strategies reduce the risk of cardiovascular disease
and death, and a study in patients with more recent onset of type 2
diabetes than ACCORD participants showed a trend toward a reduction
in MI.

"This body of research strongly suggests that lowering glucose
levels to levels that are typically observed in people without
diabetes could reduce the risk of cardiovascular disease in people
with established type 2 diabetes. But, until ACCORD, no major
clinical trial had studied whether lowering a raised blood-sugar
level to a level similar to that seen in people without diabetes
reduces the risk of cardiovascular disease in people with type 2
diabetes. In addition, no clinical trial has studied the effects of
intensive blood-sugar lowering in people with longstanding type 2
diabetes who already have cardiovascular disease or who have
multiple risk factors for cardiovascular disease in addition to
diabetes," Gerstein stated. This was the rationale for ACCORD.

How ACCORD Differs From Previous Studies

Dr Judy Fradkin (National Institute of Diabetes and Digestive and
Kidney Diseases, Bethesda, MD) reviewed how ACCORD differs from
earlier studies of intensive glycemic control. She noted that a
crucial difference was that ACCORD studied the effects of lowering
glucose to a near-normal level, a lower level than that targeted in
earlier studies. In addition, patients enrolled into ACCORD were
older (average 62 years), had had diabetes for a longer time (an
average of 10 years), and were at a higher risk for cardiovascular
disease than patients enrolled in earlier studies of intensive
glucose control.

"It is not yet known whether controlling glucose to near-normal
levels will prevent heart disease and extend life in other groups
such as younger people with diabetes, those earlier in the course of
disease and in whom glucose is easier to control, and those without
established cardiovascular disease," she said. The results also
cannot be extrapolated to patients with type 1 diabetes, she added.

National Heart, Lung, and Blood Institute. ACCORD telebriefing
prepared remarks. February 6, 2008. Available at:
http ://www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm.

Results of a large case-control study suggest that current use of
calcium-channel blockers, but not other antihypertensive agents, is
associated with a significantly reduced risk for Parkinson's disease
(PD).

The results are published online February 6 in Neurology.

"Current long-term use of calcium-channel blockers was associated
with a significantly reduced risk of a Parkinson disease diagnosis,
while the risk was not materially altered for users of angiotensin-
converting-enzyme [ACE] inhibitors or beta blockers and, with less
statistical precision, for users of angiotensin II antagonists," the
researchers, with senior author Christoph R. Meier, PhD, from the
Basel Pharmacoepidemiology Unit, University Hospital Basel,
Switzerland, conclude.

Possible Neuroprotection?

In the search for neuroprotective agents, the authors note, recent
studies in rodent and nonhuman primates have shown "promising"
results with ACE inhibitors and calcium-channel blockers, including
a reduction of experimentally induced dopaminergic cell loss and an
increase in striatal dopamine levels. One double-blind, placebo-
controlled trial in 7 patients with moderately severe PD showed an
improvement in motor function after 4 weeks of treatment with the
ACE inhibitor perindopril.

In this study, the researchers used data from the General Practice
Research Database, containing information on more than 5 million
people registered with general practitioners in the United Kingdom,
to carry out a retrospective case-control analysis examining the
possible association between the use of antihypertensive drugs,
including in this case also angiotensin II antagonists and beta-
blockers as well as ACE inhibitors and calcium-channel blockers, on
the risk of developing a first-time diagnosis of Parkinson's disease.

Cases were 40 years of age or older, with an incident PD diagnosis
between 1994 and 2005. Controls were matched with PD cases on age,
sex, general practice, index date, and duration of previous history
in the database. A total of 3637 cases were identified and compared
with an equal number of controls; 40% of these were women.

Antihypertensive use was assessed by timing and exposure duration.
Odds ratios were calculated using conditional logistic regression,
with adjustment for body-mass index, smoking, and a number of
cardiovascular, metabolic, and psychiatric diseases and dementia.

They found that current long-term exposure, defined as 30 or greater
prescriptions, to calcium-channel blockers was associated with a
reduced risk of developing PD compared with no antihypertensive use,
while no association was seen with the other antihypertensive agents
assessed.

The effect of calcium-channel blockers persisted in the model when
adjusted for the use of other antihypertensive agents. The risk
reduction was slightly stronger in women with long-term use than in
men, although not in those with less than 30 prescriptions.

The effect was strongest in those 80 years of age and older, they
note. This finding is interesting given recently reported findings
that dopaminergic neurons rely increasingly on L-type Cav1.3-calcium
channels for their activity, making them more vulnerable to
neurologic damage, while neurons in younger people use different
mechanisms, the authors write. "If these calcium channels are
blocked, neurons again make use of the less harmful mechanisms, and
cell damage may be decreased," they speculate.

PD is often associated with autonomic insufficiency and hypotension,
the authors note. PD cases, then, may receive fewer antihypertensive
drugs than controls that may potentially lead to a spurious low odds
ratio. They did find in this cohort that hypertension was
significantly more common in controls than cases. While controls
therefore would be expected to be treated more often with
antihypertensives, they still saw a decreased PD risk only with
calcium-channel blockers and not the other antihypertensives.

"We also analyzed the risk of a PD diagnosis in association with the
use of calcium-channel blockers in a subgroup of cases and controls
without hypertension," they add. In this subgroup that received
calcium-channel blockers for indications other than hypertension,
the risk estimate for PD was 0.60 (95% CI, 0.42 ¡V 0.86).

More research is needed to determine why calcium-channel blockers
appear to protect against PD, whether this is in fact a causal
association, and why other antihypertensives do not appear to afford
a similar reduced risk, Dr. Meier said in a statement from the
American Academy of Neurology.


The authors declare no conflicts of interest.

Neurology. Published online February 6, 2008.

Just over a third of MI survivors participate in outpatient cardiac
rehabilitation programs, according to a survey of people across the
US reported by the Centers for Disease Control and Prevention (CDC),
one that discloses continuing shortfalls in implementing an
important guidelines-recommended secondary-prevention strategy [1].
Men were more likely to engage in a program than women and married
persons more so than singles, and the likelihood went up with
educational level, according to the report in the February 1, 2008
Morbidity and Mortality Weekly Report.

The findings, which are largely consistent with other studies of the
subject, derive from telephone interviews conducted in 2005 with
more than 129 000 randomly selected adults in 21 states and the
District of Columbia as part of the Behavioral Risk Factor
Surveillance System (BRFSS) survey. Of those interviewed, 7230, or
4.2%, reported they had been told by a health professional that they
had experienced "a heart attack, also called a myocardial
infarction." Of those who reported whether they had also received
outpatient cardiac rehab services, 34.7% said they had participated
in such a program.

Rehab participation went up steadily with household income but
didn't significantly vary by employment status or whether the
patient had health-insurance coverage, according to the analysis.

Among the reasons behind the shortfalls, the CDC report speculates,
is the possibility that "physicians might not be aware of the
importance of cardiac rehabilitation for patients after a heart
attack and therefore might not refer patients to rehabilitation
services."

The report concludes, "Programs and policies directed at increasing
the number of patients who are referred to and participate in
cardiac rehabilitation need to be strengthened. Future research
should focus on identifying barriers to cardiac rehabilitation
participation and interventions to improve referral and receipt of
outpatient rehabilitation services."

Centers for Disease Control and Prevention. Receipt of outpatient
cardiac rehabilitation among heart attack survivors--United States,
2005. MMWR Morb Mortal Wkly Rep 2008; 57:89-94. Abstract

A majority of patients with coronary heart disease (CHD) still had
poor diets one year after their diagnosis of CHD, a new study has
found [1]. Although they were limiting their calories, the patients
were eating the wrong kinds of food--not enough nutrients to protect
them and too many harmful things such as trans fatty acids, say Dr
Yunsheng Ma (University of Massachusetts Medical School, Worcester)
and colleagues, in one of the few studies to have looked at the
diets of CHD patients following diagnosis.

The study is published in the February 2008 issue of the Journal of
the American Dietetic Association.

Coauthor and cardiology nutritionist Dr Barbara Olendzki (University
of Massachusetts Medical School) told heartwire: "About 80% of
patients are not doing what they are supposed to be doing. I think
cardiology patients are confused." She believes doctors, and
cardiologists in particular, need to improve on the advice they give
to patients.

"Doctors are confused with providing dietary recommendations, so
they tend to avoid it. They just say, 'It would help if you lost a
little weight,' and then they are leaving it to their patients to
figure out how to do that, and the patients don't know what to do!
Also, physicians are not referring patients to dieticians or cardiac
rehabilitation programs because they are not sure if their patients
are eligible in terms of insurance coverage." Tellingly, she says
the majority of her referrals come from primary care rather than
cardiologists. Pilot studies that Olendzki has conducted show that
keeping the message simple will be the key to improving dietary
advice to patients, she says.

Effecting Behavioral Change is Complex

The 555 patients were participants in a clinical trial to improve
adherence to lipid-lowering medications and were recruited from the
cath lab. Using the Alternative Health Eating Index (AHEI) to assess
diet quality, the researchers collected data from a 24-hour dietary
recall one year after CHD diagnoses. Nutrient scores were computed,
and the AHEI was then calculated to determine dietary quality.

Although the participants had reduced their caloric intake, with the
average daily calorie intake in the study being 1775 kcal per day,
the diets of the majority were still of poor quality. Olendzki noted
to heartwire that baseline dietary information was not collected, so
it may be that the patients had actually improved their diets (or
thought they had) since CHD diagnosis. "We don't know whether maybe
they were even worse before," she commented.

Of a maximum 80 points--which indicates the healthiest diet--the
average AHEI score was 30.8, with individual scores ranging between
5.1 and 69.8. The mean AHEI score was poorer than scores reported
for samples of healthy individuals from the Health Professionals
Follow-up Study and the Nurses' Health Study. "Thus, a high
proportion of the patients had not made the necessary improvements
to their diets to help reduce the risk of a secondary CHD event,"
the researchers note.

In a previous study by Ma and colleagues, the AHEI of several
popular weight-loss plans was calculated; the highest-scoring diet
was the Ornish Diet (AHEI=64.6), and the lowest-scoring diet was the
Atkins diet (AHEI=42.3). The fact that one year after a coronary
event patients with known CHD still have lower AHEI scores than
these popular diets indicates the complexity of effecting and
sustaining behavioral changes, say Ma et al.

Low-Carb Diets a Culprit, as are Trans Fats

Only 8% of patients met the cereal fiber recommendation, and just
5.2% of the participants limited their trans-fat intake to 0.5% of
total calories or less, as advised. And nearly 11% of calories were
from saturated fat (less than 7% is recommended).

Olendzki believes the fad for low-carbohydrate diets is partly to
blame, "although hopefully this is past its zenith." On average,
just 50% of calories were from carbohydrates, "and I think they are
limiting calories by limiting carbohydrates, and they are doing it a
little too much. By eliminating carbs, they are not eating whole
grains and so don't get enough fiber," she says.

The high intake of trans fatty acids could be due to poor labeling
regulations, she adds. "In the US, manufacturers are allowed to put
that there are no trans fatty acids in a product if it is less than
0.5 g per serving, the same rule as for saturated fats. But trans
fatty acids are much more devastating than saturated fats when it
comes to inflammatory disease like cardiovascular disease. A lot of
patients may be mistakenly thinking, 'Oh, it says zero for trans
fatty acids.' "

The patients ate too much salt, too--"more than 3000 mg per day was
the mean, and often these patients had comorbidities such as
hypertension," Olendzki says.

Finally, "the patients did not eat enough fruit and vegetables,
which is no surprise because, in general, Americans don't do that
very well," she says. Only 12.4% of the participants met the optimal
daily recommendations for the consumption of vegetables and just
7.8% for fruit.

Increase Fiber, Reduce Saturated Fat is Best Advice

Olendzki told heartwire that her team has just conducted a pilot
study to find out, for doctors, how best to communicate simple
dietary recommendations to patients. "If we say to physicians we
want you to do seven different things from the AHA recommendations,
they say, 'I don't know how to do that.' "

"We found that two simple approaches worked well--asking patients to
increase their dietary fiber to a goal of 30 g per day, which by
doing so they increased a lot of protective foods in the diet and
substituted for those that are detrimental. Second was asking
patients to reduce their saturated-fat intake--this worked well too
but it took them longer because we are asking them to remove
something." Both groups improved, but the dietary-fiber group got
more rapid results--within three months--"and they felt more
satisfied in terms of hunger levels," she noted.

"By keeping the message simple they did improve their overall
dietary quality. I would tend to go with one of those
recommendations--or both--depending on how motivated the patient is.
Keeping the message simple means at least they pay attention to
something, and anything is better than nothing at all."

Ma Y, Li W, Olendzki B, et al. Dietary quality 1 year after
diagnosis of coronary heart disease. J Am Diet Assoc 2008; 108:240-
246. Abstract

"Remarkable" new data from two previously published studies suggest
that high levels of plasma HDL cholesterol and large HDL particles
are associated with an increased risk of coronary artery disease [1].

The findings, from the Incremental Decrease in Endpoints through
Aggressive Lipid Lowering (IDEAL) and European Prospective
Investigation into Cancer and Nutrition (EPIC)-Norfolk studies,
showed that when apolipoprotein A1 (apoA-1) and apolipoprotein B
(apoB) values were kept constant in regression analyses, increased
HDL-cholesterol levels and HDL particle size conferred a risk of
major coronary events. ApoA-1, on the other hand, did not turn into
a significant risk factor at high plasma concentrations.

Investigators, led by Dr Wim van der Steeg (Academic Medical Center,
Amsterdam, the Netherlands), say the findings have clinical and
scientific implications, especially as they relate to risk
assessment and novel treatment strategies. "On the basis of these
data," the group writes, "interventions that primarily raise plasma
HDL cholesterol but do not or hardly change apoA-1 levels may not be
expected to have potent beneficial effects on atherosclerosis."

The results of the study are published in the February 4, 2008 issue
of the Journal of the American College of Cardiology.

Can HDL Cholesterol Become Proatherogenic?

Since the spectacular bust of torcetrapib, a novel cholesterol-ester-
transfer protein (CETP) inhibitor that raised HDL-cholesterol levels
but increased the risk of mortality and cardiovascular events, in
December 2006, there have been questions as to why the HDL-raising
drug failed to provide the expected benefit. According to the
authors, including lipid expert Dr John Kastelein (Academic Medical
Center, Amsterdam, the Netherlands), one possible explanation for
the unexpected outcome with torcetrapib might be structural changes
of the HDL particle induced by CETP inhibition.

With these concerns in mind, that high levels of HDL cholesterol
might actually be harmful, post hoc analyses of the IDEAL data, a
randomized, open-label, blinded-end-point trial evaluating
simvastatin 20 mg and atorvastatin 80 mg in secondary prevention,
and the EPIC-Norfolk case-control study, were performed to assess
the relationship between HDL-cholesterol levels, HDL particle size,
and coronary heart disease.

The findings, which were first presented last year in Helsinki,
Finland, at the European Atherosclerosis Society annual meeting and
reported by heartwire at that time, showed that without adjustment
for apoA-1 and apoB, HDL cholesterol was significantly and inversely
related with risk of major coronary events in IDEAL and EPIC-
Norfolk, as was HDL particle size in EPIC-Norfolk. When the
regression models, however, were adjusted for apoA-1 and apoB, the
risk estimates for HDL cholesterol became significantly positively
related to occurrence of events. ApoA-1 was negatively related to
the risk of coronary events in both studies.

In the paper, van der Steeg and colleagues state there is no clear
biological explanation as to how HDL cholesterol can become
proatherogenic. When HDL cholesterol particles become very large,
the antiatherogenic capacity might be affected, resulting in less
functional or possibly even dysfunctional HDL cholesterol, the group
notes. In addition, because apoA-1, unlike HDL cholesterol, did
not "switch" toward a positive relationship at higher levels, the
finding supports apoA-1 as the active component of HDL
particles, "possibly defining the atheroprotective capacity of this
lipoprotein fraction," they add.

In terms of clinical utility, although these findings need to be
confirmed in other comparable data sets, apoA-1, given the uniform
lower risk with higher levels, might be a valuable alternative risk
marker. Novel biomarkers that provide information about HDL
functionality would also be useful, suggest van der Steeg and
colleagues.

"Given the present results," they write, "it can be hypothesized
that strategies primarily raising plasma apoA-1 levels with small
molecular compounds, infusion of small lipid-poor apoA-1 particles,
or apoA-1 gene therapy will have a more pronounced effect on
atherogenesis."

HDL as a Goal is Fraught with Danger

In an editorial accompanying the published study [2], Dr Jacques
Genest (McGill University, Montreal, QC) said the findings have
important clinical implications, as the data suggest that naturally
occurring high levels of HDL might not protect against heart disease
and that HDL cholesterol "as a therapeutic goal may be fraught with
dangers."

He writes that while the findings must be replicated in other
clinical and epidemiologic studies, there are a number of questions
that remain. The first is whether raising HDL-cholesterol levels is
beneficial in terms of cardiovascular health. So far, he notes,
there are no data showing unequivocally that raising HDL cholesterol
by pharmacologic means reduces cardiovascular risk. Other questions--
does the means by which this increase is achieved matter? is HDL or
apoA-1 the appropriate measurement for therapeutic targets? and is
HDL cholesterol simply a marker of cardiovascular health?--must also
be answered, writes Genest.

Flashback to the 2007 American Heart Association

Final results of the torcetrapib ILLUMINATE and ILLUSTRATE trials
were presented in November at the American Heart Association (AHA)
2007 Scientific Sessions and published simultaneously online in the
New England Journal of Medicine [3]. The study showed that the HDL-
increasing drug stimulates aldosterone, which possibly accounted for
its adverse outcomes.

At the meeting, lead ILLUMINATE investigator Dr Philip Barter (Heart
Research Institute, Sydney, Australia) commented: "There have been
concerns voiced that the HDL produced by CETP inhibitors may be
dysfunctional in some way. But our results, along with new data from
the ILLUSTRATE study, are not consistent with that idea. Rather,
they are supportive of other in vitro studies that suggest the HDL
formed by these drugs is functional." He added, "The observation
that torcetrapib increases aldosterone levels is very exciting. If
this off-target toxicity were not there, the clinical outcome
results might have been very different."

Others were more skeptical. Dr Raymond Gibbons (Mayo Clinic,
Rochester, MN) told heartwire: "I've heard all this hype about these
findings over the past few days, but now that I've heard the
presentation and read the paper, I don't understand what the fuss is
about. I can't see the good news here. These new data have not ruled
out CETP inhibition as the cause of the adverse outcomes with
torcetrapib."

Van der Steeg WA, Holme I, Boekholdt M, et al. High-density
lipoprotein cholesterol, high-density lipoprotein particle size, and
apolipoprotein A1: significance for cardiovascular risk. J Am Coll
Cardiol 2008; 51:634-42.
Genest J. The yin and yang of high-density lipoprotein cholesterol.
J Am Coll Cardiol 2008; 51:643-44.
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in
patients at high risk for coronary events. N Engl J Med 2007;
357:2109-2122. Abstract

The risk of hip fracture has increased in diabetic patients in
Taiwan, according to a study published in the January issue of
Diabetes Care.

"Diabetic patients, who have already been crippled by various
microvascular and macrovascular complications, were reported to have
increased risks of hip fracture," Dr. Chung-Yi Li, of National
Taipei College of Nursing, Taiwan, and colleagues write. "Much of
the previous research, however, focused on women or on older
patients aged older than 65 years so that relatively few data were
available for specific risks in various age groups and sex groups."

The researchers used Taiwan's National Health Insurance claim data
to examine age-, sex-, and urban area-specific effects of diabetes
on the incidence and relative risks of hip fracture between 1997 and
2002 in the diabetic population. A total of 500,868 diabetic
patients and 500,248 age- and sex-matched control subjects were
linked to inpatient claims to identify hospitalizations for
nontransport accident hip fracture.

The overall incidences of hip fracture for men and women with
diabetes were 3.01 and 6.75 per 1000 person-years, respectively.
These were higher than those for control men and women, which were
2.48 and 4.21 per 1000 person-years, respectively. Significant
interactions were observed between diabetes and age and diabetes and
urbanization status.

The team reports that the highest sex- and age-specific hazard ratio
(HR) of hip fracture was found for diabetic men (HR, 2.45) and
diabetic women (HR, 3.19) between 35 and 44 years of age. The sex-
specific risks of hip fracture in diabetic men aged older than 74
years and diabetic women aged older than 84 years were similar to
those of control subjects (HRs 0.98 and 0.91, respectively).

Diabetic men (HR, 1.43 versus 1.22) and women (HR, 1.82 versus 1.67)
living in rural areas tended to have higher HRs of hip fracture than
their urban counterparts.

"Given the potentially serious health and economic consequences of
hip fracture, we must look into the underlying causes for increased
risk of hip fracture among young and rural diabetic patients and
implement a multifaceted intervention program accordingly to ensure
the effective prevention of hip fracture in these high-risk diabetic
populations," Dr. Li and colleagues recommend.

Diabetes Care 2008;31:75-80.

Baking soda has a lot of uses, but is there one too many? Perhaps,
according to a retrospective look at >11 000 radiographic imaging
cases in which sodium bicarbonate, increasingly given intravenously
to prevent contrast-induced nephropathy (CIN) in patients undergoing
CT or angiography, seemed actually to cause the serious complication
rather than protect the kidneys [1].

The analysis casts doubt on a practice that has won the esteem of
practitioners based primarily on one small randomized trial [2] with
important limitations, according to the new study's authors, led by
Dr Aaron M From (Mayo Clinic, Rochester, MN) and colleagues.

"The clinical use of sodium bicarbonate for renal protection should
be reconsidered until further investigation can elucidate its proper
use," the group writes in the January 2008 issue of the Clinical
Journal of the American Society of Nephrology.

In another finding from the study, no increased CIN risk was
observed among patients treated with another agent frequently given
for renal protection, N-acetylcysteine, or those who received both
that agent and sodium bicarbonate.

Speaking to heartwire, From said his group has documented
an "exponential increase" in the use of sodium bicarbonate
prophylaxis immediately after the 2004 publication of a 119-patient
randomized study from Merten et al, in which CIN developed in 13.6%
of patients hydrated with saline only but in only 1.7% of those who
received sodium bicarbonate (p=0.02).

"Sodium bicarbonate is now the standard of care at our institution,"
Merten coauthor Dr W Patrick Burgess (Carolinas Medical Center,
Charlotte, NC) told heartwire when the study was published. "We have
not dialyzed a patient for contrast nephropathy for a year and a
half. And that's unheard of."

An informal survey of heartwire stories as well as reviews and
original studies on Medline appearing since the Merten publication
does suggest that interventional cardiology has embraced the use of
sodium bicarbonate, often combined with N-acetylcysteine, for CIN
prophylaxis. Recommendations for preventing CIN published by the
Society of Cardiovascular Angiography and Interventions in 2006
cautiously recommend sodium bicarbonate in high-risk cases [3].

But Merten et al, From said, "were very selective about the patients
they included, and in our study we used a real-world population." It
consisted of 7911 adult patients encompassing 11 516 cases of
contrast administration, almost always with a low-osmolar nonionic
agent, for which there were both pre- and postprocedure creatinine
readings but no preprocedure elevations of >8 mg/dL and no history
of dialysis. Thoracic and abdominal CT accounted for more than three-
fourths of the imaging procedures, and coronary angiography and
interventions most of the rest.

In an analysis that adjusted for "known and hypothesized" predictors
of CIN, the odds ratio for CIN among patients getting sodium
bicarbonate alone was 3.10 (95% CI 2.28¡V4.18, p<0.001) compared
with no prophylaxis and 2.73 (95% CI 1.86¡V3.97, p<0.001) compared
to N-acetylcysteine alone. The covariates included hydration volume;
use of beta blockers, diuretics, nonsteroidal anti-inflammatory
drugs, ACE inhibitors, angiotensin-receptor blockers, or aspirin;
age; sex; preprocedure creatinine; contrast iodine load; prior
exposure to contrast agents; type of imaging study; and heart
failure, hypertension, renal failure, multiple myeloma, or diabetes
mellitus.

The CIN risk with sodium bicarbonate alone vs no prophylaxis was
significantly increased whether or not it was administered according
to the same protocol used in the Merten study, the authors observe.

On the other hand, From acknowledged when interviewed, his group's
patients usually received contrast agents intravenously for
noncoronary and noncardiac CT imaging. That's unusual for a study on
contrast nephropathy, he said, and distinguishes them Merten et al's
patients, most of whom received contrast agents intra-arterially at
cardiac catheterization. But CT is a growth area in cardiac imaging,
he observes.

"It was odd that [sodium bicarbonate] was adopted so quickly without
much data," From commented. Usually such an innovation would take
several randomized controlled trials or at least one very large one,
he said. "I think people thought that it would be helpful and that
there would be no harm." His group's findings are "a warning that
sometimes when you study these agents in a real-world population,
you find something different from [what you would] studying them in
a randomized trial."

From AM, Bartholmai BJ, Williams AW, et al. Sodium bicarbonate is
associated with an increased incidence of contrast nephropathy: A
retrospective cohort study of 7977 patients at Mayo Clinic. Clin J
Am Soc Nephrol 2008; 3:10-18. Abstract

Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-
induced nephropathy with sodium bicarbonate: A randomized controlled
trial. JAMA 2004; 291:2328-2334. Abstract

Schweiger MJ, Chambers CE, Davidson CJ, et al. Prevention of
contrast induced nephropathy: recommendations for the high-risk
patient undergoing cardiovascular procedures. Catheter Cardiovasc
Interv 2007; 69:135-140. Abstract

Testosterone therapy lessens the gain in visceral adipose tissue and
the loss of skeletal muscle in aging men who are not obese,
Australian researchers report in the January issue of the Journal of
Clinical Endocrinology and Metabolism.

As lead investigator Dr. Carolyn A. Allan told Reuters Health, "Our
study showed preservation of skeletal muscle and prevention of
accumulation of visceral -- intra-abdominal -- fat in men treated
with testosterone versus placebo over a 12-month period."

Dr. Allan of Monash University, Clayton and colleagues note
that "obesity is an important confounder in the presentation of
androgen deficiency," so they chose to study nonobese aging men, who
had symptoms of androgen deficiency and low-normal serum
testosterone levels.

Included in the study were 60 healthy men aged 55 years or more with
testosterone levels below 15 nM. They were treated with transdermal
testosterone (5.0 mg) or placebo patches.

At 1 year, serum testosterone had increased by 30% in the active
treatment group. Compared to the placebo group, there was a
significant increase in total body fat-free mass and skeletal
muscle; thigh skeletal muscle loss was prevented, and visceral fat
accumulation decreased.

"Given the strong association of visceral fat with metabolic
syndrome -- leading to diabetes -- and cardiovascular disease,"
continued Dr. Allan, "these findings suggest testosterone may be
used to modify the age-related increase in visceral adipose tissue,
and possibly the associated adverse metabolic changes."

These findings, she added, "have provided a basis for our ongoing
work looking at the effect of testosterone on markers of
cardiovascular disease and diabetes risk in obese men -- who are
increased risk for these diseases."

J Clin Endocrinol Metab 2008;93:139-146.

Medscape's editors have gathered the most important news articles,
accredited for CME, that received the most participants during this
month. Take a look at what other healthcare professionals are
reading.

Calcium Supplements Increase Vascular Events?
BMJ, January 24, 2008
A new study has shown that calcium supplementation might increase
vascular events in elderly women; current evidence has demonstrated
that increased calcium intake may lead to an improved ratio of high-
density lipoprotein cholesterol to low-density lipoprotein
cholesterol, as well as playing a role in blood pressure reduction
and weight loss.

Primary Care Management of Eating Disorders Reviewed
American Family Physician, January 18, 2008
Primary care management of patients with eating disorders is
reviewed in the January 15 issue of the American Family Physician,
along with diagnostic criteria for anorexia nervosa, bulimia
nervosa, and binge-eating disorder.

Guidelines Updated on Palliative End-of-Life Care
Annals of Internal Medicine, January 14, 2008
The American College of Physicians has issued updated guidelines on
palliative care of pain, dyspnea, and depression at the end of life.

Staying Active and Drinking Moderately Is Key to a Long Life
European Heart Journal, January 11, 2008
Both physical activity and a moderate alcohol intake are important
to lower the risk of fatal ischemic heart disease and all-cause
mortality, a new study from the European Heart Journal shows.

Immunization Schedule for Children and Teens Updated
Morbidity & Mortality Weekly Report, January 8, 2008
The American Academy of Pediatrics has issued an updated
immunization schedule for children and adolescents aged 0 to 18
years, as well as a catch-up immunization schedule for those aged 4
months to 18 years who start late or who are more than 1 month
behind.

Prophylaxis for venous thromboembolism (VTE) in the acute hospital
care setting is substantially underused worldwide, a large
international trial shows [1]. Results from the Epidemiologic
International Day for the Evaluation of Patients at Risk for Venous
Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study
were first presented at a conference last year and have now been
published in the February 2, 2008 issue of the Lancet by Dr
Alexander T Cohen (Kings College Hospital, London, UK) and
colleagues.

"We found that half of all patients in medical and surgical wards
worldwide are at risk of thrombosis--a potentially life-threatening
condition--yet only half of them are getting something to stop this.
So half the people are left at risk for something that has got a
simple, inexpensive--£1 a day--therapy to prevent death. That's
pretty striking," Cohen told heartwire. His team also found there
were wide geographic variations between countries in terms of the
use of VTE prevention and that medical patients were particularly
poorly served.

In an accompanying comment [2], Drs Walter Ageno and Francesco
Dentali (University of Insubria, Italy) say that while the volume of
evidence is growing with regard to the prevention of VTE, "the
number of patients receiving adequate prophylaxis is not. To improve
the rate of appropriate thromboprophylaxis use, we must determine
why practice and recommendations are discordant." They believe one
of the main explanations for this is ongoing disagreement about VTE
risk among physicians themselves--certain specialties remain to be
convinced of the benefits of prophylaxis, as do clinicians in
particular countries, they state.

Over half of all medical and surgical patients at risk of VTE

ENDORSE, a multinational cross-sectional survey, was conducted in 32
countries and involved 68 183 patients in 358 hospitals. Cohen said
the study was unique in scope, as previous research has focused
on "two or three hospitals, this ward or that, these types of
patients, whereas we randomly selected institutions and stratified
for academic and nonacademic hospitals so we could really see what
factors were determining the use of preventive therapies."

Using the 2004 American College of Chest Physicians (ACCP)
guidelines and hospital chart review, the patients in ENDORSE were
assessed for risk of VTE, and the proportion of at-risk patients who
received effective prophylaxis was determined.

The researchers found that the risk for VTE is common--present in
51.8% of patients, including 64.4% of surgical cases and 41.5% of
medical patients--but that VTE prophylaxis is underused, with only
58.5% of surgical patients receiving it overall and just 39.5% of
medical cases.

Two surprises: Risk is constant worldwide and everyone can do better

Cohen said the results were not that unexpected, as other studies
had indicated the problem to a certain extent. "But two things did
surprise us. First of all, everyone did worse than they thought.
Even the best countries have got big holes. When you talk to people
who work in Germany or Switzerland, they say, 'All our patients get
thromboprophylaxis,' but then you look at the results and you see,
no, they don't. So there is room for improvement even in the good
countries.

"The second thing that was striking was that the risk is constant,
at around 50%, throughout the world," says Cohen. Bangladesh, India,
Pakistan, and Thailand were among the countries with the lowest
rates of prescription in ENDORSE, at 16% or lower in surgical
patients.

"People always said, 'We don't have patients at risk,' in, for
example, Thailand and Bangladesh. But they do. Clearly people don't
realize that they've got so many patients at risk and they are not
doing much about it," he adds.

Ageno and Dentali concur. "The incidence of postsurgical VTE has
long been thought to be low in Asian populations," but recent
studies such as AIDA [3] "have challenged this view by showing that,
without thromboprophylaxis, the rate of venous thrombosis in
patients of Asian origin is similar to that previously reported in
Europe and North America," they point out.

A silent, underestimated killer

Cohen says there are a number of reasons why VTE is often seemingly
ignored. "This is a silent, undiagnosed disease that kills people--
we get the diagnosis right prior to death only in three out of 10
cases. So in seven out of 10 patients who die of thrombosis, we say
it's something else. And it's massively underestimated. Last year we
published a paper showing that more than 500 000 people a year in
the EU are dying from thrombosis, which is more than twice all the
deaths combined from breast cancer, prostate cancer, traffic
accidents, and HIV infection.

"If you go out on the street and ask individuals, 'Do people die of
thrombosis?' they say, 'No, that's what you get on an airplane.'
They are just not aware, and doctors aren't aware. Thrombosis is a
complication of heart failure, surgery, and cancer therapy, to name
a few. Because of the compartmentalization of medicine, people have
become specialists--they know how to look after the heart, for
example, but they are not looking at the whole patient."

The use of recommended VTE prophylaxis was particularly poor in
medical patients in ENDORSE, a finding that is also consistent with
other studies, says Cohen. For example, only 37% of patients with
active malignancy and ischemic stroke--two of the highest-risk
groups for VTE--received prophylaxis. And even in countries where
prevention is commonly provided to at-risk patients, he said, "We
noted that rates of prophylaxis were low in medical patients with
high-risk conditions such as congestive heart failure."

Improved awareness essential

Cohen says last year he attended the European Society of Cardiology
meeting, the European Respiratory Society conference, and the
European Society of Medical Oncology meeting to try to raise
awareness about thrombosis. "There are no recommendations on
preventing thrombosis in heart-failure guidelines, and at the
oncology meeting there was not a single abstract or paper on
thrombosis, despite it being the second commonest cause of death if
you have cancer."

And Ageno and Dentali say that different perceptions of the
benefit/risk ratio of pharmacological prophylaxis exist among
ischemic stroke specialists, "with some stroke guidelines not
recommending routine use of pharmacologic prevention strategies."

"This disagreement . . . is not unique to stroke specialists but
also has been an important limitation of VTE prophylaxis by general
surgeons, urologists, and others," the Italian doctors say.

"Work is need to improve prevention of VTE in hospitalized patients.
Local programs, such as electronic alerts to encourage prophylaxis
in daily clinical practice, are effective and should be promoted,"
they continue.

"However, before these tools can be globally and successfully
implemented, the prevalence of hospitalized patients who are at high
risk for VTE must be better appreciated, and guidelines supporting
the appropriate use of prophylactic strategies should be endorsed by
all medical and surgical societies," they conclude.

ENDORSE was sponsored by Sanofi-Aventis. Disclosures for the authors
and for Ageno can be found in the papers.

Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk
and prophylaxis in the acute hospital care setting (ENDORSE study):
a multinational cross-sectional study. Lancet 2008; 371:387-394.
Ageno W and Dentali F. Prevention of in-hospital VTE: why can't we
do better? Lancet 2008; 371:361-362.
Piovella A, Wang CJ, Lu H, et al. Deep vein thrombosis rates after
major orthopedic surgery in Asia: an epidemiological study based on
postoperative screening with centrally adjudicated bilateral
venography. J Thromb Haemost 2005; 3:2664-26670. Abstract

Adding surgical ventricular restoration (SVR) to CABG in selected
patients with ischemic dilated cardiomyopathy, compared with CABG
alone, can improve LVEF and HF functional class and prevent
hospitalization for heart failure, concluded researchers here
earlier this week at the Society of Thoracic Surgeons 2008 Annual
Meeting [1]. Their retrospective single-center study addresses a
longstanding question about SVR, which many believe improves patient
outcomes on its own but whose effects have been difficult to tease
out from those of the CABG generally accompanying it.

The analysis, according to the study's senior investigator, Dr John
V Conte (Johns Hopkins University, Baltimore, MD), based on several
years of experience at his center, suggests that it's not only the
CABG but also the resizing and reshaping of the heart by SVR that
makes patients better off after the combined surgery. With this new
evidence, more than ever, patients with ischemic heart failure and a
dilated left ventricle should be at least considered for SVR,
especially before a CABG or any other heart surgery is planned, the
surgeon told heartwire. About 5% of CABG candidates with heart
failure at his institution, he said, may also be suitable candidates
for SVR.

Accepted as a surgical option in ischemic cardiomyopathy for years
now, SVR, by helping to normalize left ventricular size and shape,
can make the heart a more efficient pump and reduce myocardial
oxygen demand. But it has been accepted without randomized trial
data. The first prospective, randomized study to look at how SVR
plus CABG compares with CABG alone, the ongoing Surgical Treatment
for Ischemic Heart Failure (STICH) trial, completed enrollment last
year, heartwire reported in December.

Conte and his colleagues went back to 224 patients with a post-MI
LVEF <35% who underwent CABG surgery with or without SVR at their
center from 2002 to 2005. From among the 162 patients who had CABG
only, he identified 58 who would have been good candidates for
concomitant SVR based on his blinded review of the CABG-only group's
preoperative echocardiograms and ventriculograms.

The "ideal" candidate, according to Conte, would have had an
anteroseptal infarction leading to LV enlargement with substantial
akinetic or dyskinetic ventricular myocardium. In the current
analysis, the CABG-only SVR candidates hadn't received the
restoration surgery because they were managed by other surgeons; at
the time, Conte said, he was the only surgeon at his center who did
SVR.

Thirty-day mortality was about the same for the CABG-only patients
and the 62 who had received both CABG and SVR, at 6.9% and 6.5%,
respectively.

Both groups showed a significant jump in LVEF (p<0.001) after
surgery, but the proportional increase wasn't as pronounced for the
CABG-only patients (33%, vs 52% for CABG/SVR cohort; p=0.01). That
difference was paralleled by changes in NYHA class; only about half
of the 87% of CABG-only patients who were in class 3-4 before
surgery improved at least to class 2, whereas the prevalence of NYHA
class 3-4 fell from 97% to 20% in the CABG/SVR group (p=0.01).

The CABG-only group's rate of heart-failure rehospitalization was
also greater at 55%, compared with 24% for CABG-SVR patients
(p=0.006).

There were no significant long-term survival differences, Conte
observed; the rates at two and four years were 73% and 62%,
respectively, for CABG only, and 80% and 75%, respectively, for
CABG/SVR. But the survival curves started to separate in favor of
the combination procedure at about three years, he said, "and I
expect that by five to eight years, that's when we're going to see a
[significant] survival difference." When the STICH trial results are
available in several years, he said, "I think we will find out that
the benefit isn't short term, but long term."

Conte reports receiving research support from Chase Medical.
Coauthor Nishant D Patel (Johns Hopkins University School of
Medicine) "was the 2005 Chase Medical Scholar for surgical
ventricular restoration."

Prucz RB, Weiss ES, Patel ND, et al. Coronary artery bypass grafting
with or without surgical ventricular restoration: A comparison
between two treatment options for ischemic cardiomyopathy in SVR-
eligible patients. Society of Thoracic Surgeons 2008 Annual Meeting.
Presented January 28, 2008. Abstract 15. Available at:
http://www.sts.org/documents/pdf/annmtg/2008AM/2008Monday.pdf.