Early clinical data with budiodarone (ARYx Therapeutics, Fremont, CA), a novel
antiarrhythmic medication that is a chemical analog of amiodarone, showed that
the drug significantly reduced atrial-fibrillation burden in a dose-dependent
manner and was safe and well tolerated at even the highest doses studied.

Presenting the results of the study here at the Heart Rhythm Society 2009
Scientific Sessions, lead investigator Dr Michael Ezekowitz (Lankenau Institute
for Medical Research, Wynnewood, PA) told heartwire that budiodarone appears "to
be a very user-friendly drug, at least as part of this initial evaluation, but
naturally we will need do perform a larger, more definitive phase 3 clinical
trial."

During the late-breaking clinical-trials session, Ezekowitz explained that
budiodarone shares similar mechanisms of action with amiodarone, in that it
works as calcium-, potassium-, beta-, and alpha-receptor blocker, as well as a
sodium-channel antagonist. However, it has a much more positive side-effect
profile because it has a short half-life, just seven hours, and is cleared by
the body in 48 hours. Moreover, it is metabolized by tissue esterases and has a
reduced dependence on CYPP450 for clearance, which is subject to considerable
variability in patients.

"Amiodarone, at least long term, is associated with high complication rates
involving the lungs, kidneys, liver, skin, and neurologic complications, and the
presumed mechanism is that it remains in the body for a very long time, often
greater than three or four months after the last oral administration," Ezekowitz
told heartwire . "So what budiodarone does is capitalize on the mechanism of
action of amiodarone--it's practically identical--but it's rapidly removed from
the body and has a rapid onset of action. In all likelihood, the side-effect
profile is going to be much less."

Data From the PASCAL Study

In this phase 2 study, known as the Paroxysmal Atrial Fibrillation Study with
Continuous Atrial Fibrillation Logging (PASCAL), researchers tested safety and
efficacy in 72 patients randomized to placebo or to 200-mg, 400-mg, or 600-mg
doses of budiodarone. They included patients with dual-chamber pacemakers to
detect and log atrial-fibrillation data and excluded patients with NYHA class 3
and 4 congestive heart failure.

After 12 weeks of treatment, budiodarone significantly reduced
atrial-fibrillation burden, doing so in a dose-dependent manner. From baseline,
there was a significant 54% and 75% reduction in disease burden with the 400-mg
and 600-mg doses, respectively. With the 200-mg dose, there was a nonsignificant
10% reduction in atrial-fibrillation burden.

In an analysis of patients treated with the 600-mg dose, the number and duration
of atrial-tachycardia/atrial-fibrillation episodes decreased by at least 50%
over the 12 weeks, while the time spent in normal sinus rhythm increased. In an
assessment of patient impressions, most were satisfied with the medication, and
nearly 50% reported "a lot of improvement or complete relief."

During his presentation, Ezekowitz noted there were observed side effects, but
none of these progressed and all were reversible. Creatinine elevations were
observed, similar to what was reported with amiodarone and dronedarone, although
there was no evidence of renal toxicity. Also, there were minor changes in
thyroid function, and two cases of elevated liver enzymes without an increase in
total bilirubin levels.

"I think that if the drug is shown to be efficacious in larger studies, without
major side effects, then the competitor will be dronedarone, which I think will
be approved," said Ezekowitz. "The only negative of that drug is in patients
with heart failure; otherwise it's a very safe drug. The problem with
dronedarone is that it doesn't appear to be as effective as amiodarone. The
advantage of budiodarone is that we're seeing a dose response. At the lowest
dose, it doesn't work. You can increase the dose, which you can't do with
dronedarone and which you can't really do with amiodarone, because the side
effects are really dose related."

This past March, a Food and Drug Administration advisory panel voted 10 to 3 to
recommend approval of dronedarone for the treatment of atrial fibrillation. The
yes vote, however, was tempered with cautions against using the drug in patients
with severe systolic heart failure, based in large part on the ANDROMEDA trial.

Ezekowitz reported consulting fees and grant support from Boehringer Ingelheim,
ARYx Therapeutics, Portola, Wyeth, Sanofi-Aventis, Bristol Myers-Squibb,
AstraZeneca, Daiichi Sankyo, and Medtronic.

A new study in the general US population has found that the sharp drop in use of
hormone-replacement therapy (HRT) in the three years from 2002 onward was
associated with significantly fewer MIs among women, but that the stroke rate
was unaffected [1]. Dr Kanaka D Shetty (RAND Corp, Santa Monica, CA) and
colleagues report their findings in the May 2009 issue of Medical Care.

They explain that the use of HRT was curtailed dramatically in 2002 following
the results of the WHI trial, which found that HRT increased the risk of
coronary heart disease in healthy postmenopausal women. This was in contrast to
the prior perceived benefit of HRT on cardiovascular risk--Shetty et al thus
exploited this "natural experiment" to see whether the cardiovascular harms (or
benefits) of HRT seen in randomized controlled trials such as WHI extended to
the general population of women.

"We found that the decline in US HRT use after 2002 appeared to cause a decline
in the AMI rate (while controlling for other factors); we did not observe
statistically significant changes in the stroke rate," Shetty told heartwire .
She and her colleagues say their findings mirror those of a previous study,
which used this same natural experiment in a different context, to conclude that
the reduction in HRT use led to a substantial drop in incidence of breast
cancer.

Dr Rita Redberg (University of California, San Francisco), who was not involved
in this research, told heartwire : "This is a very interesting study; they did a
very careful look at some large databases and found a fairly dramatic drop in MI
rates and a temporal association." However, she countered that, as this was an
observational study, "you can't assume this was due to the decline in HRT use,
you can never show causation, but it's a striking observation."

Observational Data Useful, But Individual Responses Still Important

Shetty et al examined the relationship between HRT use and cardiovascular
outcomes (deaths and nonfatal hospitalizations) in the entire US population of
women aged 40 to 79 years using death records and hospital-discharge data
obtained from Healthcare Cost and Utilization Project's Nationwide Inpatient
Sample and nationally representative surveys of medication usage and behavioral
risk factors.

Decreases in HRT use were not associated with significant changes in
hospitalization or death due to acute stroke, but they were associated with 25
fewer MIs per 10 000 person years (p=0.021).

This means that for every 10 000 additional HRT users in a single year there
would be 25 more cases of AMI, say the researchers. And although direct
comparisons are not possible--because they are measuring treatment effects for
different populations--these figures are of the same magnitude as the WHI data,
which found seven more coronary heart disease events per 10 000 on HRT for a
year, they say.

They note, however, "unlike the WHI trial, we find no significant change in the
number of strokes as consequence of the decline in HRT use." Redberg says she is
not particularly perturbed by this finding: "MIs and stroke do share the same
risk factors, so you would think they would both go down, but we accept
differences in risk of MI and stroke with other medications, such as aspirin,"
she notes.

Shetty told heartwire their findings "indicate that randomized clinical trial
[RCT] results--like the WHI study--may not fully predict effects in typical
users. The selection criteria for RCTs make the experimental results cleaner,
but the generalizability poorer. Clinicians should be cautious about
automatically applying RCT results to clinical questions."

And although the new data represent the mean effect across all subpopulations,
results may differ in individual HRT users: "For this reason, we are undertaking
a study of the effects of HRT on individual persons in the overall population,"
she said.

Effect Not Likely to Be Caused by Awareness Campaigns

The researchers note a number of limitations to their study, including the fact
that they could not specifically examine the so-called "timing hypothesis"--the
suggestion that HRT use in early menopause is protective against heart disease,
because they had no information on how soon after menopause women began using
HRT. Also, they could not look at different types of HRT, only overall HRT use.

To heartwire , Shetty countered claims in some news reports [2] that it was
premature to attribute her findings to the decline in HRT use and that they
could be explained by AHA and National Heart, Lung, and Blood Institute
women-and-heart-disease awareness campaigns, which began around the same time.

"We didn't specifically control for that campaign. However, we did control for
trends in treatment and smoking, which answers this point to some extent. If
this campaign was that successful, it should be reflected in increased treatment
of risk factors as well as decreased smoking. [But] we can't control for other,
more subtle, findings like general awareness.

"Although the campaign could have caused this effect, it's not likely. In
addition, I think our conclusions were pretty cautious regarding causation," she
says.

HRT Use Short-Term for Menopausal Symptoms Is Reasonable

As to recommendations for HRT use, Shetty says: "The short-term benefit of HRT,
in terms of [menopause] symptom relief, may outweigh negative cardiovascular
effects. This concords reasonably well with current guidelines but deserves
further study. We did not have sufficient statistical power to answer this
question. Given the fact that HRT remains widely used for symptom relief, this
remains an important research area."

Redberg agrees that the existing guidance for use of HRT is reasonable: "I try
to recommend nonpharmacological approaches to women, but if they are still
suffering symptoms, I tell them I don't think they are at increased
cardiovascular risk by taking HRT for six months."

Women who had a food intake similar to the Dietary Approaches to Stop
Hypertension (DASH) diet, with high consumption of fruits, vegetables, and whole
grains and a low intake of fat and dairy products, had a reduced risk of
developing heart failure in a recent study [1].

The DASH diet has been shown to reduce blood pressure, and observational studies
have also suggested that it may reduce the risk of coronary heart disease and
stroke. The current research, published in the May 11, 2009 issue of the
Archives of Internal Medicine, looked at whether such a diet could also reduce
the risk of heart failure in healthy women.

Researchers, led by Dr Emily Levitan (Beth Israel Deaconess Medical Center,
Boston, MA), studied 36 019 women aged 48 to 83 years taking part in the Swedish
Mammography Cohort. The women did not have heart failure, diabetes, or a history
of MI at baseline. Diet was measured using food-frequency questionnaires. A
score was created to assess consistency with the DASH diet, and heart-failure
hospitalization or death was determined using the Swedish inpatient and
cause-of-death registers.

Results showed that women in the top quartile of the DASH component score ate,
on average, three servings of fruit, 3.5 servings of vegetables, 5.1 servings of
whole grains, 1.6 servings of low-fat dairy products, 0.1 servings of sweetened
beverages, and 0.8 servings of red or processed meat per day. In comparison,
women in the bottom quartile of the score ate, on average, 1.4 servings of
fruit, 1.8 servings of vegetables, 3.3 servings of whole grains, 0.6 servings of
low-fat dairy products, 0.4 servings of sweetened beverages, and 1.3 servings of
red or processed meat per day.

During the seven years of follow-up, 443 women developed heart failure. Women in
the top quartile of the DASH diet score had a 37% lower rate of heart failure
after adjustment for age, physical activity, energy intake, education status,
family history of MI, cigarette smoking, postmenopausal hormone use, living
alone, hypertension, high cholesterol concentration, body-mass index, and
incident MI.

Levitan commented to heartwire : "This is the first time it has been shown that
DASH diet is associated with a lower risk of developing heart failure. Previous
studies have suggested a reduced risk of CHD and stroke. I think we can now say
that the blood-pressure benefits known to occur from this diet do seem to
translate into reduced cardiovascular events, including the development of heart
failure."

She noted that, like this study, the heart-disease and stroke studies were also
conducted in women, which is somewhat unusual for cardiac research, which tends
to focus on men. "That was one of the reasons we wanted to focus on women,"
Levitan commented. "And heart failure is a major problem in older women. I would
say the gender difference is less than something like MI. But we have a
follow-up study planned in men," she added.

She pointed out that in the original DASH study, the diet was associated with a
5.5-mm-Hg reduction in blood pressure, which would have accounted for the
reduction in heart failure seen in this study. But reducing lipids and other
mechanisms may also play a role in the benefit seen.

And while only 20% of the women in this study had hypertension, Levitan believes
that a reduction in blood pressure is still beneficial for those normal blood
pressures. "We looked at people with raised blood pressure and those with normal
pressures at baseline, and the DASH diet was protective in both groups. We think
lower blood pressure is better in almost everyone until you get down to very low
pressures. Even if you have a pressure of 125/90, it would probably be better if
it were 115/80," she said. She added that the main goal of the DASH diet is to
increase electrolytes such as calcium, which are thought to antagonize sodium,
which is known to increase blood pressure.

"Our population did not have heart failure at baseline, but I would recommend
patients with heart failure follow this diet. I would also say that this diet is
a particularly healthy one to follow for everyone, but especially for those with
blood-pressure issues," Levitan commented.

Hypertension the Most Common Condition for Which Women Sought Treatment

Approximately 25 million women in the US--most over the age of 45--were treated
for high blood pressure in 2006, making it the most common condition for which
women sought treatment, according to the latest "News and Numbers" from the
Agency for Healthcare Research and Quality (AHRQ) [2]. The statistical analysis
by the AHRQ found that the other most common diseases for which women aged over
45 sought treatment in 2006 included hyperlipidemia, heart disease, and
diabetes.

In terms of expenditure, heart disease tops the table for both men and women.

The data include treatment in doctors' offices and hospital outpatient clinics,
emergency rooms, hospitals, and by home healthcare providers. This analysis was
based on data from AHRQ's Medical Expenditure Panel Survey, which collects
information each year from a nationally representative sample of the US civilian
noninstitutionalized population about their healthcare use, expenses, access to
services, health status, and the quality of the healthcare they obtained.

Biosite is voluntarily recalling one lot of its Triage Cardiac Panel, a test
used to aid in the diagnosis of MI [1]. The product has been recalled nationwide
in the US due to reports of low recovery of quality-control samples containing
creatinine kinase MB (CK-MB), troponin I, and myoglobin on the affected lot.

Although there have been no reports of patient misdiagnosis associated with this
lot--catalog 9700HS, lot #W444467B--which was distributed to labs in the US
between January and February of this year, Biosite has notified customers to
discontinue use of the affected lot and discard any remaining product.

Two large analyses estimating the cardiovascular and stroke benefit with initial
drug treatment for hypertension showed that only angiotensin receptor blockers
(ARBs) were not significantly better than placebo for the prevention of coronary
events, while all antihypertensive drugs were better than placebo for the
prevention of stroke.

Regarding the lack of cardiovascular protection with ARBs, investigators suggest
that this is the result of a limited number of studies and cardiovascular
outcomes in these trials compared with the other drug classes.

"People should feel very comfortable that when their doctor is giving them a
certain medication they don't have to worry," said lead investigator Dr William
Elliott (Rush Medical College, Chicago, IL). "The concern we have with the ARBs
is probably because we simply don't have enough data at this time. . . . There
really aren't enough data with ARBs to make a really strong statement."

The two meta-analyses were presented here this week at the American Society of
Hypertension (ASH) 2009 Scientific Meeting.

Meta-Analysis Includes Recent Hypertension Trials

During a press conference with assembled media, Elliott said that the last
meta-analysis estimating outcomes with initial hypertensive therapy was
performed in 2003, before the publication of Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 7). In that analysis, researchers concluded there was a
reduction in stroke with any hypertensive drug but that low-dose diuretics were
the most effective first-line agents for preventing cardiovascular disease.

However, with the publication of the Avoiding Cardiovascular Events in
Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH),
a study showing the ACE inhibitor benazepril plus the calcium-channel blocker
amlodipine was more effective than treatment with the ACE inhibitor and diuretic
in reducing major fatal and nonfatal cardiovascular events, there is some
uncertainty if this is still true, said Elliott.

In the two new meta-analyses, investigators included all published
outcomes-based clinical trials with minimum follow-up of one year. All subjects
included in the analysis were required to have hypertension, thereby excluding
studies such as HOPE, PROGRESS, EUROPA, PEACE, and ONTARGET, among others, and
the drug used must have been prescribed as initial antihypertensive therapy. The
reference drug in the two analyses was diuretic therapy.

In an analysis estimating the reduction in stroke risk with the hypertensive
medications, which included nearly 270 000 hypertensive patients in 60 clinical
trials, all medications were significantly better than placebo for reducing the
risk of stroke. Diuretics and calcium-channel blockers were slightly more
protective than ARBs but were significantly better than ACE inhibitors and beta
blockers.

Investigators noted that the results were identical whether the reference
diuretic was chlorthalidone or hydrochlorothiazide and that the overall network
findings were confirmed by Bayesian analysis. Moreover, the data are robust to
numerous changes in the data set, which included the addition of ACCOMPLISH to
the analysis as well as different studies that included add-on drug therapy for
the treatment of hypertension and studies that didn't include patients with high
blood pressure.

"The fact is that it doesn't really matter when you add in these other studies,
you get the same answer," said Elliott.

Cardiovascular Risk Reduction With Antihypertensive Drugs

In the second meta-analysis examining coronary heart disease risk reduction with
the different antihypertensive drugs, the researchers used the same entry
criteria and included 57 clinical trials involving 276 000 patients. In that
analysis, all drugs, except ARBs, were significantly better than placebo or no
treatment for reducing the risk of coronary events.

"The good news is that all of the generically available medicines are
significantly better than placebo, and the take-home message for patients and
doctors is that you can be sure whatever generic medicine you're taking does
protect you better than placebo or no treatment for heart attack and sudden
cardiac death," said Elliott.

The findings also showed that ACE inhibitors were significantly better than ARBs
and beta blockers for coronary heart disease risk reduction, which echoes
previous reports suggesting ACE inhibitors have pleiotropic effects independent
from blood-pressure lowering that protect patients from cardiovascular events.

Like the stroke findings, the results were similar when different studies were
added to the analysis and when the different diuretics were used as the
reference drugs.

Speaking with the media, Elliott noted that the results have been heralded as a
"tempest in a teapot" because most patients with hypertension are treated with
multiple antihypertensive drugs, whereas this analysis was concerned primarily
with looking at risk reduction with initial hypertension therapy. However, since
treatment in the US follows "road maps," and patients are typically started with
one drug, it is important to know the differences with the different pathways
that lead to getting blood pressure down, he said.

Elliott reports serving as a consultant to Novartis Pharmaceuticals and is on
the speakers' bureau for Novartis, Pfizer, a Bristol
Myers-Squibb/Sanofi-Synthelabo partnership, and Sanofi-Aventis.

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Journalist
Michael O'Riordan
Michael O'Riordan is a journalist for Medscape. Before becoming a journalist for
theheart.org, now part of the WebMD Professional Network, he worked for WebMD
Canada. Michael studied at Queen's University in Kingston and the University of
Toronto and has a master's degree in journalism from the University of British
Columbia, where he specialized in medical reporting. He can be contacted at
MORiordan@....
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Information
Authors and Disclosures
Michael O'Riordan
Michael O'Riordan is a journalist for Medscape. Before becoming a journalist for
theheart.org, now part of the WebMD Professional Network, he worked for WebMD
Canada. Michael studied at Queen's University in Kingston and the University of
Toronto and has a master's degree in journalism from the University of British
Columbia, where he specialized in medical reporting. He can be contacted at
MORiordan@....


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Black children with primary hypertension (PHTN) are nearly twice as likely to
have left ventricular hypertrophy as children from other racial backgrounds with
PHTN, investigators reported here at the Pediatric Academic Societies 2009
Annual Meeting.

Cozumel S. Pruette, MD, pediatric nephrology fellow at Johns Hopkins Children's
Center, Baltimore, Maryland, and colleagues at 3 tertiary care medical centers
conducted a cross-sectional study of 139 children between the ages of 3 and 21
years presenting to their centers for evaluation of high blood pressure between
1997 and 2005. The children were eventually diagnosed with PHTN.

The investigators evaluated the children for left ventricular hypertrophy and
found an overall prevalence of 42%.

There were 35 black children in the cohort, 60% of whom had left ventricular
hypertrophy. Of the other 104 children in the cohort from other races, 37% had
left ventricular hypertrophy on presentation. The difference was significant (P
= .02).

The body mass index z-score was significantly higher in children with left
ventricular hypertrophy compared with those without it but was not significantly
different between the races (P = .4).

Total cholesterol was significantly elevated in black children with left
ventricular hypertrophy compared with black children without it. These
differences were not present among children of other races.

"Our study identifies black children with hypertension as a special group who
may be at particularly high risk for heart disease as they age because of
several risk factors, and pediatricians treating these kids should follow them
very closely," Dr. Pruette said.

"Children with left ventricular hypertrophy need more aggressive screening," she
told Medscape Pediatrics. "These children may possibly need earlier and more
aggressive pharmacologic treatment ¡X but this study doesn't address that.... We
will be looking at that in future studies," she added.

"These findings make sense," Robert M. Jacobson, MD, chairman of the Department
of Pediatrics at the Mayo Clinic in Rochester, Minnesota, commented in an
interview with Medscape Pediatrics. "We need to take a careful history and a
very careful physical assessment, evaluating these children for early signs of
cardiovascular disease.

"We know in adults that left ventricular hypertrophy is a marker of increased
cardiovascular morbidity and mortality," Dr. Jacobson said. "If we monitor these
children closely, we can detect signs of disease earlier.... We don't know yet
if early treatment of these children will reduce their risk. These studies are
ongoing."

Dr. Pruette has disclosed no relevant financial relationships. Dr. Jacobson
receives support as a member of Kaiser Permanente of Northern California's
Safety Review Committee for Gardasil Immunization, which he notes is not
relevant to this study.

Pediatric Academic Societies (PAS) 2009 Annual Meeting: Abstract 2530.6.
Presented May 2009

Drinking up to half a glass of wine daily may increase longevity by 5 years in
men, but more studies are needed, according to the results of a study reported
online first in the April 30 issue of the Journal of Epidemiology and Community
Health.

"Light to moderate alcohol intake lowers the risk of cardiovascular mortality,
but whether this protective effect can be attributed to a specific type of
beverage remains unclear," write M.T. Streppel, from the National Institute for
Public Health and the Environment, Bilthoven, the Netherlands, and colleagues.
"Moreover, little is known about the effects of long-term alcohol intake on life
expectancy."

The goal of this analysis was to determine the effect of long-term alcohol
intake and types of alcoholic beverages consumed on cardiovascular mortality and
life expectancy at age 50 years. The study cohort consisted of 1373 men enrolled
in the Zutphen Study who were born between 1900 and 1920 and evaluated
repeatedly between 1960 and 2000.

Time-dependent Cox regression models were used to calculate hazard ratios (HRs)
for total alcohol intake and for intake of alcohol from wine, beer, and spirits.
Areas under survival curves were used to assess life expectancy at age 50 years.
Light alcohol intake was defined as consumption of not more than 20 g/day.

Compared with no alcohol consumption, long-term light alcohol intake was
strongly and inversely associated with risks for cerebrovascular mortality (HR,
0.43; 95% confidence interval [CI], 0.26 ¡V 0.70), total cardiovascular
mortality (HR, 0.70; 95% CI, 0.55 ¡V 0.89), and all-cause mortality (HR, 0.75;
95% CI, 0.63 ¡V 0.91).

Long-term wine consumption averaging less than half a glass per day was strongly
and inversely associated with coronary heart disease (HR, 0.61; 95% CI, 0.41 ¡V
0.89), total cardiovascular mortality (HR, 0.68; 95% CI, 0.53 ¡V 0.86), and
all-cause mortality (HR, 0.73; 95% CI, 0.62 ¡V 0.87), independent of total
alcohol intake. Differences in socioeconomic status did not explain these
results. Compared with men who did not consume alcohol, men who drank, on
average, less than half a glass of wine per day had a life expectancy about 5
years longer.

"Long-term light alcohol intake lowered cardiovascular and all-cause mortality
risk and increased life expectancy," the study authors write. "Light wine
consumption was associated with 5 years longer life expectancy; however, more
studies are needed to verify this result."

Limitations of this study include lack of data on drinking frequency, average
long-term alcohol intake was relatively low, most participants used more than 1
type of alcoholic beverage in their usual diet, and for those men who were newly
included in the study in 1985, information on alcohol intake was missing for the
period 1960 to 1970.

"The inverse associations between wine consumption and mortality remained after
adjustment for total alcohol intake," the study authors conclude. "Wine
consumers had a 5 years longer life expectancy compared with no alcohol
consumers; however, more studies are needed to draw conclusions on the strength
of the association between wine consumption and mortality."

The former Inspectorate for Health Protection and Veterinary Public Health, at
present integrated in the Food and Consumer Product Safety Authority, the
Netherlands, supported this study. The authors have disclosed no relevant
financial relationships.

J Epidemiol Community Health. Published online April 30, 2009.

The use of lipid-modifying therapy in South Asian patients with established
coronary heart disease results in reductions in LDL cholesterol and increases in
HDL cholesterol similar to those in white patients, according to the results of
a new study [1]. The findings suggest that South Asian patients be treated with
atorvastatin and simvastatin, the two most commonly prescribed statins in this
retrospective analysis, at doses that would be prescribed to white patients, say
researchers.

"Applicability is limited in that these are patients with coronary disease, as
opposed to a primary-prevention¡Vtype population, and we really only had the
power to evaluate simvastatin and atorvastatin," said lead investigator Dr Milan
Gupta (McMaster University, Hamilton, ON). "But I think it's a reasonable
conclusion that in South Asians with coronary disease in whom you are
prescribing simvastatin or atorvastatin, if you're concerned you might not get
the same lipid effect as in a white population, that concern is unfounded."

The results of the study are published online April 27, 2009 in the Journal of
Clinical Pharmacology.

Speaking with heartwire , Gupta explained that there exists a generalized
notion, derived from studies of East Asian, primarily Japanese, populations,
that Asian patients require lower doses of statins. This generalization has
extended to South Asians from the Indian subcontinent, such as those from India,
Pakistan, Sri Lanka, Nepal, and Bangladesh. The Canadian Cardiovascular Society
guidelines, for example, recommend the use of lower statin doses for all Asian
patients. Also, the Food and Drug Administration recommends all Asian patients
start with rosuvastatin 5 mg.

In an analysis of the ongoing Prospective Assessment of Cardiovascular Risk and
Treatment of Canadians of Varying Ethnicity (PRACTICE) registry, the researchers
wanted to compare the lipid-modifying effects of statin therapy in South Asian
and white patients with documented coronary heart disease. To assess the effects
of statins, the group contacted the primary-care physician and obtained baseline
LDL- and HDL-cholesterol levels prior to starting statin therapy. The selection
and dosing of statin therapy was at the discretion of their doctor, but the goal
was to treat patients to secondary-prevention lipid targets. Most patients were
treated with atorvastatin and simvastatin 20 mg, and all were treated with the
drugs for a minimum of six weeks.

Both statins resulted in similar decreases in LDL cholesterol: 35% and 43% with
simvastatin and atorvastatin, respectively, in South Asians, and 37% and 41% in
white patients. There were similar increases in HDL-cholesterol levels with both
statins in both patient populations. Regression analyses showed that the
expected decrease in LDL cholesterol for atorvastatin 10 mg and 20 mg was
similar with both groups of patients.

"There is a similar degree of LDL lowering, dose for dose, and there is a
similar effect on HDL cholesterol, in South Asians and Caucasians," said Gupta.
"We can't make conclusions for the other statins, because their usage was quite
infrequent in this patient population. However, in this type of population,
there doesn't appear to be any need to alter the dose of atorvastatin or
simvastatin, at least with respect to lipid efficacy."

Speaking with heartwire , Dr James de Lemos (University of Texas Southwestern,
Dallas) said that most clinicians are aware the South Asian patients have a
higher risk-factor profile than other patients, but that he is not surprised by
the findings, given the genetic dissimilarities between East Asian and South
Asian patients. He added that he sees a large number of South Asian patients in
his clinic, but he does not prescribe lower statin doses for them. Dr Roger
Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) agreed with
de Lemos, noting that even starting Japanese patients on lower doses remains
controversial in clinical practice.

A new French study has found that men whose heart rate increased the most in the
period just before an exercise test had twice the risk of sudden cardiac death
(SCD) in later life than those whose heart rate did not increase to the same
extent [1]. These results are "novel and largely unexpected," say Dr Xavier
Jouven (Hôpital Européen Georges Pompidou, Paris, France) and colleagues in
their paper published online April 28, 2009 in the European Heart Journal.

They explain that this "mild mental stress" just before exercise is usually
associated with an increase in heart rate by just a few beats per minute (bpm).
They have previously shown an association between SCD and heart-rate increase
during physical stress and that an insufficient increase in heart rate during
strenuous exercise is predictive of SCD, but this is first time an association
of this kind has been seen, they note.

Taking a pulse during this time period could provide a simple tool for
identifying people who may be at increased risk of SCD, they conclude.

"This study shows that the heart-rate increase during mild mental stress in
preparation for exercise is a strong predictor of sudden death. The findings
have significant clinical implications," says Jouven in a European Society
Cardiology statement [2]. "Sudden death . . . is a major public-health problem.
Less than 5% of people suffering a heart attack are successfully resuscitated,
and so being able to identify early on those who are at greatest risk in a
general and apparently healthy population would be a big step forward in
preventing some of these deaths."

Long, Prospective Study

The researchers analyzed data from 7746 French policemen participating in the
Paris Prospective Study, who were aged 42 to 53. The men were examined between
1967 and 1972 and given ECGs and physical examinations, and their resting heart
rate was measured. Heart rate was measured again in the few minutes before they
took an exercise stress test, during the test, and afterward during the recovery
period.

Complete data on the exercise stress test were available for 6456 men; 388 of
these were excluded from the analysis because of an ischemic response to
exercise or an impaired chronotropic response.

During an average 23 years of follow-up, there were 1516 deaths--including 81
sudden cardiac deaths and 129 non–sudden cardiac deaths--and 355 men were lost
to follow-up.

The risk of SCD rose progressively with heart-rate increase during the
mild-mental-stress period before the exercise test (p for trend=0.02). After
multifactorial adjustment, men who had the highest increase in heart rate during
this period (an increase of more than 12 bpm) had twice the risk of SCD of those
who had the lowest increase in heart rate (increase of less than 4 bpm), a
relative risk of 2.09. No such relationship was observed for non–sudden cardiac
death. There were no SCDs among the 440 men who increased their heart rate the
least during this period and the most during the exercise test. The highest
proportion of SCDs was among the 471 men who increased their heart rate the most
during mild mental stress and the least during exercise.

Different Neural Responses Have Differential Impact on Arrhythmic Risk

The findings indicate that different neural responses to different types of
stress give a differential impact on arrhythmic risk, say Jouven et al.

"Our underlying assumption, which this study appears to have proved correct, is
that the faster the vagal withdrawal in response to mental stress, the greater
will be--during an ischemic episode--the damaging effect of sympathetic
activation unopposed by vagal activity," Jouven explained.

In addition, he and his colleagues found that the risk of SCD was influenced
strongly by genetic predisposition: it increased nearly threefold in men whose
mothers had died suddenly and nearly 10-fold when both parents had died
suddenly, compared with those whose parents had not died in this way.

This raises "the intriguing possibility of a genetic predisposition to the
autonomic responses associated with higher or lower risk for SCD," the
researchers say.

Pulse Can Be Used as Prognostic Marker, But Only in Men

"Few measurements in medicine are as inexpensive and as easy to obtain in large
general populations as to measure the heart-rate difference between resting and
being ready to perform an exercise test," Jouven notes.

"Taking a person's pulse has been part of clinical examinations for thousands of
years," he continues, "and now our study shows it can be used as a prognostic
marker. The results will contribute toward a better understanding of the
mechanisms of cardiac death.

"People who showed a higher heart-rate increase with mild mental stress could be
considered for additional investigations and for tailored preventive strategies,
aimed in the first place at reducing the probability of heart disease," he
concludes.

He and his colleagues point out, however, that the study was carried out in men
only, so it is possible that findings in women may be different.

The US Food and Drug Administration this week approved an antihypertensive
medication that combines hydrochlorothiazide with valsartan, an angiotensin
receptor blocker (ARB), and amlodipine, a calcium-channel blocker (CCB) (Exforge
HCT, Novartis).

The approval isn't for first-line hypertensive therapy. Instead, the drug is
approved for patients who are unable to obtain adequate blood-pressure control
with dual therapy that includes CCBs, ARBs, and diuretics.

The FDA has already approved a combination of valsartan and amlodipine
(Exforge), from the same company, for the second-line treatment of hypertension
or for people who are likely to require multiple drugs to control their high
blood pressure.

Even among older adults, a healthy lifestyle, one that includes physical
activity, healthy dietary habits, smoking cessation, and light or moderate
alcohol use, is associated with a significantly lower incidence of new-onset
diabetes mellitus. Researchers showed that 80% of new cases of diabetes are
attributable to these risk factors, a number that increases when obesity is
included as a risk factor.

"Our findings suggest that, even later in life, the great majority of cases of
diabetes are related to lifestyle factors," write Dariush Mozaffarian (Brigham
and Women's Hospital, Boston, MA) and colleagues in the April 28, 2009 issue of
the Archives of Internal Medicine. "Our results support the need for emphasizing
healthy and achievable physical activity and dietary goals among older adults,
including moderate leisure-time activity and walking pace, higher intake of
dietary fiber and polyunsaturated fat, and lower intake of trans fat and easily
digestible carbohydrates."

Previous studies, including a secondary analysis of the Diabetes Prevention
Program trial, have shown that structured dietary advice and physical activity
were most effective at reducing the risk of diabetes among the oldest
participants. However, as the investigators point out, that trial included
mostly high-risk patients participating in a highly structured intervention.
Other studies have shown that certain lifestyle behaviors can lower the risk of
diabetes, but these often looked at each lifestyle factor individually.

In this analysis of the Cardiovascular Health Study, Mozaffarian and colleagues
investigated the relationship between lifestyle risk factors, evaluated in
combination, and the incidence of diabetes over a 10-year period in 4883 men and
women 65 years of age and older. The group defined optimal lifestyle
characteristics and compared these low-risk behaviors with the risk of incident
diabetes mellitus.

Low-risk lifestyle behaviors were defined by physical-activity levels above the
median and never smoking or smoking <5 pack-years or having quit >20 years ago.
Alcohol use in this cohort was rare, with 94% consuming less than two drinks
daily. Individuals were also assigned a dietary score based on their intake of
dietary fiber, low glycemic index foods, lower trans fats, and a higher
polyunsaturated-to-saturated-fat ratio. Assessments of adiposity were also
performed, with a low-risk body-mass index (BMI) defined as not being
overweight, or a BMI <25, while a low-risk waist circumference for men was <92
cm and <88 cm for women.

Basic lifestyle risk factors, according to the researchers, strongly predicted
diabetes incidence, with individuals cutting their risk in half when they were
physically active and had good dietary habits. Overall, the risk of diabetes was
80% lower among individuals with physical-activity levels above the median,
healthy dietary and smoking habits, and moderate alcohol use. When healthy BMIs
and waist circumference were added to the model, the risk of new diabetes was
reduced by 89%.

If these associations are causal, "eight in 10 new cases of diabetes might have
been prevented if all older adults were in the low-risk group for these
lifestyle factors," write Mozaffarian and colleagues. When not being overweight
or not having a large waist circumference was considered as a risk factor in
addition to these other lifestyle behaviors, the number of possible prevented
cases attributable to lifestyle factors would rise to nine in 10.

"The findings provide an estimate of the public-health burden of combined
nonoptimal lifestyle risk factors for incidence of diabetes in older adults, the
fastest growing segment of the population," write the researchers.

Having 5 or more children might put a woman at risk for shortened survival if
she later needs a heart transplant, according to new research presented here at
the International Society for Heart and Lung Transplantation 29th Annual Meeting
and Scientific Sessions.

"Pregnancy may represent an independent risk factor for yearly acute rejection
risk," said lead investigator Cheri Silverstein, MD, a clinical research fellow
in the Division of Cardiovascular Medicine at Vanderbilt University in
Nashville, Tennessee.

The risk for rejection appears to be independent of sensitization to fetal
antigens, Dr. Silverstein said.

Women who undergo orthotopic heart transplantation appear to be at increased
risk for rejection, compared with men, Dr. Silverstein said, and smaller studies
have suggested that a history of pregnancy in general, and 2 or more pregnancies
in particular, puts women at increased risk for elevated panel reactive
antibodies (PRA), a marker for rejection.

To determine whether cumulative pregnancies might increase the risk for
rejection requiring treatment within the first year, Dr. Silverstein and
colleagues gathered data from the United Network for Organ Sharing (UNOS)
database on all first transplants from 1995 to 2006 in patients 16 years and
older. They found data on rejection and prior pregnancy for 2644 women, and
compared the information with data on rejection for 10,172 men.

The authors used chi-square testing to evaluate the relation between the number
of pregnancies and sex with rejection, and multivariate logistic regression
analysis to assess the ability of the number of pregnancies to predict
rejection.

When they looked at the fraction of patients with rejection by number of
pregnancies, they found a clear and significant linear relationship, with
nulliparous women having virtually no risk, and women with 5 or more pregnancies
being at the highest risk (£q2 = 22.9; P = .0008).

In an analysis of rejection by sex, the investigators found that there was no
significant difference between men and women who had never been pregnant,
although there appeared to be a trend toward a higher fraction of women with
rejection.

"We suspect, but we can't determine, that this may represent some underreporting
of pregnancies, as opposed to number of children," Dr. Silverstein said.

In an analysis of class II PRA by pregnancy number in 536 women, reserachers
found a strong correlation with higher numbers of antibodies and higher numbers
of pregnancies (£q2 = 29.7; P = .003).

In logistic regression analysis, the only significant risk factor for rejection,
other than elevated PRA, was 5 or more pregnancies, which was associated with a
more than 2-fold risk for rejection requiring treatment in the first year (odds
ratio, 2.224; 95% confidence interval, 1.031 - 4.796).

Dr. Silverstein acknowledged that the study was limited by missing data and the
fact that the database did not contain information about patients surviving less
than 275 days, meaning that the investigators could not analyze any data about
hyperacute rejections or early adverse outcomes.

"There's no question that the incidence of presensitization and antibodies goes
up with pregnancy," Stuart D. Russell, MD, moderator of the session in which the
study was presented, told Medscape Transplantation. Dr. Russell, associate
professor of medicine and clinical chief of heart failure and transplantation at
Johns Hopkins University in Baltimore, Md, was not involved in the study.

"What's intriguing to me and to others is that there was another paper presented
here [that showed that] mortality among patients with peripartum cardiomyopathy
was significantly lower at 5 years, with the primary reason being noncompliance.
With all the caveats of the UNOS dataset, it makes one wonder whether there
might be a group of young women who get into a disastrous situation, and because
of that, they may have issues with compliance, as well as the fact that they're
presensitized and, by that fact alone, are at increased risk."

Dr. Silverstein and Dr. Russell have disclosed no relevant financial
relationships.

International Society for Heart and Lung Transplantation (ISHLT) 29th Annual
Meeting and Scientific Sessions: Abstract 568. Presented April 24, 2009.

More evidence that a coordinated regional approach to the treatment of STEMI
patients, with prehospital triage and cath-lab activation, leads to a consistent
reduction in door-to-balloon times, has come from a new study [1].

The paper, published in the April 2009 issue of the Journal of the American
College of Cardiology: Cardiovascular Interventions, was authored by a team led
by Dr Ivan Rokos (University of California, Los Angeles Olive View Medical
Center).

Rokos told heartwire that this paper was the result of a collaborative effort
among 10 regions that have adopted a system of prehospital triage of STEMI
patients in which paramedics perform ECGs in the ambulance and then take the
patient to the nearest primary PCI-capable hospital, having already activated
the cath lab.

He noted that while both the AHA and the ACC have initiatives promoting such
systems, their actual implementation in practice is still somewhat pioneering.
"We are hoping that our data will encourage more regions to go down this route,"
he said. "A key rule of cardiology is 'time is muscle,' and we have clearly
shown that regions implementing a prehospital triage system for STEMI patients
consistently reduce time to PCI, which should translate into better outcomes."

The current paper reports a pooled analysis of 10 independent, prospective,
observational registries involving 72 hospitals. Data were collected on all
consecutive patients with a prehospital ECG diagnosis of STEMI. In total,
paramedics transported 2712 such patients directly to a PCI hospital. A primary
PCI was performed in 2053 patients (76%), and 86% of these had a door-to-balloon
time of less than 90 minutes, well above the ACC benchmark of 75%.

In addition, door-to-balloon times were less than 60 minutes in 50% of patients,
less than 45 minutes in 25% of patients, and less than 30 minutes in 8% of
patients, which the authors say demonstrates that this system possesses
"substantial capacity to consistently deliver very rapid primary PCI." They
suggest that such fast time to reperfusion should translate into lives being
saved, noting that a recent registry analysis has shown additional in-hospital
mortality reductions as door-to-balloon times are reduced from 90 to 30 minutes.

EMS-to-Balloon Times: A New Standard

The authors also report another measure--emergency medical services
(EMS)-to-balloon time (E2B)--which was below 90 minutes in 68% of patients in
which this was tracked. "Our data provides the first evidence that the rate of
E2B <90 minutes may represent an appropriate metric for assessing the
performance of coordinated regional STEMI care systems," they write.

In this study, time zero for EMS-to-balloon times was defined as the time of the
prehospital ECG, whereas the authors point out that the most recent STEMI
guidelines use time of EMS arrival on the scene. "In reality, the true
patient-centered time zero for STEMI systems is the time of the 911 call, and
hence this time point represents the ideal starting point of EMS-to-balloon
times that should be tracked in future analyses," they add.

Rokos explained that for the purposes of this paper, he and his colleagues
invited those regions they knew had adopted such systems to share their data. In
addition to the 10 regions included, there are some other regions that are using
similar systems but did not take up the offer to share their data at this point,
he said.

He noted that the most common method for interpreting ECGs in the ambulance was
use of a computer algorithm. "These computers read the ECG and tell you whether
the patient is having a STEMI or not. This is not quite as good as having a
cardiologist read the ECG and can lead to some false positives, but it seems to
be the most practical method at present," he added. While transmission of the
ECG to a cardiologist for interpretation would be the ideal, this has proven
challenging to implement because the different proprietary ECG systems are not
always compatible with the receiving equipment used at a particular hospital.
"It seems incredible that we can email a photograph around the world, but we
haven't yet found an easy way of transmitting an ECG to a nearby hospital,"
Rokos commented to heartwire .

Rokos noted that the data included in this paper did not include interhospital
transfer programs. "This is the other half of the equation and a very
challenging part. When patients present to a non-PCI hospital and need
transferring to a PCI center, this is a very complicated procedure, with a whole
chain of bureaucratic events that have to happen, which slows things down
considerably. Even if a patient presents to the emergency department of a PCI
hospital, because these departments are so busy, it can be difficult to get an
ECG done fast, but if a STEMI patient comes in by ambulance, these delays are
often avoided because paramedics with suspected STEMI patients can be given a
fast lane to the cath lab."

Rokos told heartwire that the director of the regional emergency services was
the ideal person to coordinate setting up a regional STEMI system such as those
described in this paper. "Primary PCI-capable hospitals must recognize that the
emergency services are responsible for the delivery of approximately one-half of
all STEMI patients, and thus they are in a unique and powerful position to
foster collaboration among competing hospitals and drive quality in a region,"
he said.

Better Data Collection Needed

In an accompanying editorial [2], Dr Christopher Granger (Duke Clinical Research
Institute, Durham, NC) describes the paper by Rokos et al as "an important
demonstration project."

"It can no longer be argued that it is impossible to establish an integrated EMS
and hospital system to provide faster primary PCI," he comments.

But he notes that the system can be improved further by recording additional
data necessary for assessing performance, such as times of first medical
contact, first ECG, and catheterization-laboratory activation; false
activations; bypass of non-PCI centers; and clinical complications during
transport. "It is an embarrassment that we have a health system in the US
whereby critical medical information from the prehospital phase of care is often
not available to hospital providers. As more critical aspects of care for STEMI,
stroke, and cardiac arrest are moved into the prehospital setting, this has
become a major deficiency that needs to be fixed," Granger writes.

Pointing out that in this study 24% of patients for whom the cath lab was
activated did not have primary PCI, he suggests that standard definitions of
"false activation" and acceptable rates of false activation are important topics
for further study, but they cannot be understood until there is better data
collection and tracking.

Granger concludes: "The most important lesson of this study is that reperfusion
with primary PCI can be provided more rapidly if EMS is placed in its rightful
position as the front line for integrated STEMI care. Expansion of what these 10
networks have done on a national scale--refined and coupled with better EMS
support, data collection, and feedback--will improve care and save lives."

Older people are less likely to receive high-quality stroke care compared with
younger patients, researchers warn. And this is despite evidence suggesting that
care is equally effective across age groups, they note. The new studies point to
ageism in stroke care ¡X the first is published online April 16 in BMJ and the
second in the March issue of the Postgraduate Medical Journal.

"We found low rates of secondary drug prevention," report the BMJ study authors,
led by Rosalind Raine, PhD, professor of health-services research from
University College London, in the United Kingdom.

The national study was of nearly 13,000 patients from 113 primary-care
practices. Only 25.6% of men and 20.8% of women received secondary prevention.
"Older patients were substantially less likely to receive treatment," they note.
The adjusted odds ratio for 80- to 89-year-olds compared with 50- to
59-year-olds was 0.53 (95% CI, 0.41 ¡V 0.69).

This variation in treatmentis important, the researchers emphasize, because the
receipt of secondary drug prevention for patients who survived the first 30 days
after a stroke wasassociated with a 50% reduction in the hazard of dying during
the first year.

Low Rates of Secondary Drug Prevention

On average, mortalitywithin the first year was 5.7% for patients receiving
treatmentcompared with 11.1% for patients not receiving therapy. There was
little evidence that the effect of treatment differed betweenthe social groups
examined.

In addition to improving the quality of life of patients, aggressive use of
drugs in secondary prevention of stroke in the elderly is likely to lower health
expenditures for rehabilitating stroke victims, Rajasree Pai Ramachandra Pai, a
resident at the University of Connecticut, in Storrs, added in a rapid response
to the paper.

In the second study, the authors found that older patients were less likely to
receive diagnostic investigations and advice for lifestyle modifications than
younger patients.

"This study highlights several important deficiencies in the management of
transient ischemic attack [TIA] and minor stroke, especially with respect to the
rates of brain and carotid imaging and echocardiograms," report the researchers,
led by Y.Y. Karen Kee, MD, from the Mayday University Hospital, in Surrey, the
United Kingdom.

Scanned Less Quickly

The research team studied 379 patients referred to a neurovascular clinic. They
compared people over the age of 75 years with younger patients. Investigators
found older patients were more likely to be in atrial fibrillation (10.1% vs
22.8%; P = .001) and have lacunar stroke (34.7% vs 22.1%; P = .04).

They found computed tomography rates were similar in the 2 groups, but most
scans were performed more quickly in younger patients. Magnetic resonance
imaging (MRI) scan rates were higher in younger patients (26% vs 4%; P = .01) as
were carotid Doppler imaging rates (92% vs 77%; P = .01). Younger patients were
also more likely to be given advice on weight reduction (30.2% vs 12.9%; P =
.01) and diet (46.3% vs 31.7%; P = .02).

"Older patients have been shown to be receptive to lifestyle modification after
a stroke if given the appropriate advice," note the researchers. "This study
shows that, although access to specialist assessment was similar for patients of
all ages, there is still underinvestigation and poor secondary-prevention advice
delivered to older patients in a neurovascular clinic."

The authors suggest: "The results of this study possibly reflect negative views,
attitudes, and behavior of healthcare professionals toward older patients." They
note, "It is important to ensure that older patients receive the same treatment
as younger patients, especially as there is growing evidence that older patients
benefit from aggressive management of their TIA or minor stroke."

The researchers have disclosed no relevant financial relationships.

BMJ. Published online April 16, 2009. Abstract

Postgrad Med J. 2009;85:115-118.Abstract

[CLOSE WINDOW]
Authors and Disclosures
Journalist
Allison Gandey
Allison Gandey is a journalist for Medscape. She is the former science affairs
analyst for the Canadian Medical Association Journal. Allison, who has a master
of journalism specializing in science from Carleton University, has edited a
variety of medical association publications and has worked in radio and
television. She can be contacted at agandey@....
[ CLOSE WINDOW ]
Information
Authors and Disclosures
Allison Gandey
Allison Gandey is a journalist for Medscape. She is the former science affairs
analyst for the Canadian Medical Association Journal. Allison, who has a master
of journalism specializing in science from Carleton University, has edited a
variety of medical association publications and has worked in radio and
television. She can be contacted at agandey@....


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A new analysis from the Rotterdam Scan Study shows that cerebral microbleeds on
magnetic resonance imaging (MRI) are more prevalent in elderly subjects who use
platelet-aggregation inhibitors than in nonusers.

In particular, strictly lobar microbleeds ¡X which may indicate the presence of
cerebral amyloid angiopathy and possibly bleeding-prone microvessels ¡X were
more frequent among those who used aspirin vs users of carbasalate calcium, the
researchers report. The association between anticoagulant use and microbleeds
was not significant.

The researchers, with senior author Monique M. B. Breteler, MD, PhD, from
Erasmus MC University Medical Center, in Rotterdam, the Netherlands, caution
that the cross-sectional design of their study prevents determining whether
these microbleeds increase the risk for symptomatic hemorrhage and point out
that the benefits of antithrombotic therapy in patients with a history of
myocardial infarction and cerebrovascular disease have been shown to outweigh
the risks.

"Nevertheless, it may be that in selected persons (eg, those with signs of
cerebral amyloid angiopathy), this risk/benefit ratio may differ for certain
drugs (eg, aspirin), thus influencing treatment decisions," they conclude.

Their report, with first author Meike W. Vernooij, MD, also from Erasmus MC
University Medical Center, is published online April 13 and will appear in the
June issue of the Archives of Neurology.

New Markers of Small Vessel Disease

Cerebral microbleeds consist of deposits of hemosiderin in macrophages and can
be seen on T2-weighted gradient recalled echo (GRE) MRI as small areas of
hypointensity, the authors write. In the past decade, "these microbleeds have
become acknowledged as new markers of small vessel disease in the brain."

Microbleeds are thought to occur in the setting of either cerebral amyloid
angiopathy or arteriosclerotic microangiopathy, they note. Their location in the
brain is thought to reflect their underlying origin: microbleeds in the deep or
infratentorial locations, for example, are thought to relate to hypertensive or
arteriosclerotic microangiopathy, while those in the strictly lobar brain sites
result from cerebral amyloid angiopathy, a bleeding-prone state, they write.

Previous work has linked the use of platelet-aggregation inhibitors and
anticoagulants to increased risk for symptomatic hemorrhage in patients with
cerebral amyloid angiopathy, raising the question of whether asymptomatic
microbleeds might also be accelerated by use of these drugs.

"We hypothesized that microbleeds, especially those with strictly lobar
locations, occur more often in persons using antithrombotic drugs," they write.

To investigate this relationship, Dr. Breteler and colleagues used data from the
Rotterdam Scan Study, a large, population-based cross-sectional imaging study of
community-dwelling elderly in the Netherlands. A total of 1062 subjects who were
60 years of age or older and free of dementia underwent MRI imaging between
August 15, 2005 and November 22, 2006. Complete information on their use of
antithrombotic drugs was obtained from automated pharmacy records.

Of the 1062 subjects, 363 (34.2%) had used any antithrombotic agent. Of these,
245 (23.1%) took platelet-aggregation inhibitors, including 67 who used aspirin
and 141 taking carbasalate calcium.


Compared with nonusers, those taking platelet-aggregation inhibitors had a
significantly increased prevalence of cerebral microbleeds. The relationship
between microbleeds and anticoagulant use was not significant.

When they looked by type of antiplatelet medication, strictly lobar microbleeds
were more prevalent among users of aspirin than among those taking carbasalate
calcium.

The difference in risk for microbleeds was even more pronounced when they
compared those who were using similar doses of each drug, they note.

These findings justify further longitudinal research into this association, the
authors conclude. "Of particular clinical interest would be a study of whether
the presence of microbleeds increases the risk of symptomatic intracerebral
hemorrhage in persons using antithrombotic medication."

The Rotterdam Study is supported by the Erasmus MC University Medical Center and
Erasmus University Rotterdam; the Netherlands Organization for Scientific
Research; the Netherlands Organization for Health Research and Development; the
Research Institute for Diseases in the Elderly; the Ministry of Education,
Culture, and Science; the Ministry of Health, Welfare, and Sports; the European
Commission; and the Municipality of Rotterdam. The study was further supported
by grants from the Netherlands Organization for Scientific Research. The authors
report no conflict of interest.

Arch Neurol. Published online April 13, 2009. Abstract

Results of a randomized trial show no overall benefit from treatment with
acetaminophen (paracetamol) in improving outcomes after an acute stroke.

The researchers had hypothesized that lowering body temperature after stroke
using acetaminophen might limit damage and improve outcome, but in this trial at
least, there was no overall effect of treatment. "These results do not support
routine use of high-dose paracetamol in patients with acute stroke," the
researchers, with first author Heleen M. den Hertog, MD, from Erasmus Medical
Center, in Rotterdam, the Netherlands, conclude.

However, in patients who presented with a body temperature above the median of
37ºC, up to 39ºC, there was some signal of benefit, they note, "but this post
hoc finding needs further study."


Results of the Paracetamol (Acetaminophen) for Ischemic Stroke (PAIS) trial,
published online March 17, are in the May issue of the Lancet Neurology. They
were first presented last September at the 6th World Stroke Congress and
reported by Medscape Neurology & Neurosurgery at that time.

Reducing Temperature

Many patients with stroke have fever or subfebrile body temperatures, which have
been associated with case fatality and poor outcome, the authors write. For
every degree increase in body temperature, the odds of poor outcome are doubled,
they note.

The PAIS trial was a randomized, double-blind, controlled trial that included
1400 patients with ischemic stroke or intracerebral hemorrhage and a body
temperature between 36ºC and 39ºC, who were enrolled within 12 hours of symptom
onset. They were randomized to receive 6 g/day of acetaminophen or placebo.

The primary outcome was improvement beyond expectation on the modified Rankin
Scale (mRS) at 3 months, according to a sliding dichotomy approach.

The primary analysis showed that 37% (260/697) of patients improved beyond
expectation in the acetaminophen group vs 33% (232/703) in the placebo group, a
difference that was not statistically significant.

However, they did find a difference in treatment effect based on baseline body
temperature. For patients with an admission body temperature of 37°C and higher,
the odds ratio for improvement in functional outcome was 1.43.

There was no difference in secondary end points or in predefined subgroups; for
example, there was no evidence of benefit for any stroke subtype or time from
stroke onset.

Importantly, there was no increase in adverse events with acetaminophen
treatment, including the rate of infections or liver-enzyme disturbances. There
were 55 (8%) serious adverse events in the acetaminophen group vs 70 (10%) in
the placebo group. Fewer patients on acetaminophen died within 14 days of their
stroke, but no difference was found in case fatality at 3 months.

While their results do not support routine use of acetaminophen, Dr. den Hertog
and colleagues conclude, they call the post hoc finding "promising," although
they point out that it requires confirmation in an independent study. "If such
an effect can be confirmed, a simple, safe, and cheap treatment with a long time
window for start of therapy will be available for patients with acute ischemic
stroke or intracerebral hemorrhage," they write.

Efforts Better Focused on Other Treatments?

In a Reflection and Reaction commentary that accompanies the paper, Scott E
Kasner, MD, from the Comprehensive Stroke Center at the University of
Pennsylvania Medical Center, in Philadelphia, notes that this trial, which was
about 5 times larger than any previous trials of this intervention, showed no
overall benefit. However, the study, which originally was planned to enroll 2500
patients, was stopped at 1400 patients for insufficient financial resources, he
points out.

The statistical plan was changed prior to termination to measure improvement
beyond expectation using this sliding dichotomy approach, Dr. Kasner notes.
"This revised approach was a good choice to maximize power, but the results are
difficult to interpret as clinical reality," he writes. "Moreover, this outcome
probably overemphasizes very small differences between groups."

Dr. Kasner agrees that "the treatment is appealing, because it is easy to use,
inexpensive, and widely applicable." However, he points out that cost would be a
major obstacle to a trial to confirm this finding, since it would require
enrollment of between 10,000 and 20,000 patients.

"Our funds, resources, and efforts may be better focused on more promising
potential treatments of acute stroke," he writes. "In clinical practice,
existing data seem sufficient for us to comfortably conclude that paracetamol is
safe and will lower high temperatures in patients with acute stroke, and that is
exactly what we should use it for and what we should expect it to do."

The study was funded by the Netherlands Heart Foundation. The authors declare no
conflict of interest. Dr. Kasner reports no conflict of interest.

Lancet Neurol. 2009;8:434-440 Abstract, 415-416. Abstract

A year of treatment with valsartan (Diovan, Novartis) in patients initially in
sinus rhythm after at least one prior episode of atrial fibrillation (AF) failed
to suppress the arrhythmia in what's said to be the first large, randomized,
placebo-controlled test of a secondary-prevention strategy that had once seemed
promising based on less definitive studies [1].

The trial's patients were also required to have a coexisting cardiovascular
disorder or diabetes and be on a stable conventional drug regimen for their
heart disease for at least a month before enrollment.

Many, therefore, were also on varying combinations of ACE inhibitors,
amiodarone, other antiarrhythmics, beta blockers, calcium-channel blockers,
statins, and other agents.

The results of the trial, called Gruppo Italiano per lo Studio della
Sopravvivenza nell'Infarto Miocardico¡VAtrial Fibrillation (GISSI-AF), are
published in the April 16, 2009 issue of the New England Journal of Medicine.

GISSI-AF reliably suggests that "in patients with frequent episodes and a
long-standing history of atrial fibrillation, the addition of an
angiotensin-receptor blocker [ARB] to standard medical therapy is not useful for
preventing recurrence of the arrhythmia," the report's corresponding author, Dr
Aldo Pietro Maggioni (Associazione Nazionale Medici Cardiologi Ospedalieri
Research Center, Florence, Italy), said to heartwire.

Over one year, AF recurred in 51% of the 722 patients randomized to receive
valsartan at up to 320 mg/day and 52% of the 720 in the placebo group. More than
one AF episode developed in 27% and 28%, respectively. The differences in both
outcomes, co-primary end points of the trial, were solidly nonsignificant
whether adjusted or unadjusted.

Nor were significant valsartan effects seen in secondary end points that
included number of AF recurrences, ventricular rate at first AF recurrence, and
all-cause and CV hospitalization.

In prospectively defined subgroup analyses, Maggioni pointed out, valsartan was
ineffective against AF recurrence whether or not patients were also on ACE
inhibitors, beta blockers, or amiodarone.

The GISSI-AF results probably don't apply to patients with heart failure or LV
systolic dysfunction, who made up only about 8% of the trial's population, he
said.

Also, there's good evidence that ARBs might still be effective at preventing AF
in patients with risk factors for but no history of the arrhythmia. "It's
possible that this kind of drug may be useful in primary prevention," according
to Maggioni.

Most of the trial's patients were taking antiarrhythmics, and a full 88% had
undergone cardioversion for AF within two weeks of randomization, suggesting
that "the substrate for atrial fibrillation was well established in the study
population," observes Dr Anne M Gillis (University of Calgary and Calgary Health
Region, AB) in an accompanying editorial [2].

"Although some data suggest that ACE inhibition may promote the regression of
atrial fibrosis, one wonders whether ARB therapy could have modified the
substrate for atrial fibrillation over the course of the brief follow-up period
of only one year," Gillis writes. "This is a particularly important point, since
approximately half of the primary end points occurred within two months after
randomization. Thus, it may not be surprising that an ARB added no incremental
benefit for the prevention of atrial fibrillation."

Gillis agreed that GISSI-AF results "do not support the adjunctive use of
valsartan for the prevention of atrial fibrillation in patients with a history
of atrial fibrillation who also have hypertension, have required recent
cardioversion, and are receiving established therapies for the prevention of
atrial fibrillation."

There were 10 thromboembolic events in the valsartan group and only two among
controls (p=0.04), despite similar numbers of patients on oral anticoagulation.

"This is probably the play of chance," Maggioni said, given that there were few
such events and no prior studies had suggested there might be such a hazard from
ARBs. In fact, he observed, the number of thromboembolic events in the placebo
group was unusually low and in the valsartan group was consistent with other
studies.

According to the report, the GISSI studies are supported by Associazione
Nazionale Medici Cardiologi Ospedalieri, Florence, and by Istituto di Ricerche
Farmacologiche Mario Negri, Milan, Italy. Maggioni reports receiving research
support and lecture fees from Novartis. Other coauthors report receiving
"institutional research support" or lecture or consulting fees from Novartis.
Maggioni and coauthor Dr Roberto Latini (Istituto di Ricerche Farmacologiche
Mario Negri) "are listed as coinventors on a patent application for the
therapeutic use of valsartan in atrial fibrillation." Gillis reports receiving
consulting fees, lecture fees, and grant support from Medtronic and St Jude
Medical.


GISSI-AF Investigators. Valsartan for prevention of recurrent atrial
fibrillation. N Engl J Med 2009; 360:1606-1617.
Gillis AM. Angiotensin-receptor blockers for prevention of atrial
fibrillation--A matter of timing or target? N Engl J Med 2009; 360:1669-1671.

One of the first studies to examine eating patterns of multiple ethnic groups
has shown that nutritional advice--in this case accordance with the Dietary
Approaches to Stop Hypertension (DASH) diet for hypertension control--should be
customized for different racial/ethnic groups [1].

In their study, published in the April 13, 2009 issue of the Archives of
Internal Medicine, Dr Sue K Gao (Amgen, Thousand Oaks, CA) and colleagues used
baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA) to look
cross-sectionally at the diets of different minorities. "We found that despite
all the publicity surrounding the DASH diet, the accordance level was low; less
than one-third were accordant with this diet. Also, we found huge ethnic
variations and some key insights for the less explored ethnicities," she told
heartwire.

Gao, who is a MESA investigator, says it is vital that advice is tailored: "When
you are doing health-promotion campaigns, it's hard to instruct people
regardless of their background--you can't send a blanket message. You need to
pick up on one or two things that they can really improve upon."

Less Than a Third of Participants Met Any DASH Target

DASH consists of an eating plan low in total fat, saturated fat, and cholesterol
and rich in fruits, vegetables, and low-fat dairy products. The underlying
nutrient targets are reduced fat, saturated-fat, and cholesterol intake and
increased protein, fiber, calcium, magnesium, and potassium intake, which have
been shown to aid hypertension control, Gao and colleagues explain. Although
DASH has been shown to be effective among white and African American patients,
it has not been critically examined in other ethnic groups, they note.

The almost 6000 MESA participants examined for this study were self-identified
as white (n=2391), African American (n=1486), Hispanic (n=1318), or Chinese
American (n=777). The analysis used cross-sectional data on diet from the
baseline visit, which consisted of a 120-item food-frequency questionnaire,
which was specially modified to accommodate ethnic foods and therefore "should
be a better reflection of the real diets of ethnic minorities" than previous
work in this field, the researchers point out.

DASH accordance with intake of each nutrient by ethnicity and hypertension
status was analyzed. The term compliance or adherence was not used, said Gao,
"because we had no information on participant knowledge or attitude toward the
DASH diet" and were unable to determine whether eating behaviors had been
consciously modified.

They found that less than 30% of MESA participants met any DASH nutrient target.
DASH accordance was lowest in saturated-fat intake and highest in cholesterol
intake (5.3% and 29.5% of the participants, respectively). Multivariate analyses
showed significant ethnic differences in DASH accordance in all nutrients but
saturated fat.

Compared with white participants, Chinese Americans were more likely to meet
DASH goals in cholesterol (odds ratio [OR], 1.37) and protein intake (OR 2.32)
but less likely to meet total fat (OR 0.47), magnesium (OR 0.58), and potassium
targets (OR 0.40); African Americans and Hispanics had greater DASH accordance
in fiber intake (OR 1.36 and 2.23, respectively) but less in calcium intake (OR
0.44 and 0.79, respectively).

Gao said they also found, somewhat surprisingly, "that hypertensive people did
not behave differently, whether they knew they had hypertension or not."

Uniquely, the researchers also included intake from dietary supplements,
something Gao said is not often done. "If you don't include them, you're missing
something, because it is a matter of reality that people are taking these." They
found in particular that misclassification would be high among whites if data on
supplement intake were not included.

Findings Should Provide Insight to Customize DASH Messages

"Ours is one of the first studies to examine the nutrient-intake patterns of
multiple ethnicities using the DASH targets," Gao stressed to heartwire. "We
found that DASH accordance in general was quite low even after taking account of
intake from both whole-food and dietary supplements and varied significantly by
ethnicity. Findings from MESA may provide insights as to how to customize DASH
messages for different racial/ethnic groups.

"For the Chinese American group, the core message should be to promote the
intake of micronutrients and fiber or their whole-food equivalents of
fruits/vegetables and dairy products. For Hispanic and African Americans, the
core message should be to promote protein and calcium-rich foods such as
seafood, beans, peas, and lean meat and to consider the use of calcium-fortified
foods," she concluded.


Gao SK, Fitzpatrick AL, Psaty B, et al. Suboptimal nutritional intake for
hypertension control in 4 ethnic groups. Arch Intern Med 2009; 169: 702-707.
Abstract

Myocardial scintigraphy, a simple nuclear imaging test that evaluates the
integrity of the sympathetic nerves supplying the heart, can identify which
heart-failure patients are more likely to have a worse prognosis, according to
the results of the ADMIRE-HF trial.

Presenting the trial at the American College of Cardiology (ACC) 2009 Scientific
Sessions, Dr Arnold Jacobson (GE Healthcare) said, "It's been known for a long
time that the sympathetic nerves are damaged in heart failure, and this test
allows better discrimination of the level of risk, identifying in particular
those at very high risk, where additional protective therapy might be best used.
It also identifies well those at much lower risk who will do very well."

The test, which has the brand name AdreView, uses the radioactive tracer 123I
meta-iodobenzylguanidine (123I mIBG), which is a physiologic analog of
norepinephrine and is taken up into sympathetic nerves. Jacobson explained that
the sympathetic nervous system is less active in heart failure, and studies in
Japan and Europe have suggested that lower uptake of 123I mIBG is associated
with poorer outcomes. But these studies have generally been single center, with
no standardization of uptake analysis methodology and diagnostic criteria, and
end points were not always prospectively established. ADMIRE-HF was therefore
conducted to be a more definitive trial.

In the trial, 964 patients with class 2 and 3 heart failure were given 123I mIBG
by IV injection and underwent nuclear imaging. Quantification of cardiac uptake
of the tracer was expressed as the ratio of counts between the heart and the
upper mediastinum--the H/M ratio. Jacobson noted that normal healthy individuals
would have an H/M ratio of around 2 and that in the sickest heart failure this
would be reduced to about 1. For the purposes of this study, a cutoff value of
1.6 was used, with values higher than this denoting high uptake and values below
this denoting low uptake.

Patients were followed for a maximum of two years. Results showed that the
composite end point, the first occurrence of NYHA heart-failure class
progression, potentially life-threatening arrhythmic event, or cardiac death, as
determined by an independent adjudication panel, occurred significantly more
frequently in patients who had low uptake of the tracer.

Jacobson also reported that there were 51 cardiac deaths in the low-uptake group
and just two in the higher-uptake group, and the negative predictive value of a
high uptake for cardiac death over two years was 98.8%.

He added that the test was particularly effective in identifying those with the
worst prognosis, with the group who were in the lowest 10% for uptake having a
death rate 10 times those in the highest 20%.

He also showed data suggesting that this test had independent prognostic
capability complementary to other commonly used markers such as LVEF and B-type
natriuretic peptide (BNP) and that it might be able to discriminate between
patients who were likely to die from heart-failure progression and those who
would have an arrhythmic event. "Those with the lowest uptakes (H/M ratio <1.2)
tended to die more from heart-failure progression, whereas arrhythmic events
tended to occur in patients with H/M ratios in the 1.2-to-1.6 range," he said.

Jacobson concluded: "The use of the imaging test is consistent with the current
trend toward gaining better and earlier understanding of heart disease at a
molecular level in order to institute more effective prevention and management
strategies. We¡¦ve known about this testing method for years, but ADMIRE-HF is
the first large-scale multicenter prospective validation of its prognostic power
and provides data that clinicians may be able to use to improve current
practice."

Could It Be Used to Guide Defibrillator Use?

Chair of an ACC press conference at which this study was highlighted, Dr Aaron
Kugelmass (Heart and Vascular Center, Springfield, MA), asked whether this sort
of test might be able to help build up a picture of which heart-failure patients
would benefit most from a defibrillator. "We would like to figure this out in a
more finely tuned way than we do at the moment," he commented. Jacobson
suggested that that might be a possibility, pointing out that in the 20% of
patients with more normal cardiac uptake the cardiac death rate was very
low--less than 1% per year.

Diabetic patients with atrial fibrillation (AF) are at a significantly greater
risk of adverse clinical outcomes than those without AF, a new analysis has
shown [1]. Compared with those without the rhythm disorder, diabetic patients
with AF are more likely to die from all or cardiovascular causes, as well as
have more cerebrovascular events and heart failure, report researchers.

"These findings are of direct relevance for the routine clinical management of
diabetic patients and indicate that detection of AF in a patient with diabetes
should prompt more aggressive treatment of cardiovascular risk factors," write
lead author Dr Xin Du (University of Sydney, Australia) and colleagues in the
report, published online March 11, 2009 in the European Heart Journal.

The findings, from an analysis of the ADVANCE study, also showed that routine
blood-pressure lowering with a fixed combination of perindopril and indapamide
(Servier) yielded similar relative risk reductions but greater absolute risk
reductions in cardiovascular and all-cause mortality in patients with and
without atrial fibrillation.

The ADVANCE Study

Results from the ADVANCE trial, a factorial, randomized trial evaluating the
effects of blood-pressure lowering and intensive blood glucose control on
vascular outcomes, have been published previously and reported extensively by
heartwire. In the blood-pressure-lowering arm, the administration of perindopril
and indapamide to a broad range of patients with type 2 diabetes was associated
with reduced risks of major vascular events, including death.

In this analysis, the ADVANCE investigators sought to evaluate the extent to
which AF increases the already-elevated risk of cardiovascular disease in
patients with diabetes and how these patients responded to
blood-pressure¡Vlowering therapy. AF is commonly observed in patients with
diabetes, with prevalence rates at least twice those among individuals without
diabetes, according to the group.

Among the 11 140 patients with type 2 diabetes, 7.6% had AF at baseline. These
patients were older, had higher body-mass indexes, higher blood pressures, and
more cardiovascular risk factors. During a mean follow-up of 4.3 years, patients
with AF at baseline were at significantly greater risk of cardiovascular events
and all-cause mortality than those without AF at baseline.

Active treatment with the drug combination resulted in similar relative risk
reductions in all-cause death, cardiovascular death, and major coronary events
in patients with and without AF. However, because of the higher baseline risk,
the absolute benefits were larger in patients with AF.

"We estimate that five years of active treatment would prevent one death among
every 39 patients with AF and cardiovascular death among every 42 patients with
AF, compared with one among 84 and 120 patients without AF, respectively," write
Du and colleagues.

The presence of AF was associated with a greater increase in the relative risk
of cardiovascular death in women than in men, a difference that could not be
explained by differences in age, cardiovascular risk factors, or use of other
drugs, including hormone-replacement therapy. The findings, however, are in line
with other reports suggesting that women with AF are at a higher risk of stroke
and cardiovascular mortality than men, report investigators.

Overall, the results highlight the importance of actively evaluating diabetic
patients for the presence of AF, according to the group. "Routine administration
of blood-pressure¡Vlowering treatment, as well as greater use of antiplatelet
agents, statins, and oral anticoagulants, may be expected to reduce the
incidence of a broad range of adverse outcomes in these patients," they write.

ADVANCE was funded by grants from Servier and the National Health and Medical
Research Council of Australia.


Du X, Ninomiya T, de Galan B, et al. Risks of cardiovascular events and effects
of blood pressure lowering among patients with type 2 diabetes and atrial
fibrillation: results of the ADVANCE study. Eur Heart J 2009; DOI:
10.1093/eurheartj/ehp055. Available at: http://eurheartj.oxfordjournals.org.
Abstract

Adult patients with asthma who are receiving statin therapy for other
comorbidities have a 33% lower risk for hospitalization or emergency-department
visits than asthmatics not receiving lipid-lowering therapy, according to
findings presented here at the 2009 American Academy of Asthma, Allergy and
Immunology (AAAAI) Annual Meeting.

"These findings support the hypothesis that statins may improve clinical
outcomes in adults with asthma and provide additional support for prospective
investigation," said principal investigator Eric J. Stanek, PharmD, senior
director of Research, Personalized Medicine, at Medco Health Solutions, Inc., in
Franklin Lakes, New Jersey, during his presentation of his group's findings.

The findings come from a retrospective claims-based cohort study from the Medco
Health Solutions national integrated database, which contains information on
more than 12 million members.

Patients in the study were older than 18 years and had been given a prescription
for an inhaled corticosteroid at some point during 2006. Patients had either
made an emergency-department visit or had been hospitalized with asthma at least
once during that year.

Patients not receiving statins were significantly younger than those who were
(57¡Ó17 years vs. 67¡Ó11 years; P < .0001). Seventy-three percent of those not
receiving statins were women, compared with 65% of those who were (P < .0001).
The mean number of days exposed to statin therapy was 270.

Cardiovascular disease had been diagnosed in 5.5% of those not receiving
statins, compared with 16.5% of those who were (P < .0001). Diabetes had been
diagnosed in 8.9% of the group not receiving statins, compared with 19.5% of
those who were (P < .0001).

At 12 months, the hospitalization incidence was 17% among the nonstatin users,
compared with just under 15% for statin users, with an 18% lower incidence in
favor of the statin group. Trips to the emergency department were approximately
15% among nonusers and 8% among users, a 44% reduction in incidence.

For hospitalizations and emergency-department visits combined, the incidence was
nearly 30% without statins and 20% with statins, for an overall reduction in
incidence of 30%.

The adjusted odds ratio for the primary end point with statin use was 0.67 (95%
confidence interval, 0.58 ¡V 0.76; P < .0001), Dr. Stanek announced.

"Inflammation is a hallmark of asthma," Dr. Stanek said. "The potential impact
of statins may be large on a population basis for patients with asthma.

"Adherence to guideline-supported asthma care absolutely remains the therapeutic
mainstay," Dr. Stanek asserted, but he pointed out that "data indicate that
between 10% and 30% of adult asthma patients have cardiovascular or diabetes
comorbidities that may require statin therapy."

Clifford W. Bassett, MD, from the Allergy and Asthma Care of New York, in New
York City, and chair of public education for the AAAAI, agreed. "A 30% lower
incidence of hospitalization with statin use is a huge number. There is some
connection, but what that is specifically, we don't know. We don't know if an
anti-inflammatory effect of the statins is reducing risk of hospitalization for
asthma. It's too soon to say.

"It's important that we manage comorbidities," Dr. Bassett told Medscape Allergy
& Clinical Immunology. "These are patients with diabetes and cardiovascular
diseases. These chronic diseases appear to be intermingling . . . and while
statins are not indicated for asthma, the results are very intriguing. We need
to be looking for other diseases that may have an effect on asthma," he said.

"We need to strongly adhere to practice guidelines with statins . . . and with
asthma," Dr. Bassett said, "and the word is getting out on the guidelines."

Dr. Stanek's study was funded by Medco Health Solutions, Inc. Dr. Bassett has
disclosed no relevant financial relationships.

2009 American Academy of Asthma, Allergy and Immunology (AAAAI) Annual Meeting:
Abstract 238. Presented March 14, 2009.

Evidence is mounting that metabolic and neurological diseases share common risk
factors. According to several reports in the March issue of the Archives of
Neurology, metabolic disorders may influence the development of Alzheimer's
disease and other forms of dementia.

"Preventing heart disease, stroke, and diabetes ¡X or making sure these
conditions are well managed in patients diagnosed with them ¡X can potentially
slow the disease progression of Alzheimer's," Yaakov Stern, PhD, from the
Gertrude H. Sergievsky Center at Columbia University, in New York, said in a
news release.

Dr. Stern is senior author of a paper in the issue exploring the effect of
vascular risk factors on cognitive impairment.

In a review article in the same issue, Suzanne Craft, PhD, from the Veterans
Administration Puget Sound Health Care System, in Seattle, Washington, reports,
"In recent years, a rapidly increasing number of studies have focused on the
relationship between dementia and metabolic disorders such as diabetes, obesity,
hypertension, and dyslipidemia."


She points out that etiological heterogeneity and comorbidity pose challenges
for determining relationships among metabolic disorders. "The independent and
interactive effects of brain vascular injury and classic pathological agents
such as beta amyloid have also proved difficult to distinguish in human
patients, blurring the lines between Alzheimer disease and vascular dementia."

Few treatment options are available to improve prognosis. Dr. Stern and his team
question whether controlling vascular conditions may be 1 way of delaying
cognitive decline.

Control Vascular Risk Factors and Delay Alzheimer's?

The investigators hypothesized that vascular factors such as heart disease,
stroke, diabetes, hypertension, smoking, and blood lipid levels may predict the
progression of Alzheimer's disease.

Led by Elizabeth Helzner, PhD, also from Columbia University, the group studied
156 patients followed for a mean of 3.5 years. Participants were from the
Washington Heights and Inwood Columbia Aging Project, a multiethnic,
community-based, prospective study of aging in northern Manhattan.

Researchers found that patients with a history of diabetes and elevated levels
of cholesterol, especially LDL cholesterol, had faster cognitive decline. In
fact, each 10-U increase in cholesterol and LDL cholesterol was associated with
a 0.10-standard-deviation decrease in cognitive score per year of follow-up (P <
.001 for total cholesterol; P = .001 for LDL cholesterol).

Investigators found that a history of heart disease and stroke were associated
with cognitive decline only in carriers of the APOE e4 allele.

"These findings indicate that controlling vascular conditions may be 1 way to
delay the course of Alzheimer's, which would be a major development in the
treatment of this devastating disease," Dr. Stern said.

In another study published in the issue, investigators show that obese
middle-aged adults and underweight elderly people have an increased dementia
risk.

Fluctuations in Weight May Boost Dementia Risk

Using data from the Cardiovascular Health Study, researchers studied the
body-mass index (BMI) of participants at mid- and late life. Patients were from
a community-dwelling sample at 4 US sites.

Investigators included 2798 people. Of these, 480 had incident dementia, 245 had
Alzheimer's disease, and 213 had vascular dementia.

They found that middle-aged patients who were obese had an increased risk for
dementia (BMI >30 vs normal-weight BMI 20 to 25), adjusted for demographics
(hazard ratio, 1.39; 95% CI, 1.03 ¡V 1.87) and for cardiovascular risk factors
(hazard ratio, 1.36; 95% CI, 0.94 ¡V 1.95).

But the risk estimates were reversed in assessments of late-life BMI.
Underweight people, those with a BMI of less than 20, had an increased risk for
dementia (hazard ratio, 1.62; 95% CI, 1.02 ¡V 2.64). Surprisingly, being
overweight later in life was not associated with an increased risk (hazard
ratio, 0.92; 95% CI, 0.72 ¡V 1.18), and being obese reduced the risk for
dementia (hazard ratio, 0.63; 95% CI, 0.44 ¡V 0.91).

"These results help explain the 'obesity paradox,' " the researchers, led by
Annette Fitzpatrick, PhD, from the University of Washington, in Seattle, write.
"Differences in dementia risk across time are consistent with physical changes
in the trajectory toward disability."

These findings suggest that the predictive ability of BMI changes across time,
they note

"Weight loss occurs with comorbidities at older ages and is often reflective of
poor health," write Dr. Fitzpatrick and her team. "Weight loss, along with
psychological, behavioral, and mobility problems, is 1 of the principal
manifestations of Alzheimer's disease. Weight loss may predate dementia onset by
as much as 10 years."

The researchers conclude: "These results reinforce the necessity of monitoring
weight loss closely in older adults."

The researchers have disclosed no relevant financial relationships.

Arch Neurol. 2009;66:300-305 Abstract, 336-342 Abstract, 343-348. Abstract

Evidence for health benefits from eating more servings of oily fish is not
conclusive--especially for primary prevention of coronary events--and must be
balanced against projections that worldwide fish stocks will be depleted in 40
years if current consumption continues, a review concludes [1].

Study researchers, led by Dr David Jenkins (University of Toronto, ON), suggest
that until alternative sources of omega-3 fatty acids from plants, algae, or
yeast become more available, "it would seem responsible to refrain from
advocating to people in developed countries that they increase their intake of
long-chain omega-3 fatty acids through fish consumption."

On the other hand, the AHA still stands by its recommendation to consume two
servings of fish--preferably fatty fish--per week to reduce risk of
cardiovascular disease, Dr Penny M Kris-Etherton (University of Pennsylvania,
University Park), a member of the AHA Nutrition Committee, told heartwire when
asked to comment on the study.

The study is published in the March 17, 2009 issue of the Canadian Medical
Association Journal.

"If you are already leading a healthy lifestyle--if you are eating a
heart-healthy diet, exercising, and you have a healthy body weight--there is
certainly no evidence from randomized controlled trials to support a benefit"
from fish oil for primary prevention of CVD, study author Dr John L Sievenpiper
(University of Toronto) told heartwire.

Meta-analyses and individual trials are divided about the value of fish oils for
prevention of CAD, the authors write. The Prevenzione trial reported a 15%
benefit in a four-way analysis for a combined outcome of all-cause mortality,
nonfatal MI, or nonfatal stroke. However, the Diet and Angina Randomized Trial
(DART-2) showed that men with angina who were advised to consume fish oil had an
increased risk of cardiac death. Similarly, a meta-analysis of three major
studies of implantable defibrillators documented that some individuals
benefitted while others were adversely affected by taking fish oil.

Fish Stocks Threatened

In contrast to the uncertainty over the value of omega-3 fish oils in the
scientific literature, there is scientific consensus about the rapid worldwide
decline in fish stocks. Since 1950, the number of fish stocks that have
collapsed--shrunk to 10% of their historic maximum yield--has grown
exponentially, and there are now over 100 confirmed cases of marine-population
extinctions. If this trend continues, all commercially exploited stocks of fish
will likely be collapsed by 2048, said Sievenpiper.

"Yet the dire status of fisheries resources is largely unrecognized by the
public, who are both encouraged to eat more fish and are misled into believing
that we still sail in the sea of plenty," the authors write.

Developed countries are importing fish from the developing world, while in the
developing world, where people depend on fish for protein, population growth is
also increasing demand for fish, Dr Ussif Rashid Sumaila (University of British
Columbia Fisheries Centre, Vancouver) told heartwire. Large demand--for example,
for shrimp--is also a factor behind bycatch--when fish other than the targeted
species are just discarded--which can be destructive to the marine habitat, he
added.

Potential Solutions

Fish farming, as currently practiced in developed countries, is unlikely to
resolve the problem, the authors write, since the fish are raised on fishmeal
and fish oils from smaller fish. According to Sievenpiper, "the equation is
quite unfavorable, because it requires an input of more fish than you get out."

On the other hand, nonmarine-based sources of the two long-chain omega-3 fatty
acids in fish oil--docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA)--might be viable solutions. Martek Biosciences (Colombia, MD) produces DHA
from algae, which is added to foods, and other companies are exploring using
yeast to produce EPA, said Sievenpiper. In addition, the plant-derived
shorter-chain fatty acid alpha-linolenic acid (ALA) might be an alternative in
populations with low intake of omega-3 fatty acid.

"We should be increasing our efforts in exploring these alternatives," he said.

Significant Health Benefits

Kris-Etherton concurs that alternate sources of omega-3 fatty acids need to be
investigated. In the meantime, depletion of fish stocks is not a reason to stop
recommending eating more fish, she said, since current fish consumption is low.

Despite negative research results, most evidence clearly shows benefits of fish
oil in cardiac patients, she added. The negative DART-2 study has been
criticized for study limitations. On the other hand, the Prevenzione trial
documented benefits that included a 45% reduction in sudden death. The many
reported heart and brain benefits from omega-3 fatty-acid consumption include a
significant decrease in age-related memory loss and Alzheimer's disease.

"Americans on average eat about one serving of fish per week. If the
population--more than 300 million--were to increase this even a little bit, this
would have very significant health benefits," she said.

Sievenpiper and Sumaila disclosed having no conflicts of interest; disclosures
of the other authors are listed in the paper. Kris-Etherton disclosed having no
conflicts of interest.


Jenkins DJA, Sievenpiper JL, Pauly D, et al. Are dietary recommendations for the
use of fish oils sustainable? CMAJ 2009; 180:633-637.

Bioabsorbable stents have been billed as a "now-you see-it-now-you-don't"
solution to problems like stent thrombosis and delayed vessel healing: two-year
imaging results from the ABSORB study of Abbott's everolimus-eluting
bioabsorbable stent, using some of the most advanced intravascular-imaging
techniques, indicate that at least one-third of the stent has been absorbed by
the vessel wall [1]. Moreover, write Dr Patrick Serruys (Thoraxcenter,
Rotterdam, the Netherlands) and colleagues in the March 14, 2009 issue of the
Lancet, all signs point to normal healing of the vessel wall and restored
vasomotion; only one major adverse cardiac event (MACE) occurred over the
follow-up period.

Commenting on the two-year results for heartwire, study coinvestigator Dr John
Ormiston (Auckland City Hospital, New Zealand) pointed out that with the
disappearance of the stent comes some peace of mind for operators. "Most of the
struts had definitely gone by two years," he said. "On optical coherence
tomography [OCT], the position of some struts could be identified, but it is
uncertain if there is remaining strut material here or not."

In preclinical studies, he explained, the spaces previously occupied by struts
are filled with proteoglycan, and this can lead to a "strutlike appearance on
OCT," even when the strut is gone. "If there are remnants of struts, they are
covered by tissue and not exposed to the bloodstream," he said. "I am very
hopeful that the risk of late thrombosis--I do not say late stent thrombosis
because the stent is gone--will be very low, lower than after even bare-metal
stenting and possibly lower than after balloon angioplasty. The stent is almost
gone and vasomotion restored. There is no significant foreign body remaining and
none exposed to the bloodstream. The drug and polymer are gone."

As previously reported by heartwire, ABSORB was the first-ever human trial of a
fully bioabsorbable stent, tested originally in just 26 patients. Published
results at the six- and 12-month mark showed low rates of MACE and no stent
thrombosis. However, late loss and higher-than-expected restenosis
rates--believed due to "shrinkage" of the new stent--led to speculation that the
bioabsorption rate might be occurring too fast for the necessary radial strength
of the stent to keep restenosis at bay.

In their latest paper, the ABSORB investigators report 18-month results using CT
angiography, 24-month clinical results, and invasive-imaging findings
(intravascular ultrasound [IVUS] and OCT).

According to Serruys et al, no stent thromboses have occurred during the course
of two-year follow-up, and only one MACE, the non-Q-wave MI reported previously,
out of 30 patients. Multislice CT, conducted in 25 patients, pointed to diameter
stenosis of 19%, while two-year angiography suggested an in-stent late loss of
0.48 mm and diameter stenosis of 27%--similar to that reported at six months.
Somewhat discordantly, however, OCT and IVUS results, in seven and 18 patients,
respectively, pointed to luminal area enlargement, a finding that the authors
speculate was due to decreasing plaque size, with no change in the size of the
vessel, or possibly merely reflects the variability inherent in a study of such
a small number of patients.

"I put much more weight on the IVUS and OCT findings because they measure what
is happening over the entire stent lumen and not just at one point, as late loss
does," Ormiston said. He points out that other research has shown increased
lumen diameter after balloon angioplasty and after bare-metal stenting over
longer follow-up.

An exciting, though preliminary, finding was that stented segments appeared to
have functionally active endothelium on vasomotion testing. "This finding is a
seminal observation that clearly needs to be confirmed," the authors write.

From Promise to Reality?

In an editorial accompanying the study [2], Drs Antonio Colombo and Andrew Sharp
(both from San Raffaele Scientific Institute, Milan, Italy) write that the
promising findings suggest "that the theoretical aims of the bioabsorbable stent
are close to becoming a reality."

But they also point to the shortcomings of the study, among them the small
number of patients and the very simple nature of the lesions studied. They also
note that while the stent has been recently redesigned in the hopes of improving
its radial strength, it's not known yet whether these changes will reduce the
bioabsorbability of the stent.

"Despite these key limitations, these new data suggest that a major objective
has been achieved, and we should indeed be looking at a major step forward in
coronary stenting," Colombo and Sharp conclude.

Also commenting on the study for heartwire, Dr Renu Virmani (CVPath Institute,
Gaithersburg, MD) stated that "bioabsorbable stents may hold the future for
[drug-eluting stents] DES."

Since the dawn of the DES-era, Virmani has raised alarm bells over the signs of
delayed healing and hypersensitivity reactions she's seen in autopsy results and
animal studies--likely in response to either the drugs or the polymer on
metallic DES. Only in recent years has her theory linking these effects to stent
thrombosis gained traction among clinicians. Now, she cautiously acknowledges
that bioabsorbable stents may be the way forward.

"We have observed in animal models--both rabbit and swine--up to three years,
total resolution of the stent with an absence of inflammation," she told
heartwire. "Although the animal data together with the two-year outcome results
from the ABSORB trial by Serruys et al suggest a clinical benefit, the overall
safety of these devices requires further conformation in large future
event-driven clinical trials."

Ormiston and one other study author are members of the Abbott Vascular advisory
board and three study authors are Abbott Vascular employees. Virmani has
reserved research support from and consulted for Abbott Vascular.


Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting
coronary stent system (ABSORB): 2-year outcomes and results from multiple
imaging methods. Lancet 2009; 373:897¡V910.
Ormiston J, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting
coronary stent system for patients with single de-novo coronary artery lesions
(ABSORB): a prospective open-label trial. Lancet 2008; 371:899-907.
Colombo A, Sharp ASP. The bioabsorbable stent as a virtual prosthesis. Lancet
2009; 373:869-870.

A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough),
suggesting it may be able to reduce ischemic events without increasing bleeding
in patients undergoing elective PCI, has now been published in the March 14,
2009, issue of the Lancet [1].

The study was first presented, and reported by heartwire at the time, at the
American College of Cardiology (ACC) meeting in 2007, where it was greeted with
much excitement over the possibility of a drug that might be able to separate
the benefits of platelet inhibition (reduced ischemic events) from the risks
(increased bleeding).

Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that
the Lancet paper contains the same data that were presented at ACC 2007, along
with "quite a lot of additional information."

"For example, at the ACC presentation, we focused on the group of patients who
actually underwent PCI, which is the set of primary interest, but in the paper
we also report on the whole population of patients, including those who received
the bolus dose of the drug but who then did not end up undergoing PCI but were
managed medically (381 patients) or underwent CABG (76 patients) and so would
not have received maintenance doses." He described this as a real-world
population that would receive the drug. He added that in the patients managed
medically, the bolus dose of SCH 530348 was associated with a very low rate of
bleeding and no TIMI major bleeding.

SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to
which thrombin binds, so the drug inhibits thrombin-induced platelet activation.
Becker explained why this is thought to be able to separate the reduction in
ischemia from the increased bleeding risk seen with other antiplatelet agents.
"The theory is that hemostasis is predominantly platelet mediated, whereas
thrombosis in the coronary artery is mediated by both platelets and thrombin
generation. This drug appears to prevent the ischemic effect of thrombin
generation by preventing thrombin from binding to platelets, whereas it still
allows thrombin to cleave fibrinogen and form fibrin--the final step in
coagulation--and it still allows platelets to aggregate for normal hemostasis.
So we are attempting to uncouple the benefit/risk relationship seen with all
previous antithrombotic drugs."

Note of Caution--Too Early to Know for Sure

While there clearly is much enthusiasm over this new drug, some experts are
being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta
(McMaster University, Hamilton, ON) summed such feeling up: "There is no
question that the mechanism of action of the drug is novel and the initial
results are promising. But remember, this is just a phase 2 study, and we need
to wait for phase 3 trials before making definitive statements with regard to
efficacy or safety. Often, drugs may initially appear to be favorable but fail
to live up to expectations when studied in larger numbers of patients," he
commented to heartwire.

A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto,
ON). He commented to heartwire: "This agent does indeed look promising, and,
compared with several other 'antithrombin' therapies we have available at
present, its mechanism of action is novel. However, as with all drugs at this
stage (phase 2, dose finding), it is too early to tell whether its potential
will be realized, and the ongoing phase 3 studies will need to inform us further
about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not
powered to definitively address either of these, but it is encouraging that the
absolute number of major and minor bleeding events (albeit quite low in this
population that included patients undergoing non-urgent PCI) was not different
from that seen in the placebo group (including in the subset of patients went on
to bypass surgery). Since the non-TIMI bleeding rates were consistently
numerically higher (although not statistically significant) in the SCH 530348
groups compared with placebo, I suspect there will ultimately be some increased
risk of bleeding when you add another antithrombin therapy to standard therapy
(eg, aspirin with or without clopidogrel) in this patient population."

Neither Mehta nor Goodman is involved with trials of SCH 530348.

Platelet-Function Tests

Becker noted that the Lancet paper also reported detailed results on
platelet-function testing showing that SCH 530348 achieved 90% inhibition of
PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the
two higher maintenance doses. "We decided to go with the highest (2.5-mg)
maintenance dose for the phase 3 studies, because the safety results suggested
this was still not associated with an increase in bleeding, and we wanted to
make sure that the drug was not underdosed in high-risk patients. Our feeling
was that if we can induce 100% inhibition of the receptor, we should do it, so
this hypothesis can be tested properly."

Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS
patients, which is being coordinated at Duke and in which SCH 530348 is being
given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the
TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in
secondary prevention in patients with prior MI, stroke, or peripheral vascular
disease. These two studies are still recruiting, and results are not expected
for several years.

Becker explained that he envisages that SCH 530348 would need to be given in
addition to aspirin and clopidogrel in patients undergoing PCI and receiving a
new stent, especially for the first few weeks, but in secondary-prevention
patients aspirin plus SCH 530348 may be all that is needed, because there is
less propensity for thrombosis in these patients.

Possible Other Indications

He also pointed out that PAR-1 also occurs on smooth-muscle cells and
inflammatory cells, and it is possible that drugs that inhibit this receptor may
have other benefits, such as stabilizing plaques and reducing in-stent
restenosis. The phase 3 studies under way will include substudies to investigate
these effects--by looking at what the drug is doing to other cell types as well
as platelets. There are several other PAR-1 blockers in development, and they
are being investigated in other areas as well as cardiology. One of these is
oncology, because there is some evidence that PAR-1 may be involved in tumor
growth and metastases.

The current phase 2 study randomized 1030 patients undergoing coronary
angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20
mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group
who subsequently underwent PCI were randomly assigned again to one of three
maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients
assigned to a placebo loading dose remained on placebo during the maintenance
phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel,
and heparin or bivalirudin). The primary end point was the incidence of
clinically significant major or minor bleeding according to the TIMI scale.

Patients who underwent PCI were the primary evaluable cohort. In this group,
there was no significant difference in bleeding rates between any of the SCH
530348 doses and placebo. The authors say: "Although the bleeding rates were low
overall, we cannot exclude a small to moderate increase in bleeding with SCH
530348."

The trial was not powered to specifically test clinical efficacy, but results
showed a trend toward fewer ischemic events in SCH-530348¡Vtreated patients. The
authors add: "The biology around inhibition of thrombin-induced platelet
activation provides a mechanistic basis for differences that might be of
clinical relevance."

They conclude: "Our study provides preliminary evidence for the feasibility and
safety of thrombin-receptor inhibition among patients with coronary artery
disease undergoing PCI."

In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini
(Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current
study suggests that SCH 530348 is safe, a conclusion strengthened by its being
used with two other antiplatelet agents. They add: "This clinical report of a
new antithrombotic drug developed on the basis of new knowledge about the
coagulation cascade suggests that the drug works. Is the dream of an effective
antithrombotic drug with a low bleeding risk becoming reality? Will this
approach be effective in the acute setting (eg, primary percutaneous coronary
intervention) and even in secondary prevention? Phase 3 trials will determine
whether we are entering a new antithrombotic era."

Becker receives research funding from Schering-Plough. Other coauthors have
received honoraria, research funding, and consulting fees from Schering-Plough
or are employees of Schering-Plough. One author owns stock and stock options in
Schering-Plough.


Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH
530348 in patients undergoing non-urgent percutaneous coronary intervention: a
randomized, double-blind, placebo-controlled phase II study. Lancet 2009;
373:919¡V928.
Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009;
373:872-873.

A new analysis from the Familial Intracranial Aneurysm (FIA) Study suggests that
small unruptured aneurysms in patients with a family history are more likely to
rupture than similar-sized sporadic aneurysms.

"We have to factor in this increased risk of rupture when we're making decisions
about whether or not we want to coil or clip, even in patients who have small
aneurysms," Joseph P. Broderick, MD, from the University of Cincinnati
Neuroscience Institute at the University of Cincinnati College of Medicine, told
Medscape Neurology & Neurosurgery.

Their findings were presented at the American Stroke Association International
Stroke Conference (ISC) 2009 and published online simultaneously in Stroke.

Familial Risk

The management of unruptured aneurysms must balance the risk for rupture with
the risk associated with intervention, the authors write. A higher risk for
rupture has been associated with larger aneurysms, a history of a prior ruptured
aneurysm, and location of the aneurysm in posterior circulation. In addition,
some studies have suggested an increased risk in older patients, females, those
who smoke, and those with multiple aneurysms.

The aggregation of intracranial aneurysms (IAs) in families suggests genetic and
common environmental factors are at play, they note. "Whether rupture rate
independent of IA formation is higher in these families is an important
unanswered question."

The overall goal of the FIA Study, funded by the National Institute of
Neurological Disorders and Stroke, is to identify gene variants that may flag
susceptibility to the formation and rupture of aneurysms.

For this analysis, first-degree unaffected relatives of subjects with a family
history of IA and a history of smoking or hypertension but no known aneurysm
themselves were offered cerebral magnetic resonance angiography (MRA).

A total of 2874 subjects from 542 FIA study families were enrolled and MRA
performed in 548 family members who had a history of smoking or hypertension.

Of these, 113 subjects, or 20.6%, had 148 IAs on MRA. In 5, these aneurysms were
greater than or equal to 7 mm.

Two patients, 1 with an aneurysm of 3 mm and the other 4 mm, both in an anterior
communicating artery, subsequently had rupture of their aneurysm, for an annual
rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14%-4.3% per
year). Conversely, none of 435 subjects with a negative MRA had a ruptured
aneurysm.

This rupture rate of 1.2% per year is 17 times higher than the rate of 0.069%
seen in the International Study of Unruptured Intracranial Aneurysm (ISUIA)
among subjects with an unruptured aneurysm less than 6 mm in diameter and no
history of subarrachnoid hemorrhage due to an IA for a matched distribution of
aneurysm size and location, but without a family history.

Survival curves between the groups with and without an MRA positive for IA were
significantly different (P = .0004).

Special Risk Category

"So in essence, these patients are a special risk category," Dr. Broderick said.
Members of families where more than 1 person has already been found to have an
IA should probably undergo some type of brain imaging, particularly if they are
hypertensive or smoke.

"All those people who had rupture in our cohort had either current smoking or
hypertension as a risk factor," he added. "The point is that the risk may be
modifiable; at least some ruptures could have been prevented had the patients
stopped smoking and/or had their hypertension very carefully controlled."

Smoking in particular is a highly modifiable risk factor, with former smokers
having a much lower risk than current smokers. "The relationship between smoking
and brain aneurysm is as strong as smoking and lung cancer," Dr. Broderick said.
Compounding the risk conferred by a family history of aneurysm by smoking, he
adds, "is like putting a loaded gun to your head."

When an unruptured aneurysm is detected, physicians should carefully consider
the patient's family history of aneurysm and screen other family members, Dr.
Broderick said. "If an aneurysm is found, that would probably tilt you more
toward doing some type of intervention to isolate the aneurysm, to clip it or
coil it, than someone with no family history."

Genes for IAs Discovered

In a separate paper presented here at ISC 2009, researchers from Yale University
School of Medicine and the Yale Program on Neurogenetics, in New Haven,
Connecticut, reported 2 novel gene loci that are associated with the development
of IAs.

The genomewide association study, performed in German and Japanese populations,
including more than 10,000 cases (most were ruptured aneurysms) and controls,
turned up common single nucleotide polymorphisms (SNPs) on chromosomes 2 and 8,
as well as confirmed the association of another on chromosome 9, which has
previously been linked to myocardial infarction, diabetes, aging, and brain and
aortic aneurysms, as well as ischemic stroke. The regions on chromosomes 8 and 9
appear to be important in maintenance and repair of the vasculature, the
researchers note.

Subjects with all 3 risk alleles had a 3-fold increase in the risk for aneurysm
over those with none of the risk alleles. However, these SNPs account for less
than 4% of the genetic susceptibility, they note, suggesting other common
variants are likely to play a role in their development.

"This study for the first time provides an opportunity to preclinically identify
at-risk individuals, because the odds ratio of an individual forming an aneurysm
increases more than 3-fold if that individual has all the risk alleles," Murat
Gunel, MD, professor of neurosurgery and neurobiology at Yale, told attendees
here. Further studies in other populations are under way, he added.

The FIA study was funded by a grant from the National Institute of Neurological
Disorders and Stroke. The authors report no disclosures. The study by Gunel et
al was supported by the Yale Center for Human Genetics and Genomics, the Yale
Program on Neurogenetics, the National Institutes of Health, and the Howard
Hughes Medical Institute.

American Stroke Association International Stroke Conference 2009. Abstracts 121
and 141. Presented February 19, 2009.

Stroke. Published online February 19, 2009. Abstract

Vascular risk-factor burden is associated with a substantially increased risk
for poor memory performance in individuals with coronary artery disease (CAD).

New research presented here at the American Association of Geriatric Psychiatry
2009 Annual Meeting showed that individuals with 5 vascular risk factors had
almost a 7-fold increased risk of having borderline or impaired verbal memory
measured by the California Verbal Learning Test, 2nd ed (CVLT–II).

"There was a very strong relationship between the number of cardiovascular risk
factors in these individuals and their degree of cognitive impairment," lead
investigator Krista Lanctôt, PhD, from Sunnybrook Health Sciences Centre, in
Toronto, Ontario, told Medscape Psychiatry.

Marker of Hippocampal Volume

According to Dr. Lanctôt, a high proportion of CAD patients experience cognitive
impairment, including verbal learning deficits. In addition, observational
studies have shown a link between cognitive impairment and cardiovascular risk
factors including hypertension, diabetes, and dyslipidemia.

However, while CAD may increase the risk of developing mild cognitive impairment
(MCI) or Alzheimer's disease (AD), the nature of this link is unclear, said Dr.
Lanctôt.

To determine whether the cumulative burden of vascular risk factors is
predictive of verbal memory deficits, researchers conducted a cross-sectional
study of 100 patients with a diagnosis of CAD who were undergoing cardiac
rehabilitation at a single center.

The average age of the study cohort was 64 years, and 78% of participants were
men. Subjects had a 50% or greater blockage of at least 1 coronary artery or a
history of prior myocardial infarction or revascularization.

Participants underwent an evaluation of vascular risk factors, including
hypertension, dyslipidemia, diabetes, and obesity, as well as exercise stress
testing and verbal memory assessment.

The researchers chose to measure verbal memory because it is widely considered
to be a marker of hippocampal volume. Dr. Lanctôt pointed out that a recent
study in a cohort of individuals with dementia with Braak stage 4 scores (a
measure of pathological burden of plaques and tangles) showed that the main
difference between subjects with and without cognitive impairment was
hippocampal volume.

Intervention Opportunity?

The results of the current study revealed that each vascular risk factor was
roughly equivalent to remembering 1 word fewer and that at a level of 5 vascular
risk factors individuals had a much greater risk of having a borderline or
impaired CVLT-II score compared with their counterparts with 2 or fewer vascular
risk factors.

"We were surprised at how tight the correlation was between the number of risk
factors and the risk of memory impairment. The good news is that many of these
factors are modifiable, and this may offer us an opportunity to intervene at an
earlier stage with a view to reducing the risk of MCI and possibly Alzheimer's
disease," said Dr. Lanctôt.

Based on these findings, she added, the team is planning a large, multicenter
interventional study of about 400 patients that will examine the impact of
reducing vascular risk factors on subsequent memory loss.

The study was funded by the Drummond Foundation and the Physician's Services
Incorporated Foundation.

American Association for Geriatric Psychiatry 2009 Annual Meeting: Abstract NR
32. Presented March 6, 2009.

Minimally invasive endovascular repair of abdominal aortic aneurysm can be
safely performed with low reintervention rates, comparable to open surgical
repair, according to a large study presented here at the Society of
Interventional Radiology 34th Annual Scientific Meeting.

In the study, prospective data were collected on a group of 453 patients who
underwent endograft repair during an 8-year period (April 2000 through January
2008). The investigators analyzed the data for associated morbidity and the rate
of secondary interventions, and they looked at whether the need for
reintervention could be predicted by routine surveillance computed tomography
(CT). If the need existed, intense surveillance with CT was continued.

Goal Is to Prevent Rupture

If an aneurysm ruptures, there is severe pain, and the grim death rate is around
80%, and 59% to 83% will die before reaching the hospital, and for patients who
reach the hospital, postsurgery, 40% will die," coauthor and presenter Tarun
Sabharwal, MD, FSIR, FCIRSE, interventional radiologist at Guy's and St. Thomas'
Hospital in London, United Kingdom, said during a news conference. "The goal of
the interventional radiologist is to prevent aneurysms from rupturing."

Of the 453 patients in the group whose aneurysms were found on screening tests,
406 patients (89.8%) opted for elective repair; 17 (3.6%) presented as urgent
cases, and 30 (6.6%) showed up as true-rupture emergency cases. The
male-to-female ratio was 11:1, with a median age of 76 years (age range, 40 ¡V
93 years).

The overall 30-day mortality rate was 3.3% (15 of 453 patients) for the
minimally invasive procedure. The historic mortality rate for elective open
surgical repair of nonruptured abdominal aortic aneurysm is 5%, according to
researchers.

Overall, reintervention was needed in 7.2% (33 of 453 patients) and, of this
group, only 1.3% (6 of 453 patients) were detected during routine CT
surveillance.

Of the reinterventions needed, endoleaks that required reintervention were seen
in 13 (2.8%) of 453 patients (10 were type I and 3 were type III). Limb
occlusion that required an extra-anatomical bypass was performed in 15 (3.3%) of
453 patients, and amputations were necessary in 2 patients. Finally, graft
explantation after infection was performed in 2 patients.

Disproved Myths

"Endovascular repair has had a mixed reception because of the rate of secondary
reinterventions, complication rates, and the long-term surveillance required
with risk of radiation cancers, but we have disproved the myths about the
durability and effectiveness of minimally invasive endovascular aneurysm
repair," said Dr. Sabharwal.

"Our results in following patients over the last 8 years contradict reports of
high rates of secondary interventions coupled with the need for prolonged
CT-scan surveillance," he said. "Recovery time is measured in days to weeks, as
opposed to surgery patients who take several weeks to months to recover; some
patients [who undergo the minimally invasive procedure] are discharged the day
after treatment."

Dr. Sabharwal concluded that endoluminal repair of infrarenal aortic aneurysms
can be performed with low reintervention rates. "The lower rates are due to
newer-generation stent grafts and we have learned to modify technique," he said.

He added that the value of prolonged surveillance of frequent CT imaging with
accompanying radiation risks appears to be limited because few complications are
detected during routine CT surveillance. "We would advocate a revision of
current surveillance protocols," he said.

Session moderator Robert L. Vogelzang, MD, interventional radiologist and
professor of radiology at Northwestern Memorial Hospital and Northwestern
University Feinberg School of Medicine, in Chicago, Illinois, told Medscape
Radiology that "this study indicates to me some hugely important results that
are long term, and their work approach is for durability and permanence of their
surgical repair technique ¡X and that's a good thing. It's a big step forward."

The study did not receive commercial support. Dr. Sabharwal and Dr. Vogelzang
have disclosed no relevant financial relationships.

Society of Interventional Radiology (SIR) 34th Annual Scientific Meeting:
Abstract 211. Presented March 11, 2009.

A model derived from a trial treating psoriatic arthritis has proven predictive
of success in a broader psoriasis trial that did not measure arthritis. The
results were presented in a poster here at American Academy of Dermatology 67th
Annual Meeting.

About a quarter of psoriasis patients concurrently exhibit evidence of psoriatic
arthritis. The 2006 ADEPT trial established the utility of the tumor necrosis
factor-alpha monoclonal antibody adalimumab (Humira) in treating psoriatic
arthritis, but large trials are not equipped at every site to measure arthritis
response.

This study used data generated in ADEPT and plugged it into a model of the large
(814 patients) REVEAL trial for label indication of adalimumab for psoriasis. At
baseline, 28% of the REVEAL patient population had psoriatic arthritis, and the
model correctly predicted 86% of the concurrent responses to both comorbidities.

Lead author Philip Mease, MD, from Seattle Rheumatology Associates, in
Washington, explained that in the ADEPT trial, the key measure was "the
concurrent time that patients were having both a 75% or more reduction from
baseline in the Psoriasis Area and Severity Index score and a 20% or more
response for arthritis in American College of Rheumatology criteria.

Dr. Mease said that "39% of the time during the 16 weeks of the trial the
patients were experiencing a significant response in both their joints and
skin." Looking at week 16 alone, the drug provided benefit to both joints and
skin in 57% of the patients, compared with virtually none of the patients
receiving placebo.

"This serves as a reminder to dermatologists to be aware that at least a quarter
of their patients are experiencing arthritis," and that this drug has been shown
to be significantly effective at treating psoriasis and arthritis alone and as
comorbidities, Dr. Mease said.

When asked if measures to reduce obesity had an effect on the arthritic
response, Dr. Mease told Medscape Dermatology that there are no definitive data,
but the field is trying to get the answer through retrospective analysis of
existing data from arthritis trials.

"There are more data if you look at just the skin aspect ¡X obesity, metabolic
syndrome, hyperlipidemia, risk for cardiovascular disease" ¡X that reducing
other risk factors has a positive effect on both disease and response to
therapy.

He noted that the average weight of a psoriasis patient is 94 kg, the average
weight of a rheumatoid arthritis patient is about 74 kg, and a typical comorbid
patient weighs 86 kg. Increased weight is associated with fatty liver disease,
and there is concern that psoriasis drugs metabolized through the liver might
put additional strain on that organ. Adalimumab does not carry this risk.

"Rheumatoid arthritis patients die 7 to 10 years earlier than age- and
gender-matched individuals, predominately because of inflammation-induced
atherogenesis and premature heart attack and stroke. It is inflammation driven,
independent of weight." Psoriasis patients suffer from increased weight and
metabolic syndrome, so the comorbidities feed upon each other in a vicious
cycle, according to Dr. Mease.

The pendulum of clinical care is swinging back from a disease-specific focus to
greater acknowledgement and treatment of associated comorbidities, "which is a
key point that a lot of people don't think about," he said.

Dr. Mease's rheumatoid arthritis practice has a close working relationship with
a dermatologist, although patients are not seen by both physicians at the same
time. Dr. Mease said he has more time to spend with a patient than a
dermatologist typically does, he can inject medications into the joints, and he
has extensive occupational-therapy referrals to meet other patient needs.

However, "if the dermatologist feels comfortable and sophisticated enough to
manage the arthritis, by all means, he should do so," he said. It may make sense
for the dermatologist to become the "medical home" in managing the comorbid
conditions, if there is interest and reimbursement issues make it possible, Dr.
Mease added.

Mark Lebwohl, MD, from Mount Sinai Medical Center, in New York City, said models
can be helpful in gaining insight into the interrelationships of treating
psoriasis and arthritis, but he cautioned that randomized clinical trials should
be conducted to reach definitive conclusions.

He told Medscape Dermatology that it is appropriate for dermatologists to pass
on general-health guidelines to their patients and to suggest that those with
specific risk factors for comorbidities, such as arthritis and cardiovascular
disease, see a specialist. Dermatologists seldom order cholesterol and other
tests to monitor for comorbidities, although that may change as the interaction
of comorbidities becomes clearer, he said.

Abbott Laboratories supported the current study, the ADEPT study, and the REVEAL
study. Dr. Mease is a private practitioner who has participated in those trials.
Dr. Lebwohl has speaking and consulting contacts with several companies,
although none are relevant to this discussion.

American Academy of Dermatology (AAD) 67th Annual Meeting: Poster 3367.
Presented March 8, 2009.

In 2002 the National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (KDOQI) Work Group defined chronic kidney disease (CKD) as the
3-month presence of proteinuria or a persistently lowered glomerular filtration
rate (GFR) regardless of the underlying pathology. According to this definition,
almost 20 million adults in the United States have CKD, and yet another 20
million are considered at risk for developing CKD. Because of its growing
prevalence and its high socioeconomic burden, CKD has recently been termed the
'silent epidemic.' The course of CKD is marked by secondary complications such
as bone disease and anemia as well as a considerably increased risk for
cardiovascular disease and, in a minority of patients, the progression to
end-stage renal disease.

Age, background cardiovascular risk, and the etiology of kidney disease have all
been described as impacting the progression of the disease independent of
baseline CKD stage. A recent study by O'Hare et al. convincingly demonstrated
the flaws of a purely GFR-based approach to CKD patients by showing a tenfold
increase in the ratio of necessary to unnecessary vascular access surgery in
elderly patients.[1] A GFR-independent marker of disease progression would help
clinicians to tailor therapy and intervention and to base their decisions on the
individual patient's risk.

Dieplinger et al.[2] (this issue) describe the ability of pro-A-type natriuretic
peptide and pro-adrenomedullin to predict disease progression in patients with
nondiabetic kidney disease enrolled in the Mild to Moderate Kidney Disease
(MMKD) Study.

A-type natriuretic peptide (ANP) is a cardiac peptide with potent natriuretic,
vasodilator, and diuretic actions. ANP stems from the enzymatic cleavage of its
precursor proANP, which is significantly more stable than the active breakdown
product. The co-released, inactive N-terminal split product is subject to
further enzymatic fragmentation, leaving the midregional breakdown product
MR-proANP as a stable and readily measurable parameter of circulating ANP
levels. ANP is primarily secreted from the cardiac atria in response to volume
overload and myocyte stretch. Increased levels of ANP have been observed in
heart failure, left ventricular dysfunction, coronary artery disease, and renal
failure.

Adrenomedullin (ADM) is also a potent natriuretic and vasodilatory peptide. It
has a short half-life and is derived from the cleavage of a larger precursor
molecule, proADM. MR-proADM is stable at room temperature and can be measured by
a sandwich immunoassay. MR-proADM directly reflects circulating adrenomedullin
levels. Increased adrenomedullin levels have been observed in disorders
associated with hypervolemia, such as heart failure, myocardial infarction, and
ESRD under hemodialysis. Pathologically increased adrenomedullin levels were
recently shown to reflect the degree of underlying cardiac dysfunction.[3,4]
While adrenomedullin has been detected in multiple tissues, disease-induced
secretion appears to stem from biventricular cardiac dilation[5] and increased
vascular shear stress.[6]

During the 7-year follow-up period covered in the MMKD Study, the combined end
point of a doubling of serum creatinine or disease progression to ESRD requiring
renal replacement therapy was reached in 65 of 177 patients. In accordance with
previous studies, Dieplinger et al.[2] found patients reaching this end point to
be older and to display higher levels of proteinuria and lower GFR.
Additionally, the authors reported higher levels of MR-proANP and MR-proADM in
progressors. The predictive accuracy of these novel biomarkers was equal to the
predictive potential of baseline GFR values (AUCMR-proANP=0.810,
AUCMR-proADM=0.876, AUCGFR=0.838). Remarkably, MR-proANP and MR-proADM retained
high diagnostic accuracy even after the adjustment for the most common cofactors
for disease progression: age, sex, GFR, and proteinuria. These results suggest
that MR-proANP and MR-proADM, two reliable markers of cardiac dysfunction, could
help clinicians to estimate the pace of disease progression, even in patients
with equal GFR and proteinuria levels.

This study extends and corroborates similar findings from the same cohort for
NT-proBNP, a quantitative marker of cardiac stress that is released
predominantly by the cardiac ventricles. BNP and NT-proBNP are co-secreted and,
under non-stressed conditions, are found only in atrial granules. In response to
stress, however, BNP and NT-proBNP are synthesized, stored, and released mainly
from ventricular myocardium. The primary stimulus for BNP and NT-proBNP
formation seems to be end-diastolic wall stress.

One important limitation, which was appropriately acknowledged by the authors,
is the lack of detailed functional and structural cardiac assessment (for
example, echocardiography) and therefore the inability to elucidate whether
MR-proANP and MR-proADM were associated with CKD progression independently of
the presence of structural and/or functional cardiac disease or whether
clinically undetected cardiac disease at least to some extent triggered the
deterioration of renal function.

The interplay between the heart and the kidneys has received widespread
attention in recent years (Figure 1). Initially, the 'cardiorenal syndrome' has
generally been considered to be driven by a failing heart causing a secondary
deterioration of kidney function. In this setting, impaired kidney function has
convincingly been shown to be associated with a significantly reduced patient
survival. This simplistic and unidirectional view has recently been challenged
after accelerated cardiac atherosclerosis, left ventricular hypertrophy and
remodeling, and myocardial microangiopathy were observed in primary kidney
diseases.[7]

To accommodate these important kidney-heart interactions, a novel five-classed
definition of cardiorenal syndromes (CRS) has been proposed.[8] In this
classification, types 1 and 2 represent the acute and chronic forms of the
'classic' cardiorenal syndrome, in which decreased cardiac function induces a
progressive and potentially permanent decline in kidney function. Similarly,
types 3 and 4 represent the acute and chronic forms of the 'renocardiac'
syndrome, in which primary kidney disease induces acute (for example, heart
failure, arrhythmia) or chronic (for example, hypertrophy, coronary
atherosclerosis) cardiac disorders. An additional type 5 includes systemic
diseases such as sepsis, amyloidosis, and systemic lupus erythematosus that are
able to induce cardiac as well as renal dysfunction.

Hence, the ability of two markers of cardiac dysfunction to predict progression
of primary kidney disease, described by Dieplinger and his co-workers,[2]
highlights the prognostic importance of the chronic cardiorenal syndromes (CRS
types 2 and 4).

Unfortunately, this obvious pathophysiological link between CKD and cardiac
dysfunction is confronted by a significant underprescription of cardiovascular
disease-modifying pharmacotherapy in CKD patients. A recent, alarming study
investigating patients after acute myocardial infarction found less than 50% of
all CKD patients to be treated with a combination of aspirin, beta-blockers,
angiotensin-converting enzyme (ACE) inhibitors, and statins.[9] Only the
minority of CKD patients receiving standard combination drug therapy experienced
30-day survival similar to that of non-CKD patients. This lack of
guideline-conforming therapy is generally caused by concerns over increasing
creatinine levels and potential nephrotoxicity. However, a short-term, ACE
inhibitor-associated increase in serum creatinine was found to reflect
successful nephroprotection in patients with renal insufficiency by a large
metaanalysis.[10]

While research activities in the cardiorenal syndromes are only beginning to
grow and consensus definitions are only being discussed, clinicians may
presently not be able to stop the vicious cycle of declining renal and cardiac
function but can nevertheless significantly slow down its progression. Treating
the shared risk factors by adequately lowering blood pressure and sufficiently
blocking the renin-angiotensin system as well as by controlling diabetes
mellitus, treating dyslipidemia, and advocating smoking cessation remains of
pivotal importance. We as clinicians need to consider and attempt to use these
powerful tools in all our CRS patients.