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#12920 From: dr_allen_wang
Date: Sat Sep 29, 2007 10:58 pm
Subject: Glitazones Increase Heart Failure but Not Mortality in New Meta-Analysis
dr_allen_wang
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A new meta-analysis of studies with the diabetes drugs rosiglitazone
(Avandia, GlaxoSmithKline) and pioglitazone (Actos, Takeda
Pharmaceuticals North America) has shown an increased risk of heart
failure but no increase in cardiovascular death with these drugs
[1]. The authors conclude that heart failure associated with the
glitazones might not carry the same risk as heart failure caused by
progressive systolic or diastolic dysfunction of the left ventricle.
But they acknowledge that longer follow-up and better
characterization of such patients is needed to determine the effect
of these drugs on overall cardiovascular outcome.

The meta-analysis is accompanied by two comments [2,3] and an
editorial [4]. Both comments contend that there is very little
evidence of any real benefits with the glitazones and because of
this they should have no major role regardless of any safety
concerns.

Does the fluid retention affect mortality?

The current study, published in the September 29, 2007 issue of the
Lancet, was conducted by Drs Rodrigo Lago, Premranjan Singh, and
Richard Nesto (Lahey Clinic Medical Center, Burlington, MA). They
note that the glitazones, also known as thiazolidinediones (TZDs),
are well known to cause fluid retention and therefore could
potentially lead to development of congestive heart failure (CHF).
But they point out that it is not known whether the heart failure
caused by TZD-related fluid retention might ultimately affect
survival. They therefore conducted a meta-analysis of pooled data
from seven randomized trials of TZDs in subjects with prediabetes or
type 2 diabetes to assess the risk of development of heart failure
and death from cardiovascular causes.

Of the 20 191 patients included in the meta-analysis, 360 had CHF
events (214 with TZDs and 146 with comparators). Compared with
controls, patients given TZDs had increased risk for development of
CHF across a wide background of cardiac risk. Results showed no
heterogeneity of effects across studies, which indicated a class
effect for TZDs. In contrast, the risk of cardiovascular death was
not increased with either of the two TZDs.

The authors note that longer follow-up and better characterization
of patients in whom CHF develops because of fluid retention is
needed to determine the effect of TZDs on overall cardiovascular
outcome and whether CHF should be regarded as an adverse event or a
characteristic cardiovascular end point.

They conclude: "Despite the glucose-lowering effect of TZDs, our
data indicate that these drugs should not be used in patients with
heart failure and should be cautiously used for glycemic control in
patients with cardiovascular disease who do not have heart failure.
In patients with type 2 diabetes without cardiovascular disease in
whom the absolute risk for congestive heart failure is much lower,
the use of TZDs should be weighed against the risks and benefits of
other antidiabetic medications."

Nissen not impressed

Commenting on this study for heartwire, Dr Steven Nissen (Cleveland
Clinic, OH) who conducted the previous meta-analysis suggesting harm
with rosiglitazone [5], said, "The authors did not examine the risk
of cardiac death in patients who developed CHF while taking a TZD
drug. Instead, they looked at overall cardiovascular mortality. This
finding neither confirms nor refutes the hypothesis that TZDs lead
to major complications of heart failure, including death."

Kaul: "Reassuring but not definitive"

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) said
the new data were reassuring in the sense that despite the increase
in CHF, there was no increase in cardiovascular death. But he added
that only randomized trials that are specifically designed to
prospectively assess cardiovascular efficacy and safety would
provide definitive answers.

Kaul pointed out that the lack of an increase in cardiovascular
death with rosiglitazone in the current analysis is consistent with
the results of the Singh et al meta-analysis published recently in
the Journal of the American Medical Association [6], but
inconsistent with Nissen's meta-analysis suggesting increased risk.
He says these discordant results are perhaps best explained by the
fact that the Nissen and Wolski meta-analysis included several small
studies where zero events in the control group outnumbered zero
events in the treatment group, without applying appropriate
corrections, which could overestimate risk.

On whether there are meaningful differences between pioglitazone and
rosiglitazone, Kaul says that both drugs increase fluid retention,
but they have some minor differences with respect to changes in
lipid profile. However, lack of a difference in cardiovascular
mortality among the TZDs brings into question the clinical relevance
of these differences in cardiometabolic profile.

Confidence intervals wide

In the first comment article, Drs John Cleland (University of Hull,
UK) and Stephen Atkin (Hull York Medical School, UK) note that while
neither rosiglitazone nor pioglitazone was associated with increased
cardiovascular mortality in the current meta-analysis, the
confidence intervals cannot exclude a 25% increase. They add that
the current meta-analysis included far fewer trials than Nissen's,
and it is not certain which set of trial selection criteria was
least prone to bias. They point out that TZDs can cause fluid
retention that might result in peripheral and pulmonary edema but
there is little evidence that such drugs affect cardiac function
adversely and that patients with edema caused by TZDs do not seem to
have an unfavorable prognosis.

To heartwire, Cleland commented: This meta-analysis is reassuring in
one way--it suggests that the heart failure these drugs produce does
not appear to be life threatening. It should not really be called
heart failure. It is actually fluid retention that produces symptoms
similar to heart failure and is not the same as actually having
damage to heart muscle."

Effectiveness should be the key issue

But in their article, Cleland and Atkin stress that "all the meta-
analyses consistently fail to spot the elephant in the room"--that
treatments should be effective rather than merely innocuous.

Cleland told heartwire: "The glitazones, like many other diabetes
drugs, have been licensed only on the basis that they reduce blood
sugar. They have no evidence of hard clinical benefits, and just
because a drug reduces blood sugar does not mean to say it will have
any real benefits." He drew an analogy to HDL and torcetrapib. "We
know high HDL is linked to a beneficial protective effect.
Torcetrapib raised HDL but actually resulted in a worse outcome. So
raising HDL does not necessary reduce event rates. The same with
blood sugar. We have evidence to suggest that high blood sugar is
linked to worse outcomes, but we don't know that lowering blood
sugar will necessarily improve event rates."

He continued: "We have to think why we treat patients with diabetes.
It is not to lower a number for blood sugar in a test tube. It is to
reduce end-organ complications. The authors of this meta-analysis
are suggesting that a treatment that lowers blood sugar and does not
increase cardiovascular event rates is useful. But I fail to see
why. I believe we should have a moratorium on these drugs until they
have some evidence of a positive impact on end-organ function."

Is longer patent protection the answer?

Cleland suggests that companies need better incentives to do the
right studies to show real effectiveness of drugs, and that means
longer patent protection. "Under the current system, companies are
not going to do a five- or 10-year study to prove effectiveness, as
by the time the drug would be approved, the patent would be up. If
drugs had 50 years of patent protection, then these studies would
get done. It would also mean that companies would not have to charge
such high prices, as they would have much longer in which to recoup
their investment," he commented to heartwire.

In the second comment piece, Drs Victor Montori, Gunjan Gandhi (Mayo
Clinic, Rochester, MN) and Gordon Guyatt (McMaster University,
Hamilton, ON) make similar points about the inadequacy of blood
sugar levels as a trial end point. "Surrogate outcomes allow
smaller, shorter, and cheaper trials; provide a faster offering of
more choices to patients and clinicians; save research money; and
allow new drugs more rapid access to market. The apparent benefits
are, however, a mirage, and the apparent savings represent false
economy. Any savings are quickly overwhelmed by costs associated
with potentially ineffective or even harmful (yet heavily
advertised) expensive therapies and the incremental costs of
treating the harms these interventions might cause. Patients and
society may end up paying dearly for drugs that cause more harm than
good," they write.

On the specific findings of this meta-analysis, Montori commented to
heartwire: "These drugs give you heart failure and osteoporosis, and
we don't know of any real benefits that they have, but these authors
are asking that we should be reassured because they don't kill you.
I don't think that is a good attitude."

Montori added: "We are not avid users of TZDs at the Mayo Clinic. I
would certainly not use them to prevent diabetes, and they have many
unattractive features in the treatment of diabetes. We are always
telling our patients of the importance of losing weight, but these
drugs make them put on weight. Patients don't like that."

He also pointed out that the discussion about whether the heart
failure they induce is benign or malignant is not the point. "We
shouldn't be using drugs that cause CHF at all. Even if it is
benign, which I do not believe has been proven by this study, why
should we give a drug that causes benign CHF when we don't know if
it has any benefits? If they have truly major benefits like a
reduction in dialysis, stroke, MI, or blindness, benign CHF may be
an acceptable cost. But if we don't know the benefits, any risk is
not worthwhile."

The editorial, by the Lancet, stresses the importance of further
studies to assess safety of these drugs and says that regulatory
agencies "must hold manufacturers' feet to the fire to ensure that
these are performed, performed properly, thoroughly evaluated, and
made available to guide decisions about prescribing." It
adds: "Unless limitations on the understanding, analysis, and
communication of drug safety issues are addressed, the
thiazolidinediones might simply become the latest in a series of
preventable drug disasters."

Nesto is involved in research funded by GlaxoSmithKline and Takeda.
Lago and Singh declare no conflicts of interest, as do Kaul,
Montori, Gandhi, and Guyatt. Cleland has received funding for
research into heart failure and carvedilol from GlaxoSmithKline; has
received speaker's honoraria and funding from Takeda for research on
candesartan; was part of a GlaxoSmithKline advisory board on
rosiglitazone-induced fluid retention; and has worked on a safety
committee reviewing adverse events with rosiglitazone. Atkin has
received speaker's honoraria and sponsorship to attend meetings from
GlaxoSmithKline and Takeda.

Lago RM, Singh PP, and Nesto RW. Congestive heart failure and
cardiovascular death in patients with prediabetes and type 2
diabetes given thiazolidinediones: a meta-analysis of randomised
clinical trials. Lancet 2007; 370: 1129”V1136.
Cleland JGF and Atkin SL. Thiazolidinediones, deadly sins,
surrogates, and elephants. Lancet 2007; 370: 1103-1104.
Montori VM, Gandhi GY, and Guyatt GH. Patient-important outcomes in
diabetes--time for consensus. Lancet 2007; 370: 1104-1106.
Ensuring drug safety: lessons from the thiazolidinediones. Lancet
2007; 370: 1101.
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes. N Engl J
Med 2007; 356:2457-2471. Abstract
Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular
events with rosiglitazone: a meta-analysis. JAMA 2007; 298:1189-
1195. Abstract

#12915 From: dr_allen_wang
Date: Fri Sep 28, 2007 11:25 pm
Subject: Serial Natriuretic Peptide Testing Can Predict Anthracycline Cardiotoxicity Risk
dr_allen_wang
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Measurement of brain-type natriuretic peptide (BNP) levels in cancer
patients receiving anthracyclines can predict the treatment's risk
of cardiotoxicity more reliably than troponin levels or
echocardiographic assessment of LV function, according to a small
prospective study [1].

For example, a BNP reading >100 pg/mL on two occasions signaled an
18-fold increase in risk of heart failure, arrhythmias, or other
cardiovascular complications. The risk was much steeper if levels
exceeded >200 pg/mL only once.

Even though oncologists well know to watch for the cardiotoxic
effects of doxorubicin and other anthracyclines, "there's a range of
how vigilant they might be," Dr Daniel J Lenihan (MD Anderson Cancer
Center, Houston, TX), a cardiologist, told heartwire. "Some might
look for them aggressively and others may not. The good thing about
this is that it's a point-of-care test, so even in a small oncology
practice, they can easily check a blood sample in their office while
they're waiting to get the IV in. You can get the results in 15
minutes."

Serial BNP testing probably isn't enough on its own to indicate
withdrawal of the drugs but can help identify patients who should be
watched more carefully for cardiac side effects, according to
Lenihan, who presented the study here at the Heart Failure Society
of America 2007 Scientific Meeting.

A lot of its 109 patients, under treatment for various malignancies,
also had cardiovascular risk factors, which may help promote
anthracycline cardiotoxicity, Lenihan and his colleagues speculate.
A tenth of the patients had documented CAD, a third had
hyperlipidemia, 50% had hypertension, 35% were obese, and 12% had
diabetes. Patients with unstable angina, a recent history of MI or
acute heart failure, or an LVEF <40% were excluded.

Biomarkers were normal at baseline in virtually everyone;
echocardiography was performed at baseline and at 18 and 24 weeks.

The patients received up to six courses of chemotherapy, each three
weeks apart and preceded and followed by measurements of BNP and
troponin I; 71 patients completed all six courses.

Eleven patients experienced cardiac events over a median of six
months; the events included symptomatic heart failure in five,
symptomatic arrhythmias in four, and ACS in two patients. All 11 had
BNP levels >150 pg/mL on at least one occasion.

Troponin levels remained normal in all but two patients, both of
whom were among those experiencing cardiac events.

In multivariate analysis, significant predictors of cardiac events
included BNP levels >100 pg/mL, >150 pg/mL, and >200 pg/mL (p<0.0001
for each) prior to any such event. History of MI also emerged as a
significant predictor (p=0.05), but it's hard to make anything of
it, since it was present in only four patients, Lenihan said.

Most studies in oncology assess cardiotoxicity according to
echocardiographic changes in LV function, he said; but a decline in
LVEF considered indicative of cardiotoxicity was not a significant
predictor of events in this study (p=0.376).

Whether elevated BNP levels by themselves are enough to justify
stopping anthracycline chemotherapy remains an open question,
according to Lenihan. They can help, he said, but it would depend on
the patient's entire clinical picture. "I think it's a marker of
risk. It doesn't necessarily mean you have to stop therapy, but it
definitely identifies a group you should be more worried about."

Lenihan reports being a consultant for St Jude Medical and receiving
honoraria from Novartis.

Lenihan DJ, Massey MR, Baysinger KB, et al. Superior detection of
cardiotoxicity during chemotherapy using biomarkers. J Cardiac
Failure 2007; 13(Supple 2):S151. Heart Failure Society of America
2006 Scientific Meeting; September 17, 2007; Washington, DC.
Abstract 265.

#12892 From: dr_allen_wang
Date: Tue Sep 25, 2007 2:55 am
Subject: CV Events Linked to Poor Glycemic Control
dr_allen_wang
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Poor glycemic control in diabetics is linked to an increased risk of
cardiovascular events, a large retrospective study suggests.
Examining data from almost 70 000 diabetics enrolled in the
Integrated Health Care Information System database (IHCIS),
researchers from Yale report that rates of first acute MI and CABG,
but not stroke, over more than two years of follow-up were higher for
subjects with higher HbA1C levels at baseline.

Dr Joseph Thomas (Yale University, New Haven, CT) reported the
results of the analysis here at the European Association for the
Study of Diabetes 2007 Meeting. While poor glycemic control has well-
established ties to microvascular and macrovascular disease, the link
with hard cardiovascular events is less clear, with much of the
current debate on the cardiovascular safety of diabetes drugs--
thiazolidinediones in particular--circling around the fact they were
approved on the grounds that they successfully improved glucose
control and not because of their effects on cardiovascular outcomes.

Now, with the caveat that the study was retrospective and included
relatively healthy, younger individuals, Thomas said that it
nevertheless provides insights into the importance of controlling
glucose.

"An elevated index A1C is a significant risk factor for AMI and CABG,
with poorer survival," he said. "Glycemic control is associated with
real-world, long-term macrovascular outcomes, and early intervention
with intensive diabetes treatment may reduce macrovascular events."

Thomas and colleagues stratified patients across quartiles of index
HbA1C level, using the cut points of <6%, 6% to 7%, 7% to 9%, and
>9%. Over a mean of more than two years of follow-up, unadjusted
incidence rates were highest in the 7%-9% HbA1C group, seeming to
level off above 7%. Of note, subjects in the highest HbA1C group also
had the most other risk factors for CVD and were more likely to be
taking cardiovascular medications and insulin.

After adjustment for comorbidities and diabetes, lipid-lowering, and
antihypertensive drugs, the link between high HbA1C levels and
cardiovascular risk was even stronger. Compared with the <6% group,
the hazard risk for the combined end point of AMI, CABG, and stroke
was 8% higher in the 7%-9% HbA1C group and 15% higher in the >9%
HbA1C group.

Kaplan-Meier survival curves looking at time to death/AMI pointed to
significantly worse survival for subjects in the 7%-9% HbA1C group,
with a hazard ratio of 1.33, and for subjects in the highest HbA1C
category, with a hazard ratio of 1.57, as compared with subjects in
the lowest HbA1C group. Similarly, for the end point of death/CABG,
hazard ratios were also increased in these groups, at 1.38 and 1.56,
respectively.

No differences between HbA1C groups were seen for the stroke end
point, a finding that Thomas acknowledged was not in keeping with the
other findings. During the discussion, however, moderator Dr Diethelm
Tschöpe (Ruhr-Universitat Bochum, Bad Oeynhausen, Germany) pointed
out that "the truth may be very different," since researchers may not
have been able to glean accurate information on stroke from the IHCIS
database.

Thomas agreed, adding that the analysis had not been able to take
into account transient ischemic attacks (TIAs). "We were not at times
clear as to whether TIAs should be considered as strokes, but
additional analyses, if we had included TIAs, would perhaps have
changed the data."

A number of ongoing trials are addressing the question of whether
lowering HbA1C levels with insulin therapy can improve CV outcomes,
among them the ORIGIN, ACCORD, and the VADT trials, Thomas noted.

#12891 From: dr_allen_wang
Date: Tue Sep 25, 2007 2:52 am
Subject: Depressed Patients Have Impaired Heart Rate Variability Recovery After ACS
dr_allen_wang
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Recovery from the drop in heart rate variability during acute
coronary syndromes (ACS) is impaired in depressed patients, a new
study suggests.

The study, using data from the Sertraline Antidepressant Heart Attack
Randomized Trial (SADHART), is published in the September issue of
the Archives of General Psychiatry.

Results also showed that at 4 months after hospitalization for ACS,
depressed patients who were treated with the selective serotonin
reuptake inhibitor sertraline (Zoloft, Pfizer) or whose mood lifted
had increased heart rate variability compared with patients treated
with placebo or patients without improved mood ”X but this was mainly
due to decreased heart rate variability in the comparison groups.

"These are new observations, that heart rate variability ”X which is
a known predictor of death and which usually recovers after a heart
attack ”X doesn”¦t recover in depressed people, and that taking
antidepressants and getting better improves it a little bit," lead
author Alexander H. Glassman, MD, from Columbia University College of
Physicians and Surgeons in New York, told Medscape Psychiatry.

"It is kind of a double jeopardy," he added. "Not only do depressed
people have lower heart rate variability to start with, but after a
heart attack, it doesn”¦t recover the way that it should."

Double Jeopardy

Previous studies have shown that low heart rate variability ”X beat-
to-beat changes in heart rate ”X predicts death after a myocardial
infarction (MI), the authors write, and heart rate variability is
reduced more in depressed than nondepressed patients after MI. Two
previous studies reported heart rate variability recoveries of 28%
and 33% at 16 weeks after MI among nondepressed patients.

This study aimed to examine, among depressed patients, the influence
of both sertraline and mood improvement on recovery of heart rate
variability after ACS.

The researchers analyzed data from 290 patients who participated in
SADHART, which recruited patients with depression who were
hospitalized for ACS and randomized them to sertraline (69 mg/day) or
placebo. Trial enrollment began in 1997, and follow-up assessments
were completed in 2001. Heart rate variability values were obtained
from 24-hour Holter electrocardiograms, which were taken at baseline
(on average, 3 weeks after hospitalization for ACS) in 290 patients
and repeated at 16 weeks post-ACS in 258 patients. Depression
severity was measured by the Hamilton Rating Scale for Depression,
and clinical response was measured with the Clinical Global
Impressions Improvement scale.

At 16 weeks, compared with baseline, the patients who took sertraline
had a 9% increase in heart rate variability, but patients who took
placebo had a 10% decrease in heart rate variability. Patients who
had decreased symptoms of depression had increased heart rate
variability compared with patients whose depression did not improve.

"Carefully Watched, Aggressively Treated"

"From a clinician's point of view, patients with depression after
myocardial infarction, especially those with prior episodes, should
be both carefully watched and aggressively treated, because they are
at an elevated cardiac risk and less likely to get better
spontaneously," the authors conclude.

The mechanisms connecting heart rate variability, depression, and
cardiac death remain to be elucidated, they add. "What is clear is
that depression is associated with biological changes involving
increased heart rate, inflammatory response, plasma norepinephrine,
platelet reactivity, decreased heart rate variability, and now absent
post-ACS heart rate variability recovery, all of which are associated
with life-threatening consequences. Understanding why these
characteristics so strongly associate with depression is crucial to
understanding the nature of depression itself."

Dr. Glassman said the group is performing follow-up research to
investigate outcomes in these high-risk patients.

The study was supported by a NARSAD Distinguished Investigator Award,
the Suzanne C. Murphy Foundation, the Thomas and Caroline Royster
Research Fund, and Pfizer. Dr. Glassman has received honoraria from
Pfizer, Forest Laboratories, and GlaxoSmithKline and has received
grant support form Pfizer. Study author Michael Gaffney, PhD, is an
employee at Pfizer in New York.

Arch Gen Psychiatry. 2007;64:1025-1031. Abstract

#12890 From: dr_allen_wang
Date: Tue Sep 25, 2007 2:54 am
Subject: Exhaled Gas Analysis May Noninvasively Monitor Blood Sugar in Diabetics
dr_allen_wang
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Analysis of elevated methyl nitrate content in exhaled gas analysis
could be developed as a tool for monitoring blood sugar in patients
with diabetes without needing a blood sample, according to the
results of a study published online September 24 in the Proceedings
of the National Academy of Sciences.

"Breath analysis has been showing promise as a diagnostic tool in a
number of clinical areas, such as with ulcers and cystic fibrosis,"
senior author Pietro Galassetti, from the General Clinical Research
Center at the University of California, Irvine, says in a news
release. "While no clinical breath test yet exists for diabetes, this
study shows the possibility of non-invasive methods that can help the
millions who have this chronic disease."

Earlier studies by this group showed that analysis of volatile
organic compounds (VOCs) in human exhaled air allowed estimation of
plasma glucose levels in healthy adults during a standard oral
glucose tolerance test.

The investigators' hypothesis was that low insulin and increased free
fatty acids and ketones in type 1 diabetes mellitus (T1DM) would give
rise to different exhaled VOC profiles in children with T1DM during
spontaneous hyperglycemia, specifically with increased levels of
exhaled methyl nitrate. During hyperglycemia, increased free fatty
acids in the blood cause oxidative stress, with methyl nitrate a
metabolic byproduct.

Ten children with T1DM participated in 18 experiments in which plasma
glucose and exhaled gases were monitored during either constant
euglycemia (n = 5) or during initial hyperglycemia with gradual
correction (n = 13). All children were given intravenous insulin and
glucose as needed. Gas chromatography using electron capture, flame
ionization, and mass selective detection allowed analysis of
approximately 100 exhaled gases in 1.9-L breath samples.

Of all the gases analyzed, the kinetic profile of exhaled methyl
nitrate most strongly statistically correlated with that of plasma
glucose (P = .003 ”V .001) in 16 of 18 experiments. This held true
even in repeated tests on children with either euglycemia or
hyperglycemia at different times. Exhaled concentrations of methyl
nitrate were increased as much as 10 times in diabetic children
during hyperglycemia than during euglycemia.

"Currently, we are involved with new studies looking at the
correlation of other gases with hyperglycemia and other variables,
including insulin," Dr. Galassetti says. "Eventually, we hope to put
together a full exhaled gas profile of diabetes, and our efforts look
promising.

"The characteristics of methyl nitrate formation suggest that this
gas may reflect, rather than hyperglycemia per se, the specific and
complex pattern of metabolic alteration accompanying hyperglycemia in
T1DM," the authors conclude. "This includes not only hypoinsulinemia
and increased lipids and ketones but also alterations in inflammatory
and oxidative markers, now considered main determinants of diabetic
vascular complications. Optimization of exhaled gas analysis in
diabetes may prove invaluable not only in monitoring glycemic control
but also in determining the actual pathogenic potential of a given
glycemic state in terms of onset/progression of diabetic
complications."

The National Institutes of Health and Juvenile Diabetes Research
Foundation supported this study. The authors report no relevant
financial relationships.

Proc Natl Acad Sci U S A. Published online September 24, 2007

#12882 From: dr_allen_wang
Date: Sun Sep 23, 2007 10:40 pm
Subject: Moderate Wine Consumption Improves Fasting Plasma Glucose Levels in Diabetics
dr_allen_wang
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A randomized trial conducted in diabetic teetotalers suggests that a
glass of wine with dinner may improve glucose control, particularly
in those with higher HbA1c levels to begin with. The study, while
small, adds to anecdotal evidence and meta-analyses that suggest
wine, whose cardiovascular benefits have been widely touted, may
hold specific benefits for diabetics.

Dr Iris Shai (Ben Gurion University, Beer-Sheva, Israel) presented
the results of the study here at the European Association for the
Study of Diabetes 2007 Meeting.

Shai noted that the proportion of alcohol abstainers is relatively
high in Israel, where the study was conducted; however, the
potential health benefits of moderate alcohol consumption persuaded
109 adults between the ages of 40 and 75 to participate. Indeed,
dropouts during the three-month trial were higher among those
randomized to the nonalcoholic diet malt beer than among those
randomized to their choice of red or white wine, with many of the
dropouts citing their disappointment over not being assigned to the
alcohol group.

At the end of three months, 91 subjects remained in the study; those
in the alcohol-intervention group experienced a statistically
significant drop in fasting plasma glucose, from a mean of 139.6
mg/dL to 118 mg/dL. By contrast, subjects in the nonalcoholic-beer
group experienced no real change in fasting plasma glucose.

Of note, alcohol consumption did not appear to affect two-hour
postprandial glucose levels. Shai pointed out that ethanol
metabolism is believed to inhibit gluconeogenesis, which could
increase the risk of hypoglycemia. "Because of this, patients were
guided to drink their beverage during dinner, which was a
carbohydrate-based meal. But this process largely controls fasting,
rather than postmeal, glycemia," she said, which might help explain
the lack of an effect on two-hour postprandial glucose.

Better glucose, better sleep

Changes in fasting plasma glucose levels were particularly marked
among patients who had higher baseline HbA1c levels, Shai noted.
Waist circumference and LDL levels were also reduced from baseline
over the three-month period in the alcohol-intervention group, but
no changes from baseline were seen in HDL levels.
While "surprising," Shai suggested that the lack of effect on HDL
might be due to the relatively short duration of the trial.

Prompting giggles in the audience, Shai said that despite a range of
other parameters queried or measured in the trial, the only other
significant difference between the two study groups was an improved
ability to fall asleep, reported in the alcohol-intervention arm of
the study.

Three months after the termination of the trial, 61% of the study
subjects told investigators that they believed alcohol was likely
beneficial and 49% were continuing to drink alcohol in moderation.

#12881 From: dr_allen_wang
Date: Sun Sep 23, 2007 10:39 pm
Subject: Galvus Combo for Diabetes
dr_allen_wang
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Novartis AG's experimental leukaemia drug Tasigna -- a follow-up to
Glivec/Gleevec -- has been recommended for approval in Europe for
patients who no longer respond to Glivec.

Tasigna works in about half of those patients who develop resistance
to Glivec, the market-leading drug for the most common type of
chronic myeloid leukaemia, or CML.

Bristol-Myers Squibb's rival product, Sprycel, is designed to treat
the same group of patients.

The European Medicines Agency also said on Friday it had backed a
new product, called Eucreas, combining the Swiss group's Galvus
(vildagliptin) with metformin as a treatment for diabetes. Eucreas
will be the first single-tablet combination of a DPP-4 inhibitor
drug and metformin in Europe.

Galvus itself won a positive recommendation in Europe in July and
may be formally approved by European authorities later this month or
in October.

Recommendations for marketing approval by the agency's Committee for
Medicinal Products for Human Use (CHMP) are normally endorsed by the
European Commission within a couple of months.

Galvus's path to market in the key U.S. market has been delayed by
worries over skin toxicity.

#12878 From: dr_allen_wang
Date: Fri Sep 21, 2007 11:10 pm
Subject: DAVID-2
dr_allen_wang
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Low-LVEF patients with implantable cardioverter-defibrillators
(ICDs) who don't need pacing for bradycardia have about the same
quality-of-life outcomes with their devices set to provide atrial-
based pacing, activated at a heart rate of 70 bpm (AAI-70), as with
devices programmed for only single-chamber backup pacing (VVI-40),
according to a randomized trial [1].

The secondary finding from the second Dual Chamber and VVI
Implantable Defibrillator (DAVID-2) trial, presented here at the
Heart Failure Society of America 2007 Scientific Meeting, adds
further weight to its previously reported primary results, that
neither pacing mode offered a clinical advantage over two years.

The trial's message, according to Dr James R Cook (Baystate Medical
Center, Springfield, MA), who is on the DAVID-2 executive committee,
remains that ICDs set to VVI-40 are fine for most eligible low-LVEF
patients with healthy sinus nodes. Patients in DAVID-2 had been
randomized to one of the two pacing modes while on, in the
overwhelming majority, optimal medical therapy that included beta
blockers and either ACE inhibitors or angiotensin receptor blockers;
all had LV systolic dysfunction, and most were in heart failure.

Misconceptions about pacing support with ICDs

Cook explained that electrophysiologists, at least, had believed
that pacing support was routinely necessary in such patients with
ICDs. "One of the things we believed, especially with the prevalent
use of amiodarone in the past, was that you couldn't [otherwise]
treat the patients optimally with beta blockers, because then you'd
be limited by heart rate and blood pressure."

After dual-chamber, rate-responsive pacing (DDDR) apparently
worsened outcomes for such patients in the first DAVID trial, "the
argument became that maybe it's ventricular pacing that's the issue,
and if you atrial pace, you can help people receive the medicine
they deserve and improve their quality of life." That trial saw a
significantly increased risk of death or heart-failure
hospitalization over one year for DDDR compared with VVI-40 pacing.
The trial had entered predominantly patients with LV systolic
dysfunction secondary to ischemic heart disease.

So the second DAVID was launched to see whether AAI-70 pacing would
do at least as well as ventricular backup pacing while allowing
optimal medical therapy, Cook observed. Ventricular backup pacing at
the time was considered less problematic than DDDR but still thought
to entail a potentially detrimental level of right-ventricular
stimulation.

The trial randomized 300 patients to AAI-70 and the same number to
VVI-40 following successful ICD implantation. All had an LVEF <40%,
87% had a history of MI, and two-thirds had chronic heart failure.

AAI-70 comparable to VVI-40

Among the approximately 90% of patients who received any pacing
during the two-year study, surprisingly few heartbeats were actually
paced in the VVI-40 group: only 1.2% of beats after three months and
1.0% after 24 months. The corresponding figures for AAI-70 pacing
were 47% and 51%, respectively.

The trial's primary outcomes, presented earlier this year at the
Heart Rhythm Society 2007 Scientific Sessions and reported by
heartwire at the time, included no significant two-year differences
between the pacing modes in a composite end point consisting of
death or rehospitalization for new or worsened heart failure. The
annualized mortality was about 5% in both groups.

Cook told heartwire that all the patients had received dual-chamber
pacemakers, but only the atrial wire and only the ventricular wire
were activated for AAI-70 and VVI-40 pacing, respectively. Fewer
than 8% of the patients had the second wire activated for dual-
chamber pacing; such crossovers were at the physicians' discretion.

"There are patients who do have sinus-node dysfunction or AV-
conduction disorders, but they are limited and certainly not as
prevalent as we thought they were when we had embraced the DDDR
pacing mode as necessary to deliver optimal medical therapy and
chronotropic support," Cook said.

No effect of pacing mode on quality of life

Patients rated themselves using several quality-of-life instruments,
including the SF-36 health survey, which has been validated for
rating general functional status and well-being in patients with
heart disease, Cook noted; the Minnesota Living with Heart Failure
Questionnaire (MLHFQ), also widely used; and the Simple Outcome
Screen (SOS) and Global Rating Change (GRC) surveys designed for
outcomes assessment in patients with stroke and survivors of cardiac
arrest.

The two groups showed statistically similar quality-of-life
improvements as measured by the MLHFQ, but there were also
suggestions of greater improvement for the VVI-40 group by the SF-36
and for the AAI-70 group according to the SOS/GRC evaluations. With
quality-of-life outcomes seemingly all across the board, the
investigators interpreted the divergent findings of the SF-36 and
SOS/GRC evaluations as "chance variation" and concluded that there
was no evidence of better improvement in either group.

"Atrial pacing may be considered a safe alternative, but it offers
no clear advantage or disadvantage over ventricular backup pacing,
VVI-40," Cook said when presenting the DAVID-2 quality-of-life
results. "If I were to get a defibrillator today and I were a heart-
failure patient, I'd get a single-chamber ICD programmed at VVI-40
and maximize medical therapy."

To heartwire, Cook said, pacing the heart at 70 bpm doesn't
translate into clinical benefit compared with ventricular backup
pacing, but in DAVID-2, "at least it did no harm." If clinicians
want to put in a dual-chamber device, he said, it should either be
programmed to AAI or use algorithms that minimize ventricular
pacing. (A number of manufacturers offer devices with such
capability.) But he added, "If there's sinus-node dysfunction or
another indication for pacing, atrial pacing can help."

DAVID-2 was supported by St Jude Medical. Cook reports receiving
grants from Boston Scientific, Medtronic, and St Jude Medical.

Cook JR. Impact of atrial pacing on quality of life in the dual
chamber and VVI implantable defibrillator (DAVID) II trial. Heart
Failure Society of America 2006 Scientific Meeting; September 19,
2007; Washington, DC. Recent and Late-Breaking Trials.

#12877 From: dr_allen_wang
Date: Fri Sep 21, 2007 11:11 pm
Subject: Moderate Wine Consumption Improves Fasting Plasma Glucose Levels in Diabeticsv
dr_allen_wang
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A randomized trial conducted in diabetic teetotalers suggests that a
glass of wine with dinner may improve glucose control, particularly
in those with higher HbA1c levels to begin with. The study, while
small, adds to anecdotal evidence and meta-analyses that suggest
wine, whose cardiovascular benefits have been widely touted, may
hold specific benefits for diabetics.

Dr Iris Shai (Ben Gurion University, Beer-Sheva, Israel) presented
the results of the study here at the European Association for the
Study of Diabetes 2007 Meeting.

Shai noted that the proportion of alcohol abstainers is relatively
high in Israel, where the study was conducted; however, the
potential health benefits of moderate alcohol consumption persuaded
109 adults between the ages of 40 and 75 to participate. Indeed,
dropouts during the three-month trial were higher among those
randomized to the nonalcoholic diet malt beer than among those
randomized to their choice of red or white wine, with many of the
dropouts citing their disappointment over not being assigned to the
alcohol group.

At the end of three months, 91 subjects remained in the study; those
in the alcohol-intervention group experienced a statistically
significant drop in fasting plasma glucose, from a mean of 139.6
mg/dL to 118 mg/dL. By contrast, subjects in the nonalcoholic-beer
group experienced no real change in fasting plasma glucose.

Of note, alcohol consumption did not appear to affect two-hour
postprandial glucose levels. Shai pointed out that ethanol
metabolism is believed to inhibit gluconeogenesis, which could
increase the risk of hypoglycemia. "Because of this, patients were
guided to drink their beverage during dinner, which was a
carbohydrate-based meal. But this process largely controls fasting,
rather than postmeal, glycemia," she said, which might help explain
the lack of an effect on two-hour postprandial glucose.

Better glucose, better sleep

Changes in fasting plasma glucose levels were particularly marked
among patients who had higher baseline HbA1c levels, Shai noted.
Waist circumference and LDL levels were also reduced from baseline
over the three-month period in the alcohol-intervention group, but
no changes from baseline were seen in HDL levels.
While "surprising," Shai suggested that the lack of effect on HDL
might be due to the relatively short duration of the trial.

Prompting giggles in the audience, Shai said that despite a range of
other parameters queried or measured in the trial, the only other
significant difference between the two study groups was an improved
ability to fall asleep, reported in the alcohol-intervention arm of
the study.

Three months after the termination of the trial, 61% of the study
subjects told investigators that they believed alcohol was likely
beneficial and 49% were continuing to drink alcohol in moderation.

#12870 From: dr_allen_wang
Date: Fri Sep 21, 2007 12:47 am
Subject: Sulfonylureas May Improve Stroke Outcome in Patients with Diabetes
dr_allen_wang
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A retrospective study suggests patients with diabetes who are treated
with sulfonylureas before and through their hospitalization for an
acute ischemic stroke may have better outcomes.

"The present study is the first to show that prior use plus postevent
use of sulfonylurea agents could have a beneficial effect on stroke
outcome," the researchers, with first author Hagen Kunte, MD, from
the Center for Stroke Research at Humboldt University, in Berlin,
Germany, write. "Patients on sulfonylurea were significantly more
likely to have favorable neurological and functional outcomes at the
time of discharge, with the magnitude of the effect being large."

Study investigator J. Marc Simard, MD, PhD, from the department of
neurosurgery at the University of Maryland, in Baltimore, told
Medscape Neurology and Neurosurgery that their study suggests, at the
very least, that diabetic patients who have a stroke should be kept
on their medication during their hospitalization and afterward if at
all possible.

Because the effect was independent of blood glucose levels, he
added, "We're planning studies in nondiabetic patients to see whether
getting on to a sulfonylurea like glyburide will benefit them when
they come in after a stroke."

Their findings are published in the September issue of Stroke.

Channel Upregulated in Ischemia

The rationale for the current study lies in previous work published
by Simard et al in animal models showing that the NC-CaATP channel,
expressed in the central nervous system only under conditions of
ischemia and regulated by sulfonylurea receptor-1, could be blocked
by the sulfonylurea agent glibenclamide (glyburide), significantly
reducing mortality, cerebral edema, and infarct volume in treated
animals when given after a stroke (Simard JM et al. Natur Med.
2006;12:433-440).

"The interesting thing about this pharmacology is that the drugs that
block this new channel that is upregulated in stroke are precisely
the same ones that have been used for many years to treat (type 2)
diabetes," Dr. Simard said.

To begin to look at this potential effect in humans, the researchers
retrospectively analyzed outcomes of patients admitted within 24
hours of an acute ischemic stroke at the Neurology Clinic, Charité
Hospital, in Berlin between 1994 and 2000. This hospital has been
keeping "excellent track" of the kind of data required for this
comparison for many years, he noted.

After exclusions, they identified 33 patients who had been taking a
sulfonylurea at admission and through discharge and 28 patients not
on a sulfonylurea. The primary outcome was a decrease of 4 points or
more from admission to discharge on the National Institute of Health
Stroke Scale (NIHSS) or a discharge NIHSS score of 0. The secondary
outcome was a modified Rankin Scale score of 2 or less at discharge.

"The bottom line is that if you are a diabetic and you happen to be
on 1 of these sulfonylureas, and you come in with stroke, the
likelihood of doing well is much better than a comparably matched
diabetic who is not on these medicines," Dr. Simard said.

Subgroup analysis suggested that the benefit was limited to patients
with nonlacunar strokes and was independent of gender, previous
transient ischemic attack, and blood glucose levels.

"So we think that, among other things, it's important for physicians
to be aware of, that when they have a diabetic patient who is already
on a sulfonylurea, they should do whatever they can to keep them on
these drugs when they come in with a stroke," Dr. Simard said.

They are currently planning studies to look at this mechanism
further, he noted, specifically in treating nondiabetic patients with
stroke using a sulfonylurea, although they will require an
intravenous formulation to do this given the difficulties in treating
acute stroke patients with an oral medication.

The researchers also hope to examine the effects of these agents in
the context of acute brain injury, Dr. Simard added.

Trial "Urgently Needed"

In an editorial accompanying the paper, Adrią Arboix, MD, PhD, from
the Hospital Universitari del Sagrat Cor, Universitat de Barcelona,
in Spain, writes that the current study "has the important merit of
showing for the first time that treatment with sulfonylureas before
cerebral ischemia and maintained during the acute phase of infarction
(similar to therapy in experimental studies) had a beneficial effect
on the short-term prognosis of patients with type 2 diabetes and
cerebral infarct.

"Although the findings cannot be generalized to all patients with
acute stroke and should be interpreted taking into account the
limitations of the study, such as its observational, unmatched,
retrospective design and the lack of information on concomitant
treatment (it may be possible that other medications may confer
neuroprotection, as just recently reported for statins or angiotensin-
converting enzyme inhibitors), the piece of work by Kunte et al opens
new encouraging perspectives for the treatment of patients with type
2 diabetes and ischemic stroke," Dr. Arboix concludes.

"In agreement with the authors, a prospective randomized trial of
sulfonylureas is justified and, in my opinion, urgently needed."

The study was supported in part by grants to Dr. Simard from the
National Institute of Neurological Disorders and Stroke, the National
Heart, Lung, and Blood Institute, and the Department of Veterans
Affairs, as well as by funding from Remedy Pharmaceuticals Inc. Dr.
Simard reports he has applied for a US patent, "A novel nonselective
cation channel in neural cells and methods for treating brain
swelling." Dr. Arboix reports no conflict of interest.

Stroke. 2007;38:2526-2530. Abstract

#12858 From: "hotrunme" <hotrunme@...>
Date: Wed Sep 19, 2007 1:44 pm
Subject: Will you be the one to come and make me into a "bad" girl?
hotrunme
Offline Offline
Send Email Send Email
 
Well, I am into Goth, music, video games, cosplay...I would love to
try anything that is NEW and FUN.I do have some gothic photos:
http://www.geocities.com/ronnielove88/ coolgothgirl maybe we should talk?

#12855 From: "Gerald Oros" <postman23_2000@...>
Date: Wed Sep 19, 2007 2:26 am
Subject: Abstract of External Counter Pulsation Therapy Study by Audio
postman23_2000
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Send Email Send Email
 
Abstract of ECPT Study by Audio

Click on link shown below. Scroll down to third author in Tour 6
segment i.e., Alon Barsheshet. "The Effect of External Counter
Pulsation Therapy on Circulating Endothelial Progenitor Cells in
Patients with Angina Pectoris." Short but very positive!

After clicking on the "View Poster" link and listening to audio
comments, click on the PDF link.

http://astute.cardiosource.com/2007/vposters/

What I keep looking for is confirmation that this study has been
published in a medical journal and so far I have had no success. Why
wouldn't the cardiology community RUSH to have this information
published ASAP?

#12854 From: dr_allen_wang
Date: Tue Sep 18, 2007 10:52 pm
Subject: New Genetic Test for Warfarin Sensitivity Approved in US
dr_allen_wang
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The US FDA has approved a new genetic test to help assess warfarin
sensitivity [1]. The FDA notes that one-third of patients metabolize
warfarin more slowly than others and therefore experience a higher
risk of bleeding. Research has shown that some of the unexpected
response to warfarin depends on variants of two genes, CYP2C9 and
VKORC1. The Nanosphere Verigene Warfarin Metabolism Nucleic Acid
Test detects some variants of both genes.

The Nanosphere test is not intended to be a standalone tool to
determine optimum drug dosage but should be used along with clinical
evaluation and other tools, including the international normalized
ratio (INR), to determine the best treatment for patients. The new
test was cleared for use on the Verigene System, a clinical
laboratory test system. Both products are manufactured by Nanosphere
Inc, in Northbrook, IL.

"Today's action offers physicians the first FDA-cleared genetic test
for warfarin sensitivity, which is another step in our commitment to
personalized medicine," said Dr Daniel Schultz (FDA Center for
Devices and Radiological Health). "With this test, physicians may be
able to use genetic information along with other clinical
information to treat their patients."

The FDA notes that warfarin can be a difficult drug to use because
the optimal dose varies, depending on many risk factors, including a
patient's diet, age, and the use of other medications. Rapidly
achieving the correct dose is important to avoid bleeding side
effects or suboptimal concentrations, but warfarin is associated
with a high rate of side effects, being the second-most-common drug,
after insulin, implicated in emergency-room visits for adverse drug
reactions.

In August, the FDA approved updated labeling for warfarin,
explaining that people with variations of the genes CYP2C9 and
VKORC1 may respond differently to the drug. The FDA cleared the new
test based on results of a study conducted by the manufacturer of
hundreds of DNA samples as well as on a broad range of published
literature. In a three-site study, the test was accurate in all
cases where the test yielded a result; 8% of the tests could not
identify which genetic variants were present.

The Wall Street Journal reports that about two million people start
taking warfarin each year, and it has been estimated that genetic
testing could prevent 85 000 serious bleeding events and 17 000
strokes a year, with savings to the healthcare system of $1.1
billion a year [2].

Food and Drug Administration. FDA clears genetic lab test for
warfarin sensitivity [press release]. September 17, 2007. Available
at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01701.html.
Mathews AW. In milestone, FDA pushes genetic tests tied to drug.
Wall Street Journal, August 16, 2007. Available at:
http://www.wsj.com.

#12853 From: dr_allen_wang
Date: Tue Sep 18, 2007 10:53 pm
Subject: Even in nondiabetics, increased HbA1c levels are associated with a significantly
dr_allen_wang
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Paclitaxel- and sirolimus-eluting stents are associated with similar
clinical outcomes at 9 months, new research shows, and with either
type, rates of clinical restenosis and major adverse cardiovascular
events (MACE) are low.

"The present study represents the largest multicenter prospective
comparison of paclitaxel- and sirolimus-eluting stent procedures in
patients receiving these devices in the US," Dr. Charles A.
Simonton, from the Carolinas Heart Institute in Charlotte, North
Carolina, and colleagues state.

The findings are based on an analysis of data entered in the
Strategic Transcatheter Evaluation of New Therapies (STENT)
registry, the first multicenter database to record long-term stent
outcomes in the "real world" setting. The current study involved
4671 patients treated with a paclitaxel stent and 4555 treated with
a sirolimus stent, between 2003 and 2005.

Dr. Simonton's team reports their findings in the September 25th
issue of the Journal of the American College of Cardiology.

At 9 months, the percentage of patients with a MACE in the
paclitaxel and sirolimus stent groups were similar, at 7.5% and
8.0%, respectively (p = 0.37). Moreover, none of the individual
components of MACE -- death, MI, or target vessel revascularization -
- differed significantly between the groups.

The rate of stent thrombosis at 9 months was identical in each
group, 0.7%, the researchers report.

"The implications of these findings are that selection of a
particular drug-eluting stent may be determined more by the
operator's comfort with the mechanical properties of the stent for a
given lesion rather than by any apparent differences in clinical
outcomes," the investigators conclude.

J Am Coll Cardiol 2007;50:1214-1222.

#12852 From: dr_allen_wang
Date: Tue Sep 18, 2007 10:53 pm
Subject: Elevated Hba1c Associated With Nonfatal CVD, Even in Nondiabetics
dr_allen_wang
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Even in nondiabetics, increased HbA1c levels are associated with a
significantly increased risk of nonfatal cardiovascular disease
after other cardiovascular risk factors are accounted for, an
analysis from the Hoorn cohort study shows.

While HbA1c is a well-established predictor of cardiovascular events
in diabetics, this is the first study to link elevated HbA1c to
fatal and nonfatal cardiovascular disease in nondiabetics, Dr Esther
van 't Riet (VU University Medical Centre, Amsterdam, the
Netherlands) reported here at the European Association for the Study
of Diabetes 2007 Meeting.

"The clinical meaning of this is that, even in subjects without
diabetes, it is very important to maintain optimal glycemic
control," van 't Riet told heartwire. "Trying to lower HbA1c may not
be the first thing you do in terms of treatment, but you can see
that when you have subjects without diabetes who have high HbA1c
levels there is some degree of risk, and when you lower HBA1c you
lower their risk of CVD. This is evidence of that relationship."

The Hoorn study is a population-based cohort analysis that enrolled
2484 subjects back in 1989 to 1990. A total of 1674 nondiabetic
subjects with data on baseline HbA1c were included in the current
analysis and analyzed by tertiles of baseline HbA1c. As van 't Riet
reported here, subjects in the highest HbA1c tertile (>5.6%) had
significantly increased risk of developing nonfatal cardiovascular
disease or dying of cardiovascular disease, even after adjustment
for age and sex: hazard ratios of 2.11 and 1.73, respectively. When
the analysis was further adjusted for cardiovascular risk factors
(hypertension, smoking, LDL, triglycerides, and waist-to-hip ratio),
a high HbA1c was still significantly associated with nonfatal CVD
(but not fatal CVD), with a hazard ratio of 1.71.

Fasting glucose levels at baseline and measures of two-hour plasma
glucose were not significantly associated with increased CVD risk.

No link to impaired glucose tolerance

To heartwire, van 't Riet said that the lack of an association with
fasting glucose levels comes as no surprise: no previous reports
have linked fasting glucose to CVD in nondiabetics. More surprising,
however, was the lack of association with two-hour plasma glucose
levels--a measure of impaired glucose tolerance. "That has been
reported before, in several large epidemiological studies," she
said, "But I think difference comes from the fact that we excluded
all diabetic subjects, whereas earlier reports included diabetic
subjects. We did an analysis in which we included diabetic subjects
[from the Hoorn cohort] and when we did that, we did find an
association with two-hour glucose levels."

Commenting on the study, Dr John S Yudkin (University College
London, UK) also observed that he would have expected impaired
glucose tolerance to be "a better marker" than HbA1c. He also
speculated on the significance of HbA1c as a measurement.

Obviously one big question is whether HbA1c is a mediator of
cardiovascular risk or merely a marker. Some of the excess risk
seems to disappear when the measured CV risk factors are adjusted
for, and those measured markers would also probably couple with
other unmeasured ones like microalbuminuria, fibrinogen, and CRP, he
proposed.

To heartwire, van 't Riet said that, in her opinion, HbA1c is
probably a marker, whereas glucose is more of a mediator. But she
reiterated that she didn't think HbA1c would necessarily be a good
marker to aggressively target in clinical practice. "When you go to
treat an individual to lower their HbA1c to decrease their risk of
CVD, you are targeting a hazard ratio of 1.71, but when you treat
blood pressure or cholesterol, you have the potential to have a much
bigger effect on CVD outcomes. I think it's much better to treat
blood pressure and cholesterol than HbA1c in subjects without
diabetes."

#12850 From: dr_allen_wang
Date: Mon Sep 17, 2007 10:56 pm
Subject: Zonisamide Plus Bupropion Combo Promotes Weight Loss
dr_allen_wang
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The combination of zonisamide and bupropion is more effective than
zonisamide alone in helping obese women lose weight, results of a
preliminary study suggest.

When studied individually in randomized trials, the anticonvulsant
zonisamide and the antidepressant bupropion were more effective than
placebo for weight loss, Dr. Kishore M. Gadde and associates note in
their paper, published in the August issue of the Journal of Clinical
Psychiatry. Combined, the researchers theorized, the two drugs would
be even more effective as a result of their effects on three
neurotransmitters involved in appetite and energy homeostasis,
serotonin, dopamine, and norepinephrine.

The research team, based at Duke University Medical Center in Durham,
North Carolina, also speculated that each of the two drugs would
cancel out the adverse effects of the other. Thus, the somnolence,
cognitive impairment, and fatigue caused by zonisamide would be
reversed by bupropion, which is associated with insomnia and
psychomotor agitation.

In an open-label, 12-week study, Dr. Gadde's team recruited 18 obese
women (mean BMI 36.8; range 30 to 44) who were randomized to
treatment with bupropion plus zonisamide or the antiepileptic agent
alone. Bupropion was started at a dose of 100 mg/day, increasing to
200 mg/day after 2 weeks. Zonisamide was started at 100 mg/day, with
gradual titration to 400 mg/day by week 4.

The subjects were also instructed to follow a reduced-calorie diet.

The "intent-to-treat last-observation-carried-forward analysis"
included nine women in the combination treatment arm and seven in the
monotherapy group. Dual treatment was associated with a significantly
greater weight loss than was monotherapy (7.2 kg versus 2.9 kg).

Seven patients on dual treatment and five on monotherapy completed
the 12-week study and were included in the per-protocol analysis.
Here too, combined treatment was associated with greater effect on
weight loss (8.1 kg versus 3.0 kg).

Dr. Gadde and colleagues suggest that larger patient populations,
trials of longer duration, and the addition of two other control
groups -- monotherapy with bupropion and placebo - will more
thoroughly assess efficacy, safety, and tolerability.

But for now, the authors conclude: "Our data provide a preliminary
suggestion that combined administration of zonisamide and bupropion
might be associated with a more robust weight-loss effect than
zonisamide monotherapy."

J Clin Psychiatry 2007;68:1226-1229.

#12849 From: dr_allen_wang
Date: Mon Sep 17, 2007 10:53 pm
Subject: Interventional Cardiologists Tackle COURAGE
dr_allen_wang
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Fourteen household names--at least in the house of interventional
cardiology--have signed on to a Viewpoint that aims to illuminate
the "truth and consequences" of the COURAGE trial [1]. The paper, by
Dr Dean J Kereiakes (Lindner Research Center, Cincinnati, OH) et al,
appearing as an "expedited" paper in the Journal of the American
College of Cardiology (JACC) today, points to several holes in the
trial design and subsequent possible misinterpretations of the
results.

"The COURAGE trial is very important and has major implications for
the way we treat patients with stable coronary artery disease, but
like any other single individual trial, it has limitations, and so we
thought it was important to present another perspective," senior
author on the paper, Dr Gregg Stone (Columbia University, New York,
NY), told heartwire.

But a counterpoint article by Drs George A Diamond and Sanjay Kaul
(Cedars-Sinai Medical Center, Los Angeles, CA), also published in
JACC today, takes aim at the points raised by the Viewpoint authors,
arguing that their paper is strong on rhetoric but short on numbers
to back up its claims [2].

"Kereiakes mentions, in all fairness, that PCI has not been
demonstrated to reduce death or MI, and he says that PCI should be
employed only in addition to optimal medical therapy [OMT] when it is
used," Diamond told heartwire. "He actually states the issues
properly at the outset and at the end of the paper, but in between, I
have to tell you, there's a lot of rhetorical stretching of the
arguments; there's not much in the way of numbers in the critique.
That's why we attempted to present numbers and hard evidence in our
response."

Flaws in COURAGE

According to Kereiakes, Stone, and colleagues, the critical flaws in
the COURAGE trial included the fact that it was designed to prove the
superiority of angioplasty, using an unrealistically optimistic power
calculation that was not supported by existing evidence. There was
also "tremendous selection bias" during trial enrollment, Stone
noted. "The average hospital in COURAGE enrolled one patient per
month, so it was very select who went into this study, and this was
after diagnostic angiography. So patients had to have the right mix
of anatomy and symptoms for the doctors to feel comfortable that they
could leave the patient's anatomy alone."

The Viewpoint authors also express concern over the different
baseline characteristics and results from the different types of
enrolling hospitals: Canadian hospitals, US Veterans' Affairs (VA)
hospitals, and non-VA hospitals. "While the trial wasn't powered to
look at these subgroups, I think it raises an important hypothesis as
to whether COURAGE applies to patients who were enrolled in non-VA
hospitals," ie, the vast majority of US patients, Stone said.

Stone and colleagues also point to the very high rates of compliance
with medical therapy in the OMT arm, something rarely seen to such a
high degree in trials, let alone the "real world." By contrast, they
argue, the quality of angioplasty in the trial fell short of
optimal. "The design of the trial was to show that angioplasty was
better than medical therapy--forget for one moment that nothing in
the previous literature suggested that would be the case. But if you
were going to do a trial to test that, at least you should do optimal
angioplasty. Unfortunately, GP IIb/IIIa inhibitors were rarely used
in this trial; clopidogrel preloading was not routinely used in this
trial; complete revascularization was the exception, not the rule;
and there were no standards, surprisingly, put in place as to how
angioplasty should be done. On the other hand, the trial spent all
its time and attention on ensuring optimal background medical
therapy. So it's a little backward as to what we would have expected
if the purpose of the trial was to show that angioplasty reduced
death and prevented MI."

As a final point, the Viewpoint authors point out that symptoms were
significantly reduced throughout three years of follow-up, and need
for antianginal medications was reduced for five years, despite the
fact that 32% of the patients in the OMT-alone arm crossed over at a
mean of 10.8 months and required angioplasty. "I think COURAGE
supported other trials that said, in America, if you want to give
people the best therapy to feel better as soon as we initiate care,
COURAGE supports an interventional approach,"Stone said.

The trial, as Kereiakes et al note, had anticipated that less that
10% would cross over, especially since half of the patients were
asymptomatic at baseline. "While we don't know what group crossed
over, it's most likely that the patients who were having significant
symptoms were the ones whose symptoms were not controlled by medical
therapy, and they required, in less than a year, angioplasty in a
very high percentage of patients," Stone explained. Moreover, if drug-
eluting stents (DES) had been used in the trial, angina symptoms and
the need for subsequent revascularizations would likely have been
further reduced, while quality of life would have been improved.

"The COURAGE investigators have interpreted the results saying that
since there were no differences in death or MI, why start with
angioplasty? I interpret it the other way," Stone told heartwire. "I
interpret it as there was no increased death or MI with angioplasty
and in fact there was a 10% to 15% trend toward reduction in death
and MI, and in the patients who had symptoms, symptoms were
significantly improved. . . . So I look at COURAGE as a supportive
trial for angioplasty as a safe and effective first-line approach if
you want to provide your optimal care to patients and especially
those who have symptoms. For the ones who don't have symptoms, there
the trial is more equivocal, and I think that, depending on the
coronary anatomy, probably either approach is acceptable."

In their counterpoint article, Diamond and Kaul minutely dissect each
of the points made by the Viewpoint interventionalists. They point
out that, in fact, COURAGE did provide the first solid evidence that,
unlike in the setting of ACS, angioplasty did not reduce death or MI
for stable coronary disease. A key point, they note, is that the lay
public "is unlikely to distinguish between unstable and stable
disease," and many people undergo elective PCI "under the belief that
it indeed prolongs their life or prevents a heart attack." They also
observe that PCI is widely used in asymptomatic patients.

Diamond and Kaul also pick apart the suggestion that PCI was not
optimally performed, noting that the relatively low rate of
additional revascularization (at 21%) suggests that initial
revascularization was durable in four out of five patients. Other
quibbles, they argue, are not necessarily supported by the evidence
or by the COURAGE trial details.

Ultimately, say Diamond and Kaul, a "wait and see approach"
is "justified" by the COURAGE trial results.

"In the end, the inference in the COURAGE trial is not that OMT is
better than PCI, but that an initial recommendation of PCI plus OMT
offers no important advantage over an initial recommendation of OMT
alone," they write. "Percutaneous coronary intervention can be
reserved for a later time with little risk that an unfavorable event
will intervene."

It's a conclusion that Stone does not fully accept. "I think you
could take COURAGE to mean that for patients who truly want medical
therapy, you are probably not putting them at risk," he told
heartwire. "COURAGE was very underpowered to find a reduction in
death and MI: the trial had to be increased in sample size and the
definition of death/MI had to be changed during the course of the
trial because they weren't getting enough events. And as it turns
out, the trial still is very underpowered for their endpoints. That's
important because there was trend towards an approx 13% reduction in
death with angioplasty and mostly accruing late. . . . So I think
that the question about whether optimal angioplasty reduces cardiac
death and large MI is unanswered and COURAGE was way underpowered to
look at that."

Room for improvement

Where Diamond and Kaul and the Viewpoint authors find some points of
agreement is over the lack of optimal medical therapy in the "real
world"--but where the Diamond and Kaul see this as an opportunity for
improvement, Kereiakes et al see this as "physically, emotionally,
[or] financially" unrealistic and justification for PCI.

"I don't know that in the real world we have the resources or the
time available to give this kind of medical therapy, but I think it
is a laudable goal, and we should shoot for this type of medical
therapy," Stone acknowledged.

To heartwire, Diamond emphasized that it is in part a failing of the
system, in which physicians are reimbursed at a higher rate for
interventions than they are for prescribing OMT. " The bottom line,
from my standpoint, is that OMT is an appropriate starting point with
proven benefits in terms of long term clinical outcomes, death and
MI, and the issue is how do we best deliver such therapy to patients
today given all of the misalignment of incentives?" Diamond
asked. "The fact is, physicians are paid much more for interventional
procedures than they are for providing good medical advice and good
medical therapy; we need to re-align those incentives." Diamond also
blames existing guidelines for being a "hodgepodge" of evidence,
opinion, and educated guesses that leave room for physicians to
justify whatever treatment option they choose. Finally, he points to
the problem of failed communication between doctors and patients.

Diamond agreed that patients, if asked, "are inclined to want
angioplasty," but he believes that's largely a product of how their
options are presented to them. "What they're being told is that OMT
is an option, but it really doesn't work well for angina and that PCI
is a better procedure for angina. . . . That's what's going on: it's
a dirty little secret, but I don't think patients are really being
given their options in a thorough and unbiased fashion. It's an
emotional issue to begin with, and I don't necessarily blame the
doctors; they're simply practicing along the lines of what they
believe. It's well-meaning, but in some cases it's wrong-minded."

In fact, Stone agreed that one of the areas for improvement could be
to pause after the diagnostic angiogram.

"We should figure out how to incorporate that discussion between the
referring physician, the general cardiologist, the interventional
cardiologist, the cardiac surgeon, and of course the patient, and it
is true that that doesn't happen when those decisions are made with
the patient on the table. On the other hand, when you talk to the
patient, they almost never want to come back for a second
procedure. . . . When a physician is honestly on the fence--should
this patient have angioplasty, surgery, or medical therapy?--the best
physicians will stop, and once the sedation wears off, have that
discussion with the patient. I do think at times there is a rush to
judgment, and I think we can do better."

Kereiakes has received research grants from Pfizer, Conor Medsystems,
Boston Scientific, Medtronic, Daiichi Sankyo, and Cordis Corp and
consulting fees from Conor Medsystems, Cordis Corp, Core Valve, Eli
Lilly, Boston Scientific, and Abbott/Bioabsorbable Vascular Solution.
Stone has received research grants from Boston Scientific and Abbott;
consulting fees from Xtent, St Jude Medical, and the Medicines Co;
honoraria from Boston Scientific, Abbott, the Medicines Co, Nycomed,
and Medtronic; has equity interests in Devax and Xtent; and is on the
board of directors of Devax. Diamond and Kaul state they have no
conflicts of interest.

Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and
consequences of the COURAGE trial. J Am Coll Cardiol 2007;
DOI:10.1016/j.jacc.2007.07.063. Available at:
http://content.onlinejacc.org.
Diamond GA, Kaul S. COURAGE under fire. On the management of stable
coronary disease. J Am Coll Cardiol 2007;
DOI:10.1016/j.jacc.2007.08.010. Available at:
http://content.onlinejacc.org.

#12848 From: dr_allen_wang
Date: Mon Sep 17, 2007 10:55 pm
Subject: Thyroid Diseases Influence Platelet Function
dr_allen_wang
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Alterations in platelet plug formation occur in patients with thyroid
diseases, which may help account for the blood coagulation
abnormalities observed in these patients, according to Austrian
researchers.

"These data provide a mechanism for the increased risk of bleeding
and cardiovascular accidents observed in hypothyroidism and
hyperthyroidism, respectively," lead investigator Dr. Monika Homoncik
told Reuters Health

In the August issue of the Journal of Clinical Endocrinology and
Metabolism, Dr. Homoncik and colleagues at the Medical University of
Vienna note that von Willebrand factor (vWF) levels are altered in
patients with thyroid abnormalities.

Because vWF plays an important role in primary hemostasis, the
researchers theorized that the increased vWF levels in
hyperthyroidism would enhance platelet plug formation, and
conversely, reduced vWF levels in hypothyroidism would diminish
platelet plug formation.

To investigate, the researchers studied 30 patients with overt
hyperthyroidism, 30 with overt hypothyroidism, and 30 with
subclinical hypothyroidism. Thirty euthyroid patients attending the
clinic for other reasons served as controls.

As anticipated, compared with the controls, baseline vWF levels were
higher in the hyperthyroid patients and lower in those with overt
hypothyroidism.

In addition, higher vWF antigen levels were associated with increased
baseline platelet plug formation and with reduced collagen
epinephrine-induced closure time (CEPI-CT). The researchers suggest
that this may contribute to the higher risk of cardiovascular disease
in these patients.

When the investigators treated the hyperthyroid patients with
thiamazole, levels of T4 and vWF normalized over 8 weeks. In the
hypothyroid patients, T4 therapy led to normalization and reversal of
their previously observed CEPI-CT prolongation.

"This provides further rationale for careful drug treatment of such
patients," concluded Dr. Homoncik.

J Clin Endocrinol Metab 2007;92:3006-3012.

#12847 From: dr_allen_wang
Date: Mon Sep 17, 2007 10:54 pm
Subject: International Approvals: Cubicin, BeneFIX, Aricept
dr_allen_wang
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The European Commission has approved daptomycin intravenous infusion
for the treatment of right-sided infective endocarditis and
bacteremia caused by Staphylococcus aureus; the European Medicines
Agency has approved new products intended to streamline the
reconstitution process for recombinant factor IX intravenous
injection; and the Japanese Ministry of Health, Labor, and Welfare
has approved donepezil HCl 10-mg tablets for the treatment of severe
Alzheimer's disease.


Daptomycin Injection (Cubicin) for RIE and Certain Bacteremias in EU

On September 5, the European Commission approved 2 new indications
for daptomycin intravenous infusion (Cubicin, Cubist Pharmaceuticals,
Inc), allowing its use for the treatment of right-sided infective
endocarditis (RIE), caused by Staphylococcus aureus, and S aureus
bacteremia (SAB) when associated with RIE or complicated skin/soft
tissue infections (cSSSi).

"In the UK alone, more than 15,000 patients are estimated to contract
SAB infections every year," the company says in a news release. "If
not quickly and effectively treated, up to one-third of these
patients may die from the infections. With growing resistance to
current treatments, these types of infections are becoming an
increasingly serious public health challenge."

The approval was based on data from a phase 3 clinical trial, showing
that daptomycin was equally effective against both methicillin-
susceptible and methicillin-resistant S aureus (MSSA and MRSA,
respectively).

Daptomycin therapy also met primary endpoints for noninferiority
compared with traditional dual therapy (semisynthetic penicillin plus
initial gentamycin for MSSA infections; vancomycin plus initial
gentamycin for MRSA infections).

"While the current standard of treatment often requires combination
therapies, [daptomycin] is a simpler approach to Gram-positive
infections as a once-daily monotherapy that requires no routine
therapeutic drug monitoring," the company notes.

The recommended dose of daptomycin for RIE and SAB caused by MSSA or
MRSA is 6 mg/kg, administered for more than a 30-minute period by
intravenous infusion in 0.9% sodium chloride once every 24 hours for
a minimum of 2 to 6 weeks.

Daptomycin previously was approved for these indications by the US
Food and Drug Administration in August 2006 and by the Taiwanese
Department of Health and the South Korean Food and Drug
Administration in August 2007. It also is approved in these countries
for the treatment of cSSSIs caused by susceptible isolates of
designated gram-positive microorganisms.


New Products Streamline Preparation of Factor IX Product (BeneFIX) in
EU

On August 20, the European Medicines Agency approved new enhancements
for recombinant coagulation factor IX intravenous injection (nonacog
alfa; BeneFIX, Wyeth Pharmaceuticals, Inc) that are intended to
streamline the reconstitution process.

These benefits include a 2000-IU dosage strength vial, to reduce the
number of vials required for a dose, and a prefilled 5-mL diluent
syringe for use with all dosage strengths that provides increased
convenience and may reduce the overall infusion volume.

"Each of these new features was designed to enable BeneFIX patients
to spend less time preparing their factor product, to prepare it more
safely and to have additional time for themselves," says Gary L.
Stiles, MD, executive vice president and chief medical officer, Wyeth
Pharmaceuticals, in a company news release.

Coagulation factor IX (recombinant) is indicated for the treatment
and prophylaxis of bleeding in patients with hemophilia B (congenital
factor IX deficiency).


Donepezil HCl 10-mg Tablets Bevacizumab (Aricept) Severe AD in Japan

On August 22, the Japanese Ministry of Health, Labor, and Welfare
approved a new 10-mg dose and corresponding indication for donepezil
HCl (Aricept, Eisai Company, Ltd), that allows its use for the
treatment of severe Alzheimer's disease (AD).

According to a company news release, the approval was based on data
from clinical trials conducted abroad and in Japan.

Results from the multicenter, randomized, double-blind, placebo-
controlled Japanese study (n = ~300) showed that whereas use of 5- or
10-mg/day donepezil significantly improved cognitive function, use of
the 10-mg/day dose also significantly improved global functioning vs
placebo at 6 months.

Adverse events most commonly reported in the higher-dose group were
gastrointestinal in nature and mild to moderate in severity.

The recommended initial dose for patients with mild to moderate AD is
3 mg donepezil once daily; this dose may be increased to 5 mg daily
after 1 or 2 weeks. Those with severe AD should start with a dose of
5 mg/day and uptitrate it to 10 mg/day after 4 weeks.

Donepezil 3- and 5-mg tablets previously were approved in Japan for
the treatment of mild to moderate AD. The 10-mg dose of donepezil and
its use for severe AD were approved by the US Food and Drug
Administration in October 2006.

#12841 From: dr_allen_wang
Date: Sun Sep 16, 2007 12:22 am
Subject: RE-NOVATE Published: Dabigatran Promising in VTE Prevention
dr_allen_wang
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The RE-NOVATE study, showing the new oral anticoagulant dabigatran
etexilate (Boehringer Ingelheim) to be as effective as enoxaparin in
preventing venous thromboembolism (VTE) after total hip replacement
surgery, has been published in the September 15, 2007 issue of the
Lancet.

#12838 From: dr_allen_wang
Date: Fri Sep 14, 2007 11:22 pm
Subject: Testosterone Deficiency Unlikely Cause of Glucose Intolerance
dr_allen_wang
Offline Offline
 
Two years of testosterone replacement had little effect on
carbohydrate tolerance, insulin secretion or glucose tolerance in
elderly men with testosterone deficiency, according to research
conducted by Dr. Rita Basu of the Mayo Clinic in Rochester,
Minnesota, and associates.

Dr. Basu's team randomized 55 testosterone-deficient men between the
ages of 64 and 77 to a testosterone patch that delivered a dose of 5
mg/day or placebo for 2 years.

At baseline, subjects had bioavailable testosterone concentrations
below 103 ng/dL and DHEA concentrations below 1.57 micrograms/mL,
which put them below the 15th percentile for healthy young men.

Fasting and postprandial glucose, insulin and C-peptide
concentrations, endogenous glucose production and glucose disposal
were compared in the two groups at baseline and after 2 years of
testosterone replacement therapy.

Measurements were similar in both groups both before and after
testosterone replacement. "Furthermore, the change over time in
insulin action and glucose effectiveness...as well as insulin
secretion and hepatic insulin clearance (measured with the C-peptide
model), did not differ in the testosterone and placebo groups," Dr.
Basu's team reports in the August issue of Diabetes Care.

"Testosterone deficiency is unlikely the cause of the age-associated
deterioration in glucose tolerance commonly observed in elderly men.
These data also argue against the premise that testosterone
replacement will delay or prevent the progression of the age-
associated deterioration in glucose tolerance that is commonly
observed in elderly men," the Mayo Clinic team concludes.

Diabetes Care2007;30:1972-1978.

#12837 From: dr_allen_wang
Date: Fri Sep 14, 2007 11:22 pm
Subject: Moderate Then Rapid Blood Glucose Increases Precede Type 2 Diabetes
dr_allen_wang
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Progression to type 2 diabetes is typically preceded by moderate
followed by rapid increases in glucose levels, according to findings
reported in the August issue of Diabetes.

"In the past, physicians may have thought that individuals developed
type 2 diabetes either with gradually worsening glucose levels or in
some erratic manner," Dr. Clinton C. Mason told Reuters
Health. "This paper suggests that the pattern of disease development
involves two distinct effects on the glucose levels, both of which
may contribute to the disease, though the rapid rise is the obvious
malefactor."

Dr. Mason, from the National Institutes of Diabetes and Digestive
and Kidney Diseases in Phoenix, Arizona and associates analyzed the
rate at which 2-hour plasma glucose concentrations change during
progression from the nondiabetic state to diabetes among Pima
Indians participating in a longitudinal study.

The best glucose effects model consisted of an initial linear
pattern of glucose increase followed by a smooth transition to a
more rapid rise in glucose, the authors report.

The exponential effect began to outweigh the linear increase as
early as 6 years before diabetes onset, the researchers note.

"The timeframe of this latter change may be very rapid for some
individuals - beyond our ability to detect with biennial exams,
meaning that some individuals transition from a normal to a diabetic
state in less than 2 years, and how much less we do not know," Dr.
Mason explained. "Hence, for physicians seeing individuals with
seemingly normal glycemic levels, the main message is that they
should not imply the patient is not at risk for diabetes."

Theoretically, "if the rapid rise could be prevented, individuals
would not pass the diabetes threshold following their initial linear
trend until many years later (we estimated as many as 30 years
later)," Dr. Mason said. "Hence, identification of the cause of the
rapid rise is essential in diabetes research and prevention and
should receive great attention."

Intervention studies such as the Diabetes Prevention Program "have
shown that type 2 diabetes can, on average, be delayed," concluded
Dr. Mason. "Further research may determine whether individual
markers can predict in whom that delay is most likely -- and in whom
it is too late."

Diabetes 2007;56:2054-2061.

#12836 From: dr_allen_wang
Date: Fri Sep 14, 2007 11:21 pm
Subject: CT Angiography Predicts All-Cause Mortality
dr_allen_wang
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One of the first large studies to look at the prognostic
capabilities of multislice computed tomography angiography (CTA)
suggests that the modality can accurately identify chest-pain
patients who face a significantly increased risk of all-cause
mortality within 15 months [1]. Authors of the study say that while
their findings need to be replicated and should also include cardiac-
specific end points such as MI and cardiac death, the study still
provides some of the first solid evidence that imaging plaques on
CTA can be used to predict survival.

"We look at a diagnostic imaging test in three ways: it needs to be
diagnostically accurate, it needs to prognosticate outcomes, and
ultimately it should prompt appropriate effective therapies so that
when individuals are treated with those therapies, they do better,"
lead author on the study, Dr James K Min (Cornell University, New
York, NY), told heartwire. "For CT, I think that the first end point
has been demonstrated . . . but what we don't have are the outcomes
studies that relate CT results to a patient's prognosis. That's why
we initiated this study. We wanted to figure out whether what we're
calling disease on a CTA really matters--ie, does the overall
coronary plaque burden and severity of coronary stenosis actually do
anything bad to patients, or are we just imaging plaques for the
sake of imaging plaques?"

Min et al's paper appears online in the Journal of the American
College of Cardiology September 12, 2007.

Extent and distribution of coronary calcium key

Min et al used CTA in 1127 patients being evaluated for chest pain,
scoring their stenosis as minimal, mild, moderate, or severe. Plaque
was further assessed according to the distribution and degree of
obstruction; according to a modified Duke coronary artery score
(which considers severity and extent of disease); and using a
simplified grading system that combined plaque extent and
distribution. All CTA assessments were then correlated with all-
cause deaths over a 15-month period, after adjustment for risk
factors and pretest likelihood of having coronary artery disease; in
all, 39 patients (3.5%) died during follow-up.

The authors report that key predictors of death were highly visible
coronary stenosis in the proximal left anterior descending (LAD)
artery or left main or moderate or severe stenosis (>50% or >70%) in
any coronary artery.

"What we found is that while the presence of severe plaque is bad,
presence of severe plaque within the proximal portion of that LAD or
the left main artery is a lot worse. And that corroborates as well
as extends what we knew from invasive coronary angiography," Min
said.

The modified Duke prognostic score also was a significant predictor
of all-cause mortality, as was the simplified clinical coronary
plaque scoring system proposed by the authors, wherein a segment-
stenosis score or segment-involvement score >5 significantly
predicted death.

"What we wanted to do was create simple scores that clinical
cardiologists could use," Min explained. "I would put forward that
one of the reasons the Duke coronary artery jeopardy score is not
widely used in clinical practice is because it's a little unwieldy
for the general cardiologist to calculate. Here we didn't want to
make a confusing scoring system, we just divided the coronary
segments into a modified AHA coronary segment model, and we just
said, how many of those segments have plaque in them? And we counted
up those segments and called that a segment-involvement score. And
we felt that was a pretty decent estimate of the overall plaque
distribution. The other thing we did was grade stenosis as none,
mild, moderate, or severe, on a scale of 0 to 3. And we said that
not only does the distribution of plaque matter, but the overall
burden matters, too. The way we did that is we took those 16
segments and however many of them had plaque, we counted up the
severity, with the total possible score being 40 and the minimum
score being 0. And we thought, that's something easy for someone to
calculate."

Overall, subjects with less than 50% stenosis had the best survival
rates, at 99.7%, whereas those with the highest Duke scores had the
worst. With the simplified clinical scoring system, patients with
scores >5 had a 5% to 6% higher absolute death rate than did
subjects with a score of <5.

Registry data in lieu of trials

Min emphasizes that further information is needed, some of which may
come from the ongoing SPARC registry. The question of whether CTA
offers anything over and above other imaging modalities, including
conventional coronary angiography or nuclear imaging, also requires
further study, he said. But Min also believes the evidence from his
registry and others may be as good as it gets.

"I know people will argue that we need a randomized controlled
trial, taking low-, intermediate-, and high-risk patients and
randomizing them to nuclear imaging or CT. . . . But I don't think
that trial is ever going to be done, because I think it would be
prohibitively expensive, particularly if you're going to study a low-
risk population of people: you'd need tens of thousands of people
enrolled."

Instead, Min says he is turning his attention to the problems of
assessing plaque composition--his study suggests that mixed
calcified/noncalcified plaque seems to be the worst in terms of
predicting mortality. Other research addressing plaque severity and
distribution in relation to left ventricular function and myocardial
perfusion as a means of predicting outcomes is also critical, he
says.

Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of
multidetector coronary computed tomographic angiography for
prediction of all-cause mortality. J Am Coll Cardiol 2007; 50:1161-
1170.

#12832 From: dr_allen_wang
Date: Thu Sep 13, 2007 10:23 pm
Subject: Mediterranean Diet Linked to Reduced Mortality Risk in AD
dr_allen_wang
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A new study has shown an association between following the
Mediterranean diet and a reduced mortality in patients with
Alzheimer's disease (AD).

"In previous studies, we had demonstrated that higher adherence to
the Mediterranean diet is protective for the development of
Alzheimer's disease, and in this study, we addressed the question of
whether following this diet further modifies the course of disease,"
first author Nikolaos Scarmeas, MD, from Columbia University Medical
Center, in New York, told Medscape. "What we found was that adherence
to this diet is related to prolonged survival in these patients."

Their report appears in the September 11 issue of Neurology.

Beneficial Dietary Pattern

The Mediterranean diet is characterized by a high intake of
vegetables, legumes, fruits, and cereals; a high intake of
unsaturated fatty acids, mostly in the form of olive oil; a low
intake of saturated fatty acids; a moderately high intake of fish; a
low to moderate intake of dairy products, mostly as cheese or yogurt;
a low intake of meat or poultry; and finally, a regular but moderate
amount of alcohol, usually wine and generally taken with meals.

Previous research on this dietary pattern has shown that following a
Mediterranean diet is protective against a variety of conditions,
including hypertension, coronary heart disease, dyslipidemia,
diabetes, obesity, and certain cancers, as well as related to a
reduction in all-cause mortality in the general population, Dr.
Scarmeas noted. He and colleagues have also previously reported that
higher adherence to this type of Mediterranean-style diet is
associated with a lower risk for AD (Scarmeas N et al. Arch Neurol.
2006;63:1709-1717; Scarmeas N et al. Ann Neurol. 2006;59:912-921.)

To look at potential effects of the diet on disease course and
outcomes in AD, they prospectively followed 192 subjects with a
diagnosis of AD over 1.5 years. Their adherence to the Mediterranean
diet was assessed using a 0- to 9-point scale, with higher scores
indicating higher adherence.

Over 4.4 years of follow-up, 85 (44%) of the AD patients died.
Adherence to the Mediterranean diet was the main predictor of
mortality in Cox models adjusted for period of recruitment, age,
gender, ethnicity, education, APOE genotype, caloric intake, smoking,
and body mass index.

For each additional point for higher adherence to the diet, mortality
risk fell, with a hazard ratio of 0.76 (95% CI, 0.65 ”V 0.89; P
= .001), even after all covariates were controlled for, they note.

Compared with those in the lowest tertile for adherence, those in the
middle tertile had a lower mortality risk, with a 1.33-year-longer
survival; those in the highest tertile had an even lower risk, with a
3.91-year-longer survival, suggesting a dose-response effect, the
authors note.

Since patients do not die of Alzheimer's disease itself, he said, it
is likely that the diet reduces mortality through other causes such
as cardiovascular disease.

"New benefits of this diet keep coming out," Dr. Scarmeas said in a
statement from the American Academy of Neurology. "We need to do more
research to determine whether eating a Mediterranean diet also helps
Alzheimer's patients have slower rates of cognitive decline, maintain
their daily living skills, and have a better quality of life."

Data on these other aspects of the AD course will be available from
the current study and are now being analyzed for future reports, he
told Medscape.

Back to the Basics?

In an editorial accompanying the paper, James E. Galvin, MD, from the
Alzheimer Disease Research Center at the University of Washington
School of Medicine, in St. Louis, Missouri, points out that several
large population studies have suggested that the Mediterranean diet
protects against death from any cause, as well as potentially
reducing the risk for AD.

"The ability to accurately measure adherence to specific dietary
patterns will become increasingly important in epidemiologic studies
not only for neurodegenerative disease, but also for numerous other
conditions, including cardiovascular disease, cerebrovascular
disease, and cancer," he writes.

In the case of AD, he notes, dietary changes but also exercise and
mental stimulation may reduce the risks for and consequences of the
disease. "It is interesting that considering all the medical and
pharmacological advances made in the past century, perhaps the most
important things we can still tell our patients, regardless of why
they come to the office, is to stay mentally active and physically
fit and eat a healthy and balanced diet," Dr. Galvin concludes.

This study was supported by grants from the National Institute on
Aging, the Charles S. Robertson Memorial Gift for Research in AD, the
Blanchette Hooker Rockefeller Foundation, the New York City Council
Speaker's Fund for Public Health Research, and the Taub Institute for
Research on AD and the Aging Brain. The authors report no conflicts
of interest. Dr. Galvin reports no conflict of interest.

Neurology. 2007;69:1084-1093 Abstract,1072-1073.

#12831 From: dr_allen_wang
Date: Thu Sep 13, 2007 10:21 pm
Subject: Continued
dr_allen_wang
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Nearly two thirds of US adults are overweight, leading to increased
mortality and adverse health outcomes, including CHD. A BMI of 25.0
to 29.9 kg/m2 is considered moderately overweight, whereas a BMI of
30.0 kg/m2 or greater is considered obese. Several mechanisms could
explain the effect of overweight on CHD independent of traditional
risk factors. These include a state of low-grade inflammation,
endothelial dysfunction, hemostatic imbalance favoring coagulation,
impaired endothelial vasodilatory responses, left ventricular
hypertrophy caused by an increased blood volume, and reduced heart
rate variability caused by withdrawal of vagal activity and
sympathetic predominance.

The aim of this review is to investigate the relationship between
overweight and CHD and the extent to which this relationship is
mediated by adverse effects of overweight on BP and cholesterol
levels.

Stdy Highlights

In this meta-analysis study, RRs of CHD associated with moderate
overweight and obesity with and without adjustment for BP and
cholesterol concentrations were calculated by the members of a
collaboration of prospective cohort studies of healthy persons and
pooled by means of random-effects models (RRs for categories of BMI
in 14 cohorts and for continuous BMI in 21 cohorts; total N =
302,296).
Most studies used either mortality from CHD or incidence of CHD (both
fatal and nonfatal events) as their endpoint.
The main outcome measure of the analysis was the age-, sex-, physical
activity”V, and smoking-adjusted RR of CHD, with and without
adjustment for BP and cholesterol levels.
A total of 18,000 CHD events occurred during follow-up.
The age-, sex-, physical activity”V, and smoking-adjusted RRs for
moderate overweight and obesity vs normal weight were 1.32 (95%
confidence interval [CI], 1.24 - 1.40) and 1.81 (95% CI, 1.56 -
2.10), respectively.
Additional adjustment for BP and cholesterol levels reduced the RR to
1.17 (95% CI, 1.11 - 1.23) for moderate overweight and to 1.49 (95%
CI, 1.32 - 1.67) for obesity. This corresponds to a decrease in
excess risk of 47% for moderate obesity and 40% for obesity.
The RR associated with a 5-unit BMI increment was 1.29 (95% CI, 1.22 -
  1.35) before and 1.16 (95% CI, 1.11 - 1.21) after adjustment for BP
and cholesterol levels. These adjustments lowered the excess risk by
45%.

Pearls

Several mechanisms could explain the effect of overweight on CHD;
these include a state of low-grade inflammation, endothelial
dysfunction, hemostatic imbalance favoring coagulation, impaired
endothelial vasodilatory responses, left ventricular hypertrophy
caused by an increased blood volume, and reduced heart rate
variability caused by withdrawal of vagal activity and sympathetic
predominance.
The adverse effects of overweight on BP and cholesterol levels could
account for about 45% of the increased risk for CHD.

#12830 From: dr_allen_wang
Date: Thu Sep 13, 2007 10:20 pm
Subject: Overweight Increases CHD Risk Independent of BP and Cholesterol
dr_allen_wang
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Even moderately overweight individuals have an increased risk of
coronary heart disease (CHD) that is independent of the effects of
their weight on blood pressure and cholesterol levels, a new meta-
analysis in more than 300,000 people shows.[1] Dr Rik P Bogers
(National Institute for Public Health and the Environment, Bilthoven,
the Netherlands) and colleagues report their findings in the
September 10, 2007 issue of the Archives of Internal Medicine.

Bogers told heartwire that it was already known that obese
individuals have an increased risk of CHD independent of blood
pressure and cholesterol, but this is one of the first studies to
show a similar finding with regard to moderate overweight. The
results are important, he says, because they indicate that even when
overweight people are optimally treated for hypertension and
hypercholesterolemia, they will still retain an elevated risk of CHD.

"This indicates that overweight or obesity should be included in
commonly used risk-stratification schemes, such as Framingham,"
Bogers told heartwire. Such models have not traditionally
incorporated body mass index (BMI) or other measures of body weight ”X
  such as waist-to-hip ratio ”X although some newer models being
assessed do include BMI, such as the recently proposed Q-RISK score
in the UK.

Effects of overweight on BP, lipids, account for half of increased
risk of CHD

Bogers and colleagues included 21 studies in their meta-analysis,
including a total of 302,296 participants and 18,000 CHD events in
predominantly white populations from around the world. They found
that a five-unit increment in BMI was associated with a 29% increased
risk of CHD and, after additional adjustment for blood pressure and
cholesterol levels, with a 16% increased risk.

"The present study indicates that adverse effects of overweight on
blood pressure and cholesterol levels could account for about 45% of
the increased risk of CHD and that there is still a significantly
increased risk of CHD that is independent of these effects," the
researchers note.

Bogers et al say that several mechanisms could underlie an effect of
overweight on CHD independent of traditional risk factors, including
a state of low-grade inflammation, endothelial dysfunction, and
hemostatic imbalance favoring coagulation, among others.

Is effect of overweight mediated through diabetes? Maybe, but only
partly so

In the US National Cholesterol Education Program Adult Treatment
Panel III, obesity is not listed as a risk factor because it is said
to operate through diabetes and other risk factors, Bogers et al
note. So including data on diabetes and glucose intolerance ”X which
were not available ”X in this meta-analysis "would have further
attenuated the RR of CHD associated with overweight," they admit.

However, Bogers told heartwire that while he believes diabetes does
also contribute to the increase in CHD associated with overweight, he
doesn't think it can account for all of the risk remaining after
adjustment for blood pressure and cholesterol.

The bottom line, says Bogers, is that "the worldwide increase in
moderate overweight may drive the incidence of CHD upward."

Source

Bogers RP, Bemelmans WJ, Hoogenveen RT, et al. Association of
overweight with increased risk of coronary heart disease partly
independent of blood pressure and cholesterol levels. A meta-analysis
of 21 cohort studies including more than 300 000 persons. Arch Intern
Med 2007;167(16):1720-1728.

#12827 From: dr_allen_wang
Date: Wed Sep 12, 2007 11:05 pm
Subject: Triglyceride Buildup in the Diabetic Heart: Imaging Study Helps Explain Developm
dr_allen_wang
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The use of magnetic resonance spectroscopy (MRS), an imaging
technology used primarily in research, has allowed investigators to
detect the accumulation of triglycerides in the hearts of patients
with impaired glucose tolerance, as well as those with type 2
diabetes mellitus [1]. The storing of excess lipids in human cardiac
myocytes is an early manifestation in the pathogenesis of type 2
diabetes, say investigators, also evident in those with impaired
glucose handling, and might help explain the myocardial dysfunction
often observed in type 2 diabetic patients.

"This study is based on previous studies where we previously showed
the buildup of fat in skeletal muscle and in the liver of patients
with insulin resistance," said senior investigator Dr Lidia
Szczepaniak (University of Texas Southwestern Medical School,
Dallas, TX). "This is a more ambitious task, measuring the fat in a
beating heart, but the study is inspired by research done in animal
models showing that as animals become insulin resistant, they have
more fat in the heart, and that these hearts are extremely
dysfunctional. In patients with insulin resistance and with
diabetes, the buildup of fat is occurring way before that function
is affected."

The results of the study are published in the September 4, 2007
issue of Circulation.

Heart failure common in diabetic patients

In discussing the study with heartwire, Szczepaniak said that in
addition to contributing to coronary artery disease risk, the
metabolic abnormalities associated with diabetes also lead to
abnormalities in cardiac function. This cardiac dysfunction, she
said, is believed to be independent of the effects of diabetes on
the vasculature. More than 30 years ago, in fact, Framingham
investigators first suggested that patients with type 2 diabetes had
an increased risk of congestive heart failure, an association that
remained even after adjustment for atherosclerotic disease.

Szczepaniak said that while the mechanisms in which diabetes causes
cardiac dysfunction are unclear, animal studies have suggested that
abnormalities in diastolic and systolic function are the result of
an excessive storing of lipids and lipotoxic injury to
cardiomyocytes. The overstorage of lipids, known as cardiac
steatosis, produces lipotoxic substances that result in oxidative
stress and can cause apoptosis, but investigators point out that it
is not known whether this overstorage of lipids is the cause or
consequence of heart failure in type 2 diabetes.

To clinically evaluate the diabetic heart, the investigators, led by
Dr Jonathan McGavock (University of Texas Southwestern Medical
School), used MRS to detect cardiac steatosis throughout the
progressive stages in the natural history of diabetes. Overall,
investigators stratified 134 individuals to undergo MRS and included
lean and obese subjects with normal glucose tolerance, those with
abnormal glucose tolerance, and those with diabetes mellitus.

As measured by spectroscopy, the myocardial triglyceride content was
elevated in the obese subjects but was higher in subjects with
impaired fasting glucose levels and diabetes. Subcutaneous and
visceral fat was lowest in the lean groups, elevated only among the
obese and those with metabolic abnormalities. The amount of fat in
the heart was unrelated to the amount of fat in the blood or liver
and suggests that these measures are not sufficient to predict
cardiac steatosis or possible cardiac dysfunction, say investigators.

The investigators say the data emphasize that in the presence of
normal glucose tolerance, obesity is not necessarily enough to cause
cardiac steatosis, mainly because the myocardial triglyceride levels
were not associated with body mass index. Also, given that the
buildup of fat in the heart of those with impaired glucose tolerance
precedes the onset of diabetes mellitus as well as ventricular
dysfunction associated with diabetes, the detection of overstorage
of lipids might be used a means to screen for cardiac dysfunction
prior to the onset of heart failure in diabetic patients.

"The main message of our work is that we can test the abnormalities
in the heart way before the symptoms of heart failure are detected,"
said Szczepaniak.

MRS uses the same principles as MR imaging, allowing researchers to
observe protons in fat and water and quantify the amount of lipids
in cardiac cells. Spectroscopy provides information about the
metabolites, explained Szczepaniak, while MRI is the two-dimensional
application of spectroscopy that creates the images. Spectroscopy is
not in high demand, thus making the hardware and software for
spectroscopy scarce. However, this type of imaging is used
frequently for measuring hepatic triglyceride levels, she noted.

Findings "make sense" but clinical utility questioned

Writing in an editorial accompanying the paper [2], Dr Frederick
Ruberg (Boston University School of Medicine, MA) notes that these
data contradict smaller studies suggesting the myocardial
triglyceride levels are related to age or body mass index but make
sense given animal and human studies showing the accumulation of
lipids in other organs in diabetes mellitus.

"This study does not imply causality but does strongly suggest that
accumulation of myocardial triglyceride is at least a marker of
early cardiac dysfunction in patients with insulin resistance,"
writes Ruberg. "More rigorous studies of diastolic characterization
in subjects with more advanced heart failure and diabetes mellitus
would be interesting to test whether increased lipid content is
associated with more profound dysfunction."

One limitation, he suggests, relates to the clinical significance of
the study. In contrast to MRI, MR spectroscopy is technically
challenging to perform, requiring high sensitivity and a precision
that might be difficult to reproduce, and is unlikely to be widely
applied clinically. However, it is an excellent research tool,
writes Ruberg, "one that will continue to provide a window into the
potential mechanism(s) of cardiac dysfunction in insulin-resistant
states."

The study by the Texas study group, he adds, is of "significant
importance because it provides strong evidence linking observations
from animal models of cardiac lipotoxicity to humans with diabetes
mellitus. With future simplification of spectroscopic techniques, it
is foreseeable that myocardial lipid content may one day be used as
a biomarker to predict the development of cardiac dysfunction in
patients with insulin-resistant states and may serve as a measurable
target for intervention before the development of diabetic
cardiomyopathy."

In terms of patients enrolled in the study, Ruberg noted that
subjects taking thiazolidinediones, agents known to modulate
intracellular lipid content, were excluded from the study to avoid
confounding the results.

McGavock JM, Lingvay I, Zib I, et al. Cardiac steatosis in diabetes
mellitus: A 1H-magnetic resonance spectroscopy study. Circulation
2007; 116:1170-1175. Abstract
Ruberg F. Myocardial lipid accumulation in the diabetic heart.
Circulation 2007; 116:1110-1113. Abstract

#12826 From: dr_allen_wang
Date: Wed Sep 12, 2007 11:04 pm
Subject: First Evidence of Causal Link Between Diesel Fumes and Ischemia
dr_allen_wang
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A new study has shown that brief exposure to dilute diesel-exhaust
fumes during exercise promotes myocardial ischemia and inhibits
endogenous fibrinolytic capacity in men with stable coronary disease
[1]. "Our findings point to ischemic and thrombotic mechanisms that
may explain in part the observation that exposure to combustion-
derived air pollution is associated with adverse cardiovascular
events," say Dr Nick Mills (Edinburgh University, Scotland) and
colleagues in their paper in the September 13, 2007 issue of the New
England Journal of Medicine.

Mills told heartwire that while a wealth of large-scale and robust
studies have been conducted in the past five to 10 years looking at
the association between air pollution and adverse cardiac
outcomes, "these have been challenged because it's been impossible
to prove causality. What's been missing in this field is an
understanding of what the mechanism is that links exposure to
adverse outcomes. We're the first group to have conducted controlled
exposures anywhere in the world, and our results are important
because they provide strength to the observational studies, and they
show that this is indeed a causal relationship we are talking
about."

In an accompanying editorial [2], Dr Murray A Mittleman (Beth Israel
Deaconess Medical Center, Boston, MA) says: "The evidence from Mills
and colleagues suggests that the risk of having an acute
cardiovascular event triggered by vigorous exertion may be
heightened with exposure to high levels of air pollution."

Precise mechanisms remain unclear

Mills et al screened and recruited 20 men who had had a prior MI but
were asymptomatic with no exertional angina and who were on optimal
secondary-prevention medication. In the double-blind, randomized,
crossover study--conducted at Umea University in Sweden--the men
were exposed for one hour to either filtered air or dilute diesel-
exhaust fumes (300 µg/m3) while intermittently riding a bicycle
ergometer for two 15-minute periods, separated by 15-minute rest
periods. Mills said the levels of diesel fumes in the study were
chosen to mimic the sorts of air pollution that would be encountered
in everyday life.

During the exposure, myocardial ischemia was quantified by ST-
segment analysis using continuous 12-lead ECG. Six hours after
exposure, vasomotor and fibrinolytic functions were assessed by
means of intra-arterial agonist infusions.

During both the air and diesel exposures, heart rate increased
similarly with exercise, but there was as much as a threefold
increase in myocardial ischemia during exposure to diesel-exhaust
fumes compared with filtered air (-22.4 vs -8 mV-sec; p<0.001).
Exposure to diesel fumes did not aggravate preexisting vasomotor
dysfunction, but it did dampen the acute release of endothelial
tissue plasminogen activator by 35%.

"We have identified two distinct and potentially synergistic adverse
cardiovascular effects of air pollution in patents with coronary
heart disease, [which] may contribute to the increased incidence of
myocardial infarction after exposure to traffic," say Mills et al.
However, they acknowledge, "the precise mechanisms by which diesel-
exhaust inhalation induces these ischemic and thrombotic effects
have not been established in our study and will need to be
determined in future work."

Mills said they also plan to examine patients with symptomatic
angina in future studies, to see whether this kind of air pollution
would be significant enough to trigger hospitalization and to try to
further explain the observations seen in epidemiologic literature.

Teasing out the guilty components is not easy

In the editorial, Mittleman observes that this study was specific in
examining the effects of dilute diesel-exhaust fumes--an extremely
complex mixture of particles and gases: "It is not possible to glean
which constituents were responsible for the observed effects.
Complicating matters further, ambient air pollution is a
heterogonous mixture of gases and particulate matter, of which
diesel exhaust is only one of many components."

Mills acknowledges this problem and says that they hope to conduct
future studies that will be able to pinpoint specifically what
components are responsible for these effects. Nevertheless, he
says: "We do believe--although we have not proven in this study--
that the effect is mediated by the particulate phase of diesel
exhaust rather than the gaseous pollutants. Particle size is also
thought to be very important," he adds. "The smaller the particle
size, the larger the surface area and the more likely the particle
is to become blood-borne and have direct effects on the blood vessel
and the heart. A diesel engine produces predominantly small
particles, called nanoparticles, and this is one reason why it has
potent toxic effects. Diesel engines produce 10 to 100 times more
fine particulate matter than equivalent-sized gasoline engines, due
to differences in the way the two engines work."

Ironically, Mills says, the move to limit greenhouse-gas emission
and reduce global warming has led to an increase in the popularity
of diesel engines, particularly in Europe. "Current legislation does
not focus strongly on particulate emissions," he notes, "but the
technology is available to try to reduce particle emissions, and
this could be legislated for in the future. "

Exercise away from traffic whenever possible

Mittleman says that while there are some important limitations to
this study with respect to generalizability, "if such exposures are
causal, these findings may represent the tip of an iceberg
constituting the effects of transient changes in exposure to
elevated levels of air pollution on cardiovascular risk. Considering
the unequivocal benefit of habitual exercise . . . the risk/benefit
ratio may be optimized if people exercise away from traffic when
possible," he concludes.

Dr Peter Weissberg (British Heart Foundation, London, UK) agrees:
"Because of the overwhelming benefits of exercise on heart health,
we would still encourage heart patients to exercise regularly, but
preferably not when there is a lot of local traffic around. Heart
patients can look out for pollution levels on their local weather
forecasts." Mills concurs, saying the take-home message has to
be: "Don't be put off exercise, because regular exercise can reduce
cardiac risk, but avoid exposure to traffic where possible."

Mills NL, Tornqvist H, Gonzalez MC, et al. Ischemic and thrombotic
effects of dilute diesel-exhaust inhalation in men with coronary
heart disease. N Engl J Med 2007; 357:1075-1082.
Mittleman MA. Air pollution, exercise, and cardiovascular risk. N
Engl J Med 2007; 357:1147-1149.

#12825 From: dr_allen_wang
Date: Wed Sep 12, 2007 11:04 pm
Subject: Idraparinux: Mixed Results in DVT and PE
dr_allen_wang
Offline Offline
 
Three studies with the new long-acting factor X inhibitor
idraparinux (Sanofi-Aventis) have shown mixed results [1,2]. While
the new agent showed similar results to standard antithrombotic
therapy in the initial treatment of deep vein thrombosis (DVT), it
was less effective than standard therapy in the treatment of
pulmonary embolism (PE).

And for extended therapy for both DVT and PE, idraparinux was more
effective than placebo in preventing recurrent thromboembolism, but
it was associated with increased, clinically significant bleeding,
and the authors say the "net clinical benefit of such treatment is
marginal."

The studies are published as two papers in the September 13, 2007
issue of the New England Journal of Medicine, one dealing with
initial treatment of both DVT and PE, and the second focusing on
extended treatment. They were all conducted by the same group of
researchers--the van Gogh investigators, led by Dr Harry Buller
(Academic Medical Center, Amsterdam, the Netherlands).

Buller commented to heartwire that the drug looks promising in DVT
and that the PE results may be explained by a lower-than-expected
recurrence rate in the standard-therapy arm. Another trial is
therefore being planned in PE. This new trial, along with a new
trial in atrial fibrillation, is using a new form of the drug, which
has an extra biotin molecule attached, which enables it to be more
easily neutralized, an important improvement given the long duration
of action of idraparinux.

Initial treatment

In the first paper, Buller et al note that the standard treatment
for both DVT and PE is an initial course of unfractionated heparin
or low-molecular-weight heparin, followed by a vitamin-K antagonist
for three to 12 months. This therapy is effective but requires
laboratory monitoring and dose adjustments. Idraparinux, a new
factor X inhibitor that has a substantially longer half-life than
fondaparinux, can be given subcutaneously once weekly, and initial
results suggest that it is effective and causes less bleeding than
vitamin-K antagonists in the treatment of venous thromboembolism.
They therefore conducted two randomized, open-label noninferiority
studies to investigate whether idraparinux alone could replace the
combination of unfractionated heparin or low-molecular-weight
heparin with a vitamin-K antagonist in 2904 DVT and 2215 PE patients.

In both trials, patients received either subcutaneous idraparinux
(2.5 mg once weekly) or heparin followed by an adjusted-dose vitamin-
K antagonist for either three or six months. The primary efficacy
outcome was the three-month incidence of symptomatic recurrent
venous thromboembolism (nonfatal or fatal).

Results showed that in the study in DVT patients, idraparinux had an
efficacy similar to that of heparin plus a vitamin-K antagonist,
satisfying the prespecified noninferiority requirement. But in
patients with pulmonary embolism, idraparinux was less efficacious
than standard therapy.

Extended treatment

In the second paper, Buller et al explain that patients who have had
venous thromboembolism have a high risk of recurrence during the
first six to 12 months after the first event. While vitamin-K
antagonists are highly effective in reducing the risk of recurrence,
their use requires close laboratory monitoring and dose adjustments
to reduce the risk of bleeding, and they are often discontinued
before the recommended period of prophylaxis. They thus conducted a
study in 1215 patients who had completed six months of initial
treatment for DVT or PE and who were then randomized to an
additional six months of prophylaxis with idraparinux or placebo.
Results showed that idraparinux was effective in preventing
recurrent thromboembolism but was associated with an increased risk
of a major hemorrhage.

Of the 11 episodes of major bleeding in the idraparinux group, three
were fatal intracranial hemorrhages. Buller et al note that of the
11 patients in the idraparinux group who had a major hemorrhage,
eight had received idraparinux for the initial six months of
treatment and three had received a vitamin-K antagonist. After
completion of the extended idraparinux treatment, there were another
five episodes of major bleeding in the idraparinux group,
observations that suggest a prolonged risk of hemorrhage in patients
treated with idraparinux for more than six months.

They also point out that the overall frequency of recurrences in the
placebo group was lower than expected, but patients who received
idraparinux for six months before randomization had a far lower
recurrence rate (less than 1%) than those who had received vitamin-K
antagonists as the initial treatment (5.9%), suggesting a prolonged
antithrombotic effect of idraparinux.

The studies were supported by Sanofi-Aventis. The steering committee
of the trial included two representatives of the company. Several of
the authors, including Buller, report receiving consulting and
lecture fees and grant support from Sanofi-Aventis and some from
other companies active in this field as well.

Buller HR, Ander TC, Davidson B, et al. Idraparinux vs standard
therapy for venous thromboembolic disease. N Engl J Med 2007;
357:1094-1104.
Buller HR, Ander TC, Davidson B, et al. Extended prophylaxis of
venous thromboembolism with idraparinux. N Engl J Med 2007; 357:1105-
1112.

#12815 From: dr_allen_wang
Date: Mon Sep 10, 2007 10:55 pm
Subject: STEEPLE at One Year
dr_allen_wang
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One-year results from the STEEPLE trial, presented by Dr Gilles
Montalescot (Hōpital Pitie Salpetriere, Paris, France) at the 2007
European Society of Cardiology Congress, should help put to rest any
lingering concerns that a 0.5-mg/kg dose of enoxaparin in the
setting of elective PCI is associated with increased mortality. Dr
Bill O'Neill (University of Miami, FL) had raised that possibility
in an editorial [1] accompanying the publication of the primary
STEEPLE results [2] in the New England Journal of Medicine one year
ago.

The original STEEPLE results indicated that a 0.5-mg/kg dose of
enoxaparin was associated with significantly lower rates of bleeding
than unfractionated heparin (UFH) at 48 hours, whereas a 0.75-mg/kg
dose was not. But as O'Neill pointed out in his editorial, there was
a nonsignificant trend toward higher mortality with the 0.5 mg/kg
dose, responsible for the decision by the trial's data and safety
monitoring committee to prematurely halt the 0.5-mg arm of the study.

Now, as Montalescot showed last week, one-year results from STEEPLE
show no differences in mortality in the three study groups, nor any
differences when one-year mortality was combined with rates of major
bleeding at 48 hours.

When results for the two doses of enoxaparin were combined, rates of
the prespecified composite end point of major bleeding at 48 hours
and one-year mortality were significantly lower in the enoxaparin
group.

Additional analyses showed that the incidence of ischemic events in
the first 30 days after PCI and major bleeding within the first two
days were the major predictors of dying within the year.

The discussant for the trial, Dr Steen Kristensen (Aarhus University
Hospital, Skejby, Denmark), pointed out that the one-year STEEPLE
results add new understanding about predictors of worse outcomes
following PCI in the modern era. More important, it also established
the safety of enoxaparin in the setting of elective PCI, he said.

"Although there was no difference in mortality at one year between
the groups, the study shows that enoxaparin is an alternative to UFH
and implementation should be considered in ESC Guidelines and
clinical practice," Kristensen stated.

Commenting on the one-year results, O'Neill told heartwire that the
message he takes from STEEPLE is that bleeding events are "extremely
harmful," pointing to the reduced one-year survival in people who'd
had major bleeds. "In fact, a major bleed is worse than an MI with a
more-than-five-times CKMB elevation," he noted.

O'Neill added that his fears about the 0.5 mg/kg dose are not
necessarily assuaged by the one-year data. "The troubling trend in
early mortality for the 0.5-mg/kg group does not achieve statistical
significance, but this study is much too small and underpowered for
that end point," he said. "I am still troubled by reports of
catheter clotting in other studies. In light of the lack of anti-
clotting monitoring that exists for this agent, I see no advantage
to the 0.5-mg dose. Catheter clotting is a rare and potentially
catastrophic risk that can be entirely avoided with adequate
anticoagulation. The 0.75-mg dose seems safe in this trial and
certainly decreases bleeding risk compared with UFH. This is the
dose I would recommend."

1. O'Neill WW. Risk of bleeding after elective percutaneous coronary
intervention. N Engl J Med 2006; 355:1058-1060. Abstract

2. Montalescot G, White HD, Gallo G, et al. Enoxaparin versus
unfractionated heparin in elective percutaneous coronary
intervention. N Engl J Med 2006; 355:1006-1017.

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