With less than a week to go before the FDA's Circulatory System
Devices Panel meets to review the safety of drug-eluting stents
(DES), another meta-analysis has been published pointing to a higher
risk of late stent thrombosis in the drug-coated devices [1].

The study, conducted by researchers at the Cleveland Clinic and
appearing in the December 2006 issue of the American Journal of
Medicine, was actually presented in 2005, but, according to senior
author Dr Deepak Bhatt (Cleveland Clinic, OH), was largely ignored
by clinicians and reporters alike.

"In fact one of our fellows, [first author Dr Anthony A Bavry]
presented this meta-analysis at the 2005 American Heart Association
meeting, and at the time it didn't really generate any interest,
certainly not from the media but not even, for that matter, among
physicians," Bhatt said. "We thought it was pretty concerning, but
at the time it was met with skepticism. People thought it was a
small excess risk, and they weren't convinced it was real."

Looking "real"

Bavry et al's study combined 14 clinical trials in which a total of
6675 patients were randomized to either a bare-metal stent or a
sirolimus- or paclitaxel-eluting stent (the Cypher or Taxus). The
trials included the entire TAXUS trial program (five trials), the
three SIRIUS studies, the RAVEL, SES-SMART, SCANDSTENT, DIABETES,
and STRATEGY trials, plus one additional randomized clinical trial
from Germany. The primary end point for the meta-analysis was
angiographic stent thrombosis, defined as a filling defect in
proximity to a previously placed stent on repeat angiography, with
angiography performed either as per protocol or due to a clinical
event. Of note, clinical events deemed by study investigators to be
caused by thrombosis, even if not confirmed angiographically, were
counted as thrombotic events.

In the combined data set, there was no statistically significant
difference in the overall rate of stent thrombosis between the DES
and bare-metal-stent groups (9.3/1000 patients for DES vs 9.0/1000
per 1000 for bare-metal stents). However, the risk of very late
stent thrombosis (greater than one year postprocedure) was five
events per 1000 in the DES-treated patients, compared with zero in
the bare-metal stent group, a statistically significant difference.
Examined separately, the difference in the risk of late stent
thrombosis in DES-treated vs bare-metal-stent-treated patients was
statistically significant for paclitaxel-eluting stents, but not for
sirolimus-eluting stents, but investigators attribute this lack of
significance in the sirolimus studies to the smaller numbers of
patients in the SIRIUS and RAVEL trials as compared with the TAXUS
trials. Of note, time to stent thrombosis was, on average, 15.5
months for sirolimus-eluting stents and 18 months for paclitaxel-
eluting stents, but only four months for bare-metal stents.

Bhatt emphasized that the absolute difference in risk between DES
and bare-metal stents remains low. "We saw a four- to fivefold
relative excess risk, but in absolute terms we're talking about
approximately a 0.5% excess rate, so about one patient in 200 or so
might have a stent thrombosis with a DES vs a bare-metal stent." The
stent-thrombosis findings are largely in keeping with those of other
meta-analyses presented at the TCT meeting, which looked only at the
SIRIUS/RAVEL and TAXUS trial programs, as reported by heartwire.

Bhatt says he hopes the new information will "inform the debate"
about DES use, particularly in light of the upcoming FDA discussions.

"I know there has been a lot of heat and noise, with some folks
saying there is no problem with stent thrombosis at all and others
saying that it's an epidemic and people are dropping dead. I think
our paper is taking the middle ground and saying there's a definite
hazard here, but in terms of degree of hazard it's not that high for
the individual patient. Unless, of course, you're the patient who
has stent thrombosis. Then it's a big deal."

No increase in death/MI

While not reported in the paper, Bhatt told heartwire he and his
colleagues did not see any excess of death and MI in DES-treated
patients in their meta-analysis, a finding that bears out the
hypothesis that DES, by reducing restenosis, also limit the number
of adverse events associated with reocclusion and revascularization
procedures. Indeed, Bhatt was senior author on the Chen et al study
much touted at the TCT meeting, which showed that more than one
third of in-stent-restenosis episodes among bare-metal stent-treated
patients present as MI or unstable angina requiring hospitalization
[2].

Asked what his expectations are for next week's FDA panel meeting,
Bhatt said he expects the committee to address the issue of
appropriate dual-antiplatelet-therapy duration, and, hopefully,
reach some consensus on the degree of risk with DES in the types of
patients currently undergoing DES implantation. "I don't have any
predictions, but I'll tell you I am looking for some guidance. I'm
hoping that they do come out with some concrete recommendations on
what to do."

He added that while interventional cardiologists may be preoccupied
with the DES safety debate, other physicians are unaware of the
issue, a situation that sometimes leads to unwarranted stoppage of
dual antiplatelet therapy.

"Even now I see patients who had DES placed, then had some kind of
minor procedure for which both their aspirin and clopidogrel were
stopped. This is a purposeful decision, and it might be the right
thing to do in some cases, but I think most of the time these
decisions are uninformed. And those are the folks who really need to
know these data, and hopefully publishing a study like this in the
American Journal of Medicine will reach the noncardiology audience
as well as the cardiology audience. I think that's also one benefit
of the FDA having this meeting--that it will reach a very broad
audience."

Bavry AA, Kumbhani DJ, Helton TJ et al. Late thrombosis of drug-
eluting stents: a meta-analysis of randomized clinical trials. Am J
Med 2006; 119: in press.
2. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is
not a benign clinical entity. Am Heart J 2006; 151:1260-1264.

There are robust data to support the cardiovascular health claims
made by manufacturers of some nutritional supplements, but for
others the evidence is shaky at best, delegates heard earlier this
month at the American Heart Association 2006 Scientific Sessions.

In a seminar entitled, "The science behind popular nutrition
claims," a host of experts presented a roundup of the research on a
number of substances claimed to "help maintain a healthy heart."

While some claims made for plant stanols and sterols, lipoic acid,
and coenzyme Q10 appear to have a basis, the data on green tea,
policosanols, and folic acid are equivocal, and there is little
evidence for any benefit of vitamin E, the researchers said.

Stanols/sterols lower LDL, but no evidence that policosanols do

Dr Alice H Lichtenstein (Tufts University, Boston, MA) explained
that plant stanols and sterols are the fat-soluble fractions of
grains, seeds, root stems, and branches and are analogous to
cholesterol in animals. Most people eat around 100 to 300 mg per day
of such substances, but vegetarians consume more, up to 500 mg per
day, she said.

"It is remarkable how consistent the impact of plant stanols is,"
she noted. "Although they need to be taken every day, data [1,2]
have shown that maximal doses of 2 to 3 g per day seem to reduce LDL
cholesterol by about 10%."

There is just one small concern, she said, namely that these
substances might decrease the absorption of some fat-soluble
vitamins. In fact, this has been demonstrated for only one--beta-
carotene--and it is not clear what the clinical impact of this is,
she noted.

Dr Peter JH Jones (McGill University, Montreal, Quebec) discussed
the evidence for policosanols, waxy substances found in sugar cane--
the most prevalent of which is known as octacosanol--that are also
claimed to lower cholesterol.

Jones explained that much of the early work on policosanols, which
claimed the benefits, was done in Cuba, but there came a realization
that these findings needed to be confirmed by independent
laboratories.

Four recently published human trials have found no effect of
policosanols on LDL cholesterol [3-6].

"So how do we explain this disparity?" he wondered. "There's a
possibility that baseline dietary intakes vary, or that there are
genetic differences across populations in lipid metabolism--but then
again, statins work across all populations, so why shouldn't
policosanols?"

In addition, no molecular mechanism to explain an effect of
policosanols on cholesterol has been defined, he noted. "Until these
disparities are explained, policosanols cannot be recommended," he
concluded.

Lipoic acid for diabetic neuropathy? Coenzyme Q10 for HF?

Dr Ishwarlal Jialal (University of California Davis Medical Center,
Sacramento) told the audience the data on lipoic acid in humans
are "very confusing, but there is one condition in which it clearly
is of benefit--diabetic neuropathy."

However, he said, there is still no consensus on the optimum dose--
which could be anywhere between 200 and 1800 mg/day--and more work
needs to be done on the best form of lipoic acid to be used as a
nutritional supplement.

Jialal also discussed coenzyme Q10, also known as ubiquinone,
ubiquinol, and ubidecarenone. Studies looking at the use of this
supplement show no clear benefit in cardiovascular disease and no
definitive effect in reducing myalgias in patients taking statins,
he said. In addition, patients taking warfarin need to exercise
caution when taking coenzyme Q10.

But there is evidence of benefit in one indication, heart failure,
he said, citing a meta-analysis in which coenzyme Q10 had shown some
improvement in ejection fraction [7].

But "much more research needs to be done in heart failure, using
state-of-the-art techniques such as echocardiography to assess
functional outcomes," he added. "Coenzyme Q10 is expensive, it's
sold to everyone, and patients take it whether or not it affords
them benefit.

"We particularly need to answer the question of whether this will
work in heart-failure patients resistant to conventional drugs such
as beta blockers," he noted.

Vitamin E gone to seed; folic acid on shaky ground

Jialal ended his talk by assessing the evidence for vitamin E (alpha-
tocopherol). The majority of trials involving vitamin E have been
negative, he said, but one study published in 2005 [8], which was
the longest-duration vitamin study ever conducted, "went against the
overwhelming data," showing a reduction in cardiovascular death
(p=0.03) and a "tremendous effect in older women (p=0.009)," he
noted.

However, "the totality of evidence does not support supplementation
with vitamin E for the prevention and/or treatment of cardiovascular
disease," he concluded, adding that there is "a general movement
against antioxidants such that it is almost impossible now to get
funding for such studies."

Dr Eric Rimm (Harvard University, Cambridge, MA) talked about folic
acid and vitamin B6. While much observational data suggested a
benefit of B6 and folate via their homocysteine-lowering effects,
major secondary-prevention studies have failed to replicate this, he
noted.

However, Rimm believes there may be a benefit of folic acid in
certain susceptible populations, as suggested by subanalyses of the
large intervention trials. "B vitamins clearly lower homocysteine,
and homocysteine increases the risk of coronary heart disease," he
stated.

Green tea: The jury is still out

Finally Dr David J Maron (Vanderbilt University, Nashville,
Tennessee) said the data on green tea were mixed, but claims of its
efficacy are founded on its well-documented antioxidant and anti-
inflammatory effects.

He explained that all types of tea are derived from the same plant--
Camellia sinensis--and that black tea is fermented, oolong tea is
partially fermented, and green tea is not fermented.

One meta-analysis found an 11% reduction in MI for every additional
three cups per day [9], but he noted heterogeneous results among the
studies--eg, an increased risk of CHD in a UK trial, an increased
risk of stroke in a study done in Australia, but reductions in risk
in continental Europe.

The largest study ever conducted on green tea--the Ohsaki study--was
recently published in the Journal of the American Medical
Association [10], he noted, and it found a reduction in deaths from
stroke, but not coronary heart disease, in those who drank five or
more cups per day compared with those who had less than one. And the
benefits were particularly noticeable in women.

But this is observational data, Maron noted, adding that the only
four intervention studies that have been conducted have found no
evidence of benefit with tea itself or green-tea extracts such as
theaflavin.

"We have no credible scientific evidence to support these health
claims," he said. Despite this, and despite the FDA issuing a letter
of denial for a claim made by the world's largest green-tea
manufacturer earlier this year, there are still myriad
advertisements touting the benefits of tea, he noted with
exasperation.

"Ideally, we need long-term intervention trials," he concluded,
adding that the same can be said for red wine and chocolate. "Stay
tuned."

Miettinen TA, Puska P, Gylling H, et al. Reduction of serum
cholesterol with sitostanol-ester margarine in a mildly
hypercholesterolemic population. N Engl J Med 1995; 333: 1306.
Katan MB, Grundy SM, Jones P, et al. Efficacy and safety of plant
stanols and sterols in the management of blood cholesterol levels.
Mayo Clin Proc 2003;78: 965-978.
Lin Y, Rudrum M, van der Wielen RP, et al. Wheat germ policosanol
failed to lower plasma cholesterol in subjects with normal to mildly
elevated cholesterol concentrations. Metabolism 2004 Oct; 53: 1309-
1314.
Greyling A, De Witt C, Oosthuizen W, et al. Effects of a policosanol
supplement on serum lipid concentrations in hypercholesterolaemic
and heterozygous familial hypercholesterolaemic subjects. Br J Nutr
2006; 95:968-975.
Berthold HK, Unverdorben S, Degenhardt R, et al. Effect of
policosanol on lipid levels among patients with hypercholesterolemia
or combined hyperlipidemia: a randomized controlled trial. JAMA
2006; 295: 2262-2269.
Kassis AN and Jones PJ. Lack of cholesterol-lowering efficacy of
Cuban sugar cane policosanols in hypercholesterolemic persons. Am J
Clin Nutr 2006; 84:1003-1008.
Sander S, Coleman CI, Patel AA, et al. The impact of coenzyme Q10 on
systolic function in patients with chronic heart failure. J Card
Fail 2006: 12:464-472.
Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary
prevention of cardiovascular disease and cancer: The Women¡¦s Health
Study: a randomized controlled trial. JAMA 2005; 294: 56-65.
Peters U, Poole C, and Arab L. Does tea affect cardiovascular
disease? A meta-analysis. Am J Epidemiol 2001: 154:495-503.
Kuriyama S, Shimazu T, Ohmori K, et al. Green tea consumption and
mortality due to cardiovascular disease, cancer and all causes in
Japan. The Ohsaki study. JAMA 2006; 296:1255-1265.

Highly trained physicians in a modern emergency department
frequently meet international guidelines for cardiopulmonary
resuscitation (CPR), according to a prospective observational study
conducted at the Medical University of Vienna in Austria.
However, "there is room for improvement," the authors say,
especially with regard to hyperventilation and failure to identify
ventricular fibrillation.

Recent reports exposed shortcomings often encountered when in-
hospital CPR is administered, Dr. Fritz Sterz and associates note in
the Archives of Internal Medicine for November 27.

In general, chest compression rates tend to be too low and
ventilation rates too high, the authors note. International
standards require a compression rate of 100 per minute, compression
depth of 40-50 mm, and ventilation rate of 12 per minute.

Dr. Sterz's group conducted their study between 2002 and 2006, under
conditions that they consider optimal. The emergency department
was "fully equipped with monitors, ventilators, and complete nursing
facilities." At least four physicians and six nurses were on duty
around the clock.

They note that the 30 physicians were well versed in CPR and had
more than 10 years of acute care clinical experience. The duration
of cardiac arrest among the 80 patients in the study averaged 11.2
minutes.

The primary outcome was the hands-off ratio, defined as the hands-
off time divided by the cardiac arrest time.

The investigators observed that hands-off ratio (mean 12.7%) was
linearly associated with duration of CPR (p < 0.001), which may be
ascribed to interruptions for too-frequent examinations and for
other procedures, such as echocardiography or insertion of arterial
lines. It might also be due to the simple fact that the physician
becomes exhausted over time, or perceives futility in prolonged CPR.

The chest compression rate averaged 96 per minute, and mean
compression depth was 63.4 mm. Median rate of ventilation was 18 per
minute.

Spontaneous respiration was restored in 46% of cardiac arrests.
However, only seven patients survived for > 6 months, and six
survived with a good neurological outcome.

The authors express concern that correct ventilation rates were
achieved only 18% of the time during CPR. "An excessive ventilation
rate during CPR will result in increased positive intrathoracic
pressures, decreased coronary perfusions, and decreased survival
rate." Also at issue was the delay in detecting ventricular
fibrillation for up to 7 minutes.

Dr. Sterz and his team recommend greater attention to ventilation
rates, and that no-flow time be reduced by keeping pulse checks and
other examinations to a minimum.

Arch Intern Med 2006;166:2375-2380

To borrow from Winston Churchill, it's a "cholesterol paradox"
wrapped in a mystery inside an enigma, counterintuitive at several
levels but consistent with a good deal of epidemiologic and
mechanistic evidence. A large observational study of patients with
acute heart failure has suggested that short-term mortality goes up
as admission serum total cholesterol (TC) levels go down, yet such
patients appear to live longer if they are on statins [1].

Chronic heart failure has previously been associated with a so-
called "reverse epidemiology," in which, for example, body-mass
index, blood pressure, and serum cholesterol are inversely
correlated with mortality [2,3], but it is unclear whether they are
mediators or simply markers of risk. The current analysis, based on
a European multicenter registry of patients hospitalized with HF,
suggests the inverse TC-mortality relationship is independent and
points to effects other than lipid modification as central to any
clinical benefit HF patients may gain from the drugs, according to
the investigators.

Twelve-week mortality for the study's >5000 patients admitted for
acute HF was about 12.5%, but the adjusted mortality odds ratio was
reduced by a significant 40% for those with serum TC >193 mg/dL (5
mmol/L) compared with lower levels and for those on vs not on lipid-
lowering therapy, which was presumed to consist primarily of
statins. The reductions were independent of other significant
outcome predictors that included creatinine, LV systolic function,
and treatment with beta blockers or ACE inhibitors, reported Dr
Periaswamy Velavan (University of Hull, Kingston-upon-Hull, UK)
recently at the American Heart Association 2006 Scientific Sessions.

The apparent paradox of an inverse TC-mortality relationship became
clearer after analysis by TC quintiles. Those with the poorest
prognosis, who had TC levels below 151 mg/dL, accounted for almost a
third of the deaths. But the curve for TC vs mortality was U-shaped
for the 26% of the cohort on lipid-lowering therapy. Among them,
those with TC levels in the middle quintiles fared the best and
those in the first and fifth quintiles did the worst. Lipid-lowering
therapy was associated with a greatly reduced 12-week mortality
regardless of admission TC levels.

The findings argue against lipid lowering per se as the mechanism of
statin benefit in the HF population, Velavan told heartwire. The
drugs' other well-recognized benefits include anti-inflammatory
effects and improvements in endothelial function, and they may also
have antiarrhythmic and angiogenic properties, he observed. But it's
unknown whether lowering initially "normal" or low TC levels with
statins will improve outcomes in the setting of HF. The current
limited analysis suggests that may be the case, but "only randomized
trials can answer that question."

Velavan explained that low TC levels in HF may reflect increased
metabolic stress due to endotoxins or oxidative or inflammatory
processes. Patients with the lowest TC levels, he said, "are
possibly the sickest patients, with the highest levels of
inflammation. We believe that it is possibly the severe inflammatory
response associated with the advanced heart-failure patient that
causes the low cholesterol." In support of that view, he said, other
conditions characterized by a severe inflammatory response and high
mortality, such as trauma or septic shock, are known to be
associated with low cholesterol levels.

Velavan P. Prognostic implications of low cholesterol and statin
therapy in heart failure. "The cholesterol paradox." American Heart
Association 2006 Scientific Sessions; November 12, 2006; Chicago,
IL. Abstract 342.
Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse
epidemiology of conventional cardiovascular risk factors in patients
with chronic heart failure. J Am Coll Cardiol 2004; 43:1439-1444.
Horwich TB, Hamilton MA, MacLellan WR, Fonarow GC. Low serum total
cholesterol is associated with marked increase in mortality in
advanced heart failure. J Card Fail 2002; 8:216-224.

Scientists in the UK have identified oligomeric procyanidins as the
likely ingredient in red wine's polyphenols that contributes to
heart health and longevity.

Dr. Roger Corder, from Queen Mary's School of Medicine and Dentistry
in London, and his associates note in the November 30 issue of
Nature that not everyone agrees that red wine actually possess such
properties, which they say may be due to the complexity and
variability in the constituents in different wines.

To look into this issue, the investigators cultured vascular
endothelial cells and exposed them to 165 different wines to
identify the most potent vasoactive polyphenols.

The total polyphenol content correlated with inhibited synthesis of
endothelin-1. High-performance liquid chromatography identified
straight-chain B-type oligomeric procyanidins as the specific
phenolic constituent responsible for this effect.

People living in Nuoro province, Sardinia, and southwest France have
higher than normal average longevity. Wines from those regions, the
researchers found, had a 2- to 4-fold higher inhibitory effect on
endothelin-1 and significantly higher oligomeric procyanidin content
than wines from Australia, Europe, South America, the US, and
Sardinia.

Dr. Corder and his associates maintain that traditional wine-making
methods and use of the flavonoid-rich grape Tannat commonly grown in
southwest France result in high levels of oligomeric procyanidins in
the local wine.

The investigators conclude, "Further investigation of oligomeric
procyanidins-rich wines and foods should provide insight into how
vascular function might be optimally maintained."

Nature 2006;444:566

Flying in the face of recent trial results that have found no
benefit of folic acid for the prevention of cardiovascular events, a
new commentary in the November 25, 2006 issue of BMJ says the
combined evidence from cohort, genetic, and randomized controlled
studies is indeed strong enough to support a modest protective
effect of this nutrient [1].

Lead author of the new paper, Dr David S Wald (Queen Mary's School
of Medicine and Dentistry, London, UK), told heartwire that 0.8 mg
of folic acid per day should be used for reduction of cardiovascular
events: "It is simple, safe, inexpensive, and undervalued." While he
acknowledges that recent interventional trials have not produced
positive results, he says that they have been "interpreted as
negative when really they have been neutral or inconclusive."

While some of the authors of these recent trials are critical of the
BMJ paper, other experts sympathize with its arguments but conclude
that there is not yet enough evidence to support routine use of
folic acid for the prevention of cardiovascular events. Dr Ian
Graham (Trinity College, Dublin, Ireland) says: "This is a good
debate to have. It is naive to believe that folic acid is some
nutritional wonder drug, but I don't believe it is dead in the water
yet."

Randomized controlled trials "leave us in the middle"

Just two weeks ago, the latest in a line of randomized controlled
trials of folic acid was reported at the American Heart Association
(AHA) 2006 Scientific Sessions. The Women's Antioxidant and Folic
Acid Cardiovascular Study (WAFACS) joined HOPE-2, NORVIT, and VISP
in failing to show any benefit of folic acid on cardiovascular
events.

But Wald told heartwire that randomized controlled trials "are only
one part of the story. They have all been too small, of too short a
duration, and inconclusive--both alone and when we put them
together." And, he says, "We must be cautious about our
interpretation of randomized controlled trials, as they tend to be
deemed positive or negative. In fact [with the folic-acid studies],
we don't have enough events to push us one way or another; rather,
they leave us in the middle."

The researchers say there are parallels to be drawn between
homocysteine and lipid lowering. "An analogy exists with medical
judgments made after the early randomized trials of treatment to
reduce serum cholesterol concentrations. The early trials achieved
only modest reductions in serum cholesterol, and their duration was
short; the two years necessary for the near-maximal reduction in
ischemic heart disease was not appreciated. Consequently, the modest
risk reductions observed were not significant and were widely
interpreted as negative. Cholesterol reduction was claimed to be
harmful."

Epidemiological and genetic data "most convincing"

For folic acid, the epidemiological data and genetic studies "are
most convincing," Wald says, "and our paper addresses the totality
of evidence." Although Wald and two of his coauthors have interests
in the polypill--which contains folic acid--including patents
(granted and pending) in the case of two of them, Wald stressed to
heartwire: "I'm not promoting folic acid because of that. We are
making conclusions on the basis of evidence."

Their argument centers on meta-analyses of cohort studies showing
significant positive associations between serum homocysteine and
ischemic heart disease events and on the fact that lower
homocysteine concentrations have been shown to have a large effect
on CVD risk in patients with homocystinuria.

And in genetic studies of people with a mutation in the
methylenetetrahydrofolate reductase gene (MTHFR)--who have
moderately raised homocysteine concentrations as a result--meta-
analyses have shown up to a 25% excess risk of cardiovascular
events, they note.

"These genetic studies avoid the confounding that could affect
cohort studies; people with and without the mutation would not be
expected to differ in other cardiovascular risk factors, and direct
observation indicates that they do not. The studies are, in effect,
natural randomized experiments, capable of testing whether
moderately raised homocysteine causes ischemic heart disease and
stroke," they note.

Folic acid, up to 0.8 mg day, lowers homocysteine concentrations in
people with and without this mutation, they say.

Graham says the British researchers have a point. When looking at
the effects of antioxidant vitamins, such as vitamin E, "the genetic
story does not apply," he says, and therefore it is easier to
conclude that they lack benefit.

Wald et al conclude: "In practical terms, folic-acid supplementation
will be expected to have a variable effect in preventing
cardiovascular disease, with greater prevention in populations with
relatively low folate intakes and less prevention in populations
with higher folate intakes."

Currently, the AHA does not recommend widespread use of folic-acid
and B-vitamin supplements to reduce the risk of heart disease and
stroke [3]. It does recommend a daily value of 0.4 mg for prevention
of neural tube defects during pregnancy. In the US, wheat flour has
been fortified with folic acid since January 1998 to add an
estimated 0.1 mg per day to the average diet, and some other Western
nations have followed suit.

Modest effects, but is folic acid safe?

Wald does concede that any benefit of folic acid is likely to "be
relatively modest" but argues that "there is no evidence of harm"
and therefore no downside to recommending its use for the prevention
of cardiovascular events.

But Graham takes issue with this. While he believes the finding in
the NORVIT study--that folic acid may actually increase the risk of
MI and stroke in MI survivors--was "very strange" and probably a
blip, "there is still a slight niggling worry that folic acid could
feed a cancer," he notes.

Graham says the crux of the matter is whether the evidence is
sufficiently good it can justify public-health intervention. "For
vascular disease, I think it's still a bit too weak."

But, he says, Wald et al "could be right. He's absolutely correct to
say that the inability to show benefit does not mean there is no
benefit." The death of the homocysteine hypothesis so often cited
recently "is premature," he believes.

"We need to wait until there are at least 10 major trials. At the
moment there are about five, and the total follow-up is not that
long and the numbers are small. What we really need is a megatrial
done in a population that does not fortify food and that has a high
rate of cardiovascular events--somewhere like Russia--with about 50
000 to 100 000 people followed for 10 years, but it's hard to see
how this will be done. There is no profit in folic acid."

No case for folic acid yet, but will susceptible subgroups be
identified?

When heartwire questioned Canadian researchers involved in the HOPE
2 trial about the conclusions of Wald et al, they were less than
enthusiastic.

Lead author Dr Eva Lonn (McMaster University, Hamilton, ON) told
heartwire that the review "is outdated; it is based on observational
studies only. There are four large randomized trials--about 17 000
people--suggesting no benefit at all. The only data that could
justify the use of folic acid would be if any of the ongoing large
randomized trials would show different results. For now, there is no
rationale for folic acid."

Dr Salim Yusuf (McMaster University) agrees: "The totality of the
data rules out any important difference for most populations."

But Dr Eric Rimm (Harvard University, Boston), who reviewed the
evidence for folic acid during a session on the science behind
nutritional claims at the recent AHA meeting, said: "I agree with
the main points made in this editorial, except in some cases they
did not go far enough. For example, they focused primarily on
homocysteine, yet folate may be beneficial through other metabolic
pathways.

"While I don't agree that the trials are underpowered, they are
mostly conducted on very high-risk individuals who are also on
statins, aspirin, etc. This would attenuate the benefit and likely
reduce power for this reason (and because many of the participants
will have sufficient folate in their diet)."

Rimm believes there may be a benefit of folic acid in certain
susceptible populations, as suggested by subanalyses of the large
intervention trials. "B vitamins clearly lower homocysteine, and
homocysteine increases the risk of coronary heart disease," he
states.

Graham believes that looking at how homocysteine affects other risk
factors might provide some answers. "Data have shown that there is
an interaction between cholesterol and homocysteine and between
smoking and homocysteine. It may be that global risk is important,
so that those at very high risk will benefit from folic acid."

Wald DS, Morris JK, Law M, et al. Folic acid, homocysteine and
cardiovascular disease: judging causality in the face of
inconclusive trial evidence. BMJ 2006; 333:1114-1117.
Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic
acid and placebo in patients with ischemic heart disease: an outcome
trial [abstract]. Circulation 2002; 106 (suppl II):741.
American Heart Association. Homocysteine, folic acid and
cardiovascular disease. November 27, 2006. Available at:
http://www.americanheart.org/presenter.jhtml?identifier=4677.

Dr Stephan Möhlenkamp tells the story of running tests on a fit,
asymptomatic, 57-year-old marathon runner as part of a communitywide
screening study. The runner had completed a marathon several days
previously and felt fine, if a bit stiff, but tests showed he
actually had acute ST-elevation MI, moderate three-vessel disease,
and required urgent revascularization.

The findings prompted Möhlenkamp and colleagues to initiate a study
specifically of "master" (>50 years) marathon runners, to screen for
asymptomatic disease. As he explained to heartwire, "We were puzzled
and started to ask, is this guy one in a million that we see, or is
this part of a bigger story? What is the extent of atherosclerosis
and cardiovascular disease in master marathon runners?"

For their study, Möhlenkamp and colleagues have enrolled more than
100 male marathon runners over the age of 50 and performed
traditional risk-factor analyses on all of them, as well as ECG,
echocardiography, MRI, and coronary artery calcium (CAC) scans. All
of the men had run at least five marathons in the past three years.

Subclinical atherosclerosis despite excellent Framingham risk scores

Earlier this month, Möhlenkamp and colleagues presented CAC scan
findings from the Masters Marathon Study at the American Heart
Association (AHA) 2006 Scientific Sessions. They reported that while
the runners had completed, on average, 20 marathons over the past
nine years and had significantly better risk-factor profiles
compared with age-matched controls (lower BMI, blood pressure, and
LDL; higher HDL), their CAC burden was no different. For the cohort
as a whole, Framingham risk scores were approximately 50% lower than
in age-matched controls; however, among age-matched controls who
were also matched by Framingham risk score, CAC scores greater than
100 were much more common, pointing to a higher incidence of
subclinical atherosclerosis despite rosy risk-factor profiles.

"Despite this favorable risk profile, the extent of subclinical
atherosclerosis was significantly higher as compared with age- and
risk-factor-matched controls from the general population," the
investigators concluded. "The unexpectedly high coronary
atherosclerotic burden may in part account for some of the exercise-
related cardiovascular events in advanced-age marathon runners."

MRI studies hint at adverse adaptive changes

This week, at the Radiological Society of North America (RSNA) 2006
Meeting in Chicago, study investigators presented MRI findings from
the same cohort, now expanded to 110 male marathoners, on average 57
years old. As Möhlenkamp explained to heartwire, some degree of left
ventricular (LV) hypertrophy is expected in extremely fit subjects,
a phenomenon dubbed athlete's heart. But what he and his colleagues--
including Dr Torleif A Sandner (University Hospital, Munich,
Germany), who presented the results--wanted to find out,
particularly given findings from the CAC scans in their marathon
runners, was whether some of the changes occurring in older
marathoners might not merely be physiologic adaptation to endurance
exercise.

What they found is that while LV volumes and LV ejection fractions
were comparable to studies of nonathletic men of the same age, LV
mass as measured by MRI was significantly higher. Moreover,
increased LV mass appeared to correlate with CAC scores.

"When we measured LV mass, we found that those marathon runners with
a mass above 150 g had a significantly higher coronary artery
calcium score than those below," Möhlenkamp told heartwire. "Usually
you would think in a marathon runner that they may have some degree
of LV hypertrophy, so an increase in myocardial mass. But what has
never been shown, as far as I know, is that this may in fact be
associated with the amount of coronary artery calcium, so the big
question is, is this 'athlete's heart' or is it early disease?"

He continued, "We believe this is the first evidence that not all of
the increase in LV mass is an adaptation to long-term training. In
some runners it may be evidence for early cardiovascular disease."

Möhlenkamp pointed out that while some of the marathoners may have
been lifelong athletes, others might have gotten into sports much
later in life, in some cases after decades of riskier
lifestyles. "You might look at these patients and think, sure,
there's increased mass because they're runners, but in fact, in some
of them, this may be an early sign of some response to earlier risk-
factor exposure," he said.

It's impossible to measure previously increased risk-factor profiles
in someone who may have lowered their risk-factor profile through
lifestyle changes, he stressed. "I can measure blood pressure, lipid
profile, ask about symptoms and lifestyle, but all this doesn't tell
me much because he's been running for 10 years," Möhlenkamp
explained. "If I look at his echo or MRI and I see increased muscle
mass, I'd think sure, he's been running for 10 years, and I put
everything down to running for 10 years when in fact we have some
initial evidence now that at least in some master marathon runners,
if you focus just on the MRI scan, some of these subjects with
increased myocardial mass have in fact early cardiac disease."

Outcome data needed

Möhlenkamp was careful to stress that he wasn't so much advocating
MRI as a standard test to screen older athletes, but rather that
MRI, in this study, had illuminated an aspect of cardiovascular risk
that might not have previously been appreciated. "I'm very careful
about making a strong statement. At this point, the fact is just
that there is a mismatch between the risk-factor profiles and the
amount of CAC, as we presented at the AHA. And now, as we're showing
at the RSNA, a muscle mass above 150 g means you have a higher
likelihood, that's statistically significant, of having a higher
calcium burden than if you have a muscle mass below 150 g. At this
point this just adds to the puzzle: what we will need is outcome
data--we'll have to wait five years to really know whether it is the
risk factors that predict outcome, or the atherosclerosis burden, or
the muscle mass. Any of these variables in the marathon runners
could predict outcome."

A common polymorphism of the beta 2 adrenergic receptor appears to
influence pulmonary function in heart failure patients, but not in
healthy age- and gender-matched control subjects, Minnesota-based
researchers report in the November issue of Chest.

However, "whether in heart failure this is due to altered adrenergic
drive influencing the beta 2 adrenergic receptors in the lungs or
indirectly through altered cardiac diastolic function is unclear,"
senior investigator Dr. Bruce D. Johnson told Reuters Health.

Dr. Johnson and colleagues at the Mayo Clinic, Rochester examined
genetic variations of ADRB2 at amino acid 16 (arginine)or glycine in
126 chronic heart failure patients and 100 controls.

Patients who were homozygous for arginine showed higher
norepinephrine levels and had lower lung function than heterozygotes
or those who were homozygous for glycine.

For example, a measure of pulmonary function (FEV1) had a mean
predicted value of 75% in arginine homozygotes versus 86 and 87% in
the other 2 patient groups. Controls homozygous for arginine did not
have reduced pulmonary function.

In addition, in patients, but not controls, there was a modest
correlation between pulmonary function and mitral valve inflow
deceleration time.

"Clinically, it may be beneficial to more aggressively manage
patients who are homozygous for arginine at amino acid 16 of this
receptor -- through neurohumoral blockade," Dr. Johnson said.

"However," he concluded, "additional studies should be pursued to
confirm the present findings."

Chest 2006;130:1527-1534.

Although there is a link between alcohol intake and increased blood
pressure, the absence or the amount of alcohol that is consumed does
not appear to be significantly associated with subsequent
hypertension-related events, according to researchers in California.

In the October 15th issue of the American Journal of Cardiology, Dr.
Arthur L. Klatsky of the Kaiser Foundation Research Institute,
Oakland and colleagues note that such relationships are difficult to
establish.

To investigate further, the researchers studied data from more than
127,000 subjects who had had health examinations between 1978 and
1988. They were stratified into five levels of alcohol consumption,
from none to three or more drinks per day.

Using a blood pressure of 120/80 mm Hg as a reference point, the
researchers examined blood pressure categories ranging up higher
than 140/90 mm Hg.

Although the risks of reaching subsequent cardiovascular endpoints,
including mortality, hospitalization and outpatient diagnosis of
hypertension were greater as blood pressure increased, this was not
significantly related to levels of alcohol use.

Thus the researchers concluded that "the risks of hypertension are
similar regardless of the amount of alcohol consumption."

They add that hypertension at any level is far from benign
and "alcohol-related hypertension belongs on the list of reasons to
avoid heavy drinking."

Am J Cardiol 2006;98:1063-1068

Psoriasis patients have an increased frequency of a variety of
cardiovascular risk factors including diabetes, obesity,
hypertension, hyperlipidemia, and smoking, results of a study
confirm.

In particular, the current results suggest that psoriasis is
associated with key components of the metabolic syndrome and that
this association is stronger in cases of severe psoriasis.

"This finding is important," write investigators in the November
issue of the Journal of the American Academy of Dermatology, given
that individuals with as few as one or two metabolic syndrome risk
factors are at heightened risk for death due to cardiovascular
disease.

In comments to Reuters Health, Dr. Joel M. Gelfand from the
University of Pennsylvania, Philadelphia noted that "our other
studies suggest that, independent of other risk factors, severe
psoriasis itself may be a risk factor for heart attack. Therefore,
patients with psoriasis should be screened for cardiovascular risk
factors, and if these risk factors are present, they should be
managed appropriately."

Dr. Gelfand and colleagues identified 127,706 patients with mild
psoriasis and 3,854 with severe psoriasis. Each psoriasis patient
was matched to up to five psoriasis-free control subjects.

Diabetes was present in 7.1% of patients with severe psoriasis and
in 4.4% of those with mild psoriasis compared with 3.3% of controls.

Hypertension was present in 20% of patients with severe psoriasis,
14.7% of those with mild psoriasis and 11.9% of controls.
Hyperlipidemia was documented in 6%, 4.7%, and 3.3%, respectively.

Nearly 20.7% of individuals with severe psoriasis and 15.8% of those
with mild psoriasis were obese compared with roughly 13.2% of
controls. Thirty-one percent of those with severe psoriasis were
smokers compared with 28% of those with mild psoriasis and 20.7% of
psoriasis-free controls.

Compared with controls, patients with mild psoriasis had a higher
adjusted odds of diabetes (OR, 1.13), hypertension (OR, 1.03),
hyperlipidemia (OR, 1.16), obesity (OR, 1.27), and smoking (OR,
1.31).

Patients with severe psoriasis had a higher adjusted odds of
diabetes, obesity, and smoking.

Additionally, diabetes and obesity were more prevalent in patients
with severe psoriasis (OR, 1.39 and 1.47, respectively) than in
those with mild psoriasis.

Based on this study and prior studies, the study team advises: "As
part of good medical care, patients with psoriasis should be
encouraged to identify and manage their modifiable cardiovascular
risk factors."

J Am Acad Dermatol 2006;55:829-835

Clinical Context
Thiazide diuretics are some of the most commonly used medications to
lower blood pressure among patients with hypertension, and an
editorial by Phillips, which accompanies the current article,
reviews the history of research into this class of medications.
Initial studies used high-dose thiazide diuretics for treatment of
hypertension, and these dosages were associated with a higher risk
for sudden death among patients with baseline electrocardiogram
abnormalities. These high dosages were not necessary, as the dose-
response curve for thiazide diuretics and blood pressure become
fairly flat at moderate dosages. Lower dosages of thiazide diuretics
have been demonstrated to reduce blood pressure as well as left
ventricular mass among patients with hypertension.

Thiazide diuretics have also been demonstrated to increase levels of
serum glucose. The current analysis of ALLHAT examines this
phenomenon as well as the clinical significance of incident diabetes
linked with antihypertensive therapy.

Study Highlights
Patients eligible for study participation were at least 55 years old
and either had blood pressure values of at least 140/90 mm Hg or
were receiving treatment of hypertension with fewer than 3
medications. Subjects also had at least 1 risk factor for CHD and a
baseline serum glucose level less than 110 mg/dL.
Participants were randomized to receive treatment with
chlorthalidone, amlodipine, or lisinopril to reduce blood pressure
to less than 140/90 mm Hg.
Serum glucose was measured at baseline and at years 2, 4, and 6. The
main study outcome was the relationship between antihypertensive
assignment, serum glucose at follow-up, and the incidence of
diabetes (defined by serum glucose > 125 mg/dL).
18,411 patients in the ALLHAT trial did not have diabetes at
baseline, and 53.2% of these subjects had FG levels examined at
subsequent visits. The mean age of participants was 66 years, and
the mean serum FG level was 93 mg/dL among all treatment groups.
The mean follow-up time was 4.9 years. Rates of maintenance of
blinded medication use at year 4 were 76.3%, 84.7%, and 83.2% among
the lisinopril, amlodipine, and chlorthalidone groups, respectively.
Glucose levels rose in all treatment groups with time. During the
first 2 years, the mean increase is serum glucose levels was 8.5,
5.5, and 3.5 mg/dL among the chlorthalidone, amlodipine, and
lisinopril groups, respectively. The difference between
chlorthalidone and the other antihypertensive drugs in this outcome
was significant and remained relatively stable at 4 years.
Compared with the chlorthalidone group, the odds ratios for
developing diabetes were 0.55 and 0.73 in the lisinopril and
amlodipine groups, respectively.
Despite the increase in serum glucose and risk for diabetes linked
with chlorthalidone therapy, subjects with these outcomes did not
have a significantly increased risk for CHD or mortality vs subjects
receiving chlorthalidone whose glucose remained stable during study
therapy. Conversely, incident diabetes increased the risk for CHD
and heart failure among subjects receiving lisinopril. The overall
risk for CHD was also increased among all subjects who developed
incident diabetes.
Pearls for Practice
High-dose thiazide diuretics can promote sudden death among patients
with hypertension and electrocardiogram abnormalities, but they can
also safely reduce blood pressure and left ventricular mass at lower
dosages among patients with hypertension.
In the current analysis of ALLHAT, chlorthalidone was associated
with a more significant increase in serum glucose level and incident
diabetes than amlodipine and lisinopril. However, incident diabetes
among subjects receiving chlorthalidone did not increase the risk
for CHD or mortality.

Fasting glucose (FG) levels increase in older adults with
hypertension regardless of whether they are treated with
chlorthalidone, amlodipine, or lisinopril, according to the results
of an analysis from the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT) reported in the
November 13 issue of the Archives of Internal Medicine. Although the
risk of developing FG levels higher than 125 mg/dL was modestly
greater with chlorthalidone, there was no conclusive or consistent
evidence that this diuretic-associated increase in risk for diabetes
increased the risk for clinical events.

"Many patients with hypertension eventually develop diabetes,"
Robert Phillips, MD, author of an editorial accompanying the
article, and director of the Heart and Vascular Center of Excellence
at the University of Massachusetts Memorial Medical Center in
Worcester, told Medscape. "Physicians and others interested in the
individual and public health are guided by the principle of primum
non nocere ¡X first, do no harm. The initial reports from the ALLHAT
trial showed that there was more diabetes associated with thiazide-
diuretic treatment, and the authors sought to determine if this was
harmful."

The objective of this analysis was to compare the effect of first-
step antihypertensive drug therapy with thiazide-type diuretic,
calcium-channel blocker (CCB), or angiotensin-converting enzyme
(ACE) inhibitor on FG levels and to determine the risks for
cardiovascular and renal disease associated with elevated FG levels
and incident diabetes mellitus in these 3 treatment groups. The
investigators performed post hoc subgroup analyses from ALLHAT among
nondiabetic participants who were randomized to treatment with
chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n =
5034). Mean follow-up was 4.9 years.

"Mean fasting glucose levels increased during ALLHAT follow-up in
all treatment groups," corresponding author Barry R. Davis, MD, PhD,
of the University of Texas School of Public Health, Coordinating
Center for Clinical Trials in Houston, told Medscape. "There was no
significant association of fasting glucose level change at 2 years
with subsequent coronary heart disease [CHD], stroke, cardiovascular
disease, total mortality, or end-stage renal disease."

At year 2, the chlorthalidone group had the greatest increase in
mean FG levels (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L]
for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The
odds ratios for developing diabetes at 2 years were 0.55 with
lisinopril vs chlorthalidone (95% confidence interval [CI], 0.43 -
0.70), and 0.73 with amlodipine vs chlorthalidone (95% CI, 0.58 -
0.91; P <.01). Incident diabetes at 2 years was not significantly
associated with clinical outcomes, except for CHD (risk ratio [RR],
1.64; P = .006), but RR was lower and nonsignificant in the
chlorthalidone group (1.46; P = .14).

"The diuretic did not appear to be the culprit responsible for the
increased CHD risk associated with new-onset DM [diabetes
mellitus]," Dr. Phillips says. "Rather surprisingly, development of
DM during treatment with ACE inhibitors was associated with an
increased risk of CHD and congestive heart failure, and development
of DM during treatment with CCB was associated with increased
mortality. We need to be cautious about the clinical implications,
but I do believe that they suggest that diuretic-induced
hyperglycemia is relatively benign. Conversely, if diabetes develops
on an ACE or CCB, it suggests that that patient has developed
insulin resistance despite being on drugs that tend to improve
insulin sensitivity, and hence the consequences are more dire."

Strengths of this study, according to Drs. Davis and Phillips, are
the large sample size providing much greater statistical power to
recognize associations and differences between medications and the
relatively long duration of follow-up. Limitations are the
retrospective design, and follow-up possibly insufficient to detect
the adverse effects of thiazide-induced hyperglycemia.

"Considerable attention was paid to quality assurance, and all
laboratory tests were done in a certified central laboratory," Dr.
Davis says. "Limitations of the study are that no FG measurements
during follow-up were available for nearly half of the cohort, owing
primarily to participants not fasting prior to venipuncture. Also,
we did not obtain measures of overall glucose control, such as
glycosylated hemoglobin, and we did not obtain information on
treatment of diabetes."

Dr. Phillips also notes that because of its design, ALLHAT did not
study the typical types of combinations of hypertensive medications
that patients frequently take, limiting generalizability of the
results. However, the International Verapamil-Trandolapril Study
showed that an atenolol-hydrochlorothiazide based strategy was as
effective as the verapamil-trandolapril strategy in preventing death
and cardiovascular outcomes in this high-risk population, even
though there was more incident diabetes associated with the former
regimen.

"I think that [the ALLHAT analysis] will help physicians to feel
more comfortable about using low-dose thiazide therapy as either the
initial drug choice as or part of combination therapy," Dr, Phillips
said. "If hyperglycemia or frank diabetes does develop, many
physicians would stop the diuretic and substitute another agent to
see if the hyperglycemia would resolve. One can't argue with that
approach, but actually we do not know if it is the correct action to
take."

"These results should reinforce the recommendations of the Joint
National Committee on Hypertension that diuretics should be
considered as a first-line treatment of hypertension and should be
part of any multidrug regimen for hypertension," Dr. Davis concluded.

This study was supported by the National Heart, Lung, and Blood
Institute. The ALLHAT investigators disclosed receiving
contributions of study medications from Pfizer (amlodipine and
doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers
Squibb (pravastatin), and financial support from Pfizer. Some of the
authors have disclosed various financial relationships with Takeda,
GlaxoSmithKline, Merck, BioMarin, Proctor & Gamble, Bristol-Myers
Squibb, Pfizer, Abbott Laboratories, AstraZeneca, Boehringer
Ingelheim, Forest Pharmaceuticals, Novartis, Reddy, Sankyo,
SmithKline Beechman/Glaxo Wellcome, Bertek, DepoMed, Medco, and/or
Wyeth. Dr. Phillips has disclosed no relevant financial
relationships.

Arch Intern Med. 2006;2174-2176, 2191-2201

HbA1c values appear to determine the long-term outcome of
intrasheath injection of triamcinolone in diabetics with flexor
tenosynovitis, also known as trigger finger, Japanese researchers
report in the November issue of Diabetes Care.

Dr. Makoto Kameyama and colleagues at Saiseikai Central Hospital,
Tokyo note that the condition is caused by a restriction in movement
between the flexor tendon and its surrounding sheath.

The incidence in the general population has been reported as being
as high as 2.6%, but as many as 20% of diabetics may be affected.
Intrasheath injection of triamcinolone is commonly used as an
initial treatment.

To investigate further, the researchers studied 179 diabetic
patients (287 fingers) with the condition. They underwent treatment
with up to 3 injections of triamcinolone acetonide mixed with
lidocaine.

Follow-up at 1 year showed success in 27 fingers (9%). However, when
the patients were divided into those with A1c less than 8% and those
with a higher value, the success rate was 1.3% in the higher A1c
group and 12.4% in the lower A1c group, a significant difference.

Outcomes were much less successful than has been reported in other
groups of patients, the researchers point out.

In light of these findings, they conclude that diabetic patients
with poor glycemic control, particularly those with an A1c of 8% or
more, "should be informed that the outcome of triamcinolone
injections is not guaranteed."

Diabetes Care 2006;29:2312-2314

Ancrod, a natural defibrinogenating agent derived from snake venom,
should not be used to treat ischemic stroke more than 3 hours after
symptom onset, a new study has found.

The European Stroke Treatment with Ancrod Trial (ESTAT) found that
attempting to extend the standard ischemic-stroke treatment window
from 3 to 6 hours using this agent increased the rate of
intracerebral hemorrhage (ICH) and 3-month mortality, compared with
placebo.

The study was published in the November 23, 2006 issue of The
Lancet.

"On the basis of our findings, ancrod should not be recommended for
use in acute ischemic stroke beyond 3 hours," the authors write.

Widening the Treatment Window

Investigators were encouraged by the results of the North American
Stroke Treatment with Ancrod Trial (STAT). Published in 2000 in
JAMA, it included 500 patients and had an almost identical design to
ESTAT. STAT found that when ancrod was given within 3 hours after
acute ischemic stroke, outcomes were better than they were in the
control group.

"Our aim [with the ESTAT study] was to see whether ancrod was
effective with a 6-hour window rather than a 3-hour window, as was
used in STAT," the authors write.

Led by Michael Hennerici, MD, from the University of Heidelberg in
Germany, the multicenter, randomized, double-blind, placebo
controlled phase 3 study included 1222 patients from Europe,
Australia, and Israel. Of these, 604 subjects were randomly assigned
to receive ancrod and the remaining 618 received placebo.

Patients over age 18 with an acute moderate or severe neurological
deficit suggestive of an ischemic event were eligible for the study.
Treatment was started within 6 hours of symptom onset. Those with
evidence of parenchymal hemorrhage and hemorrhagic transformation on
CT imaging, or with major signs of developing infarction, were
excluded from the study.

Higher Mortality

Patients received ancrod or placebo as a continuous 72-hour
intravenous infusion, followed by daily single infusions lasting
approximately 1 hour for 2 days, to reach and maintain a target
fibrinogen concentration of 1.2–2.1 µmol/L.

Ancrod was given at initial infusion rates of 1.00, 0.75, and 0.50
IU/kg, per 6 hours, based on pretreatment fibrinogen concentrations
of >13.2 µmol/L, 10.3–13.2 µmol/L, or <10.3 µmol/L, respectively.

Patients were not allowed to receive antiplatelet agents, oral
anticoagulants, thrombolytics, heparin, or other drugs that might
affect the fibrinolytic system.

Functional success at 3 months was the study's primary outcome,
which was defined as survival to follow-up with a Barthel index
score of 95 to 100, or at least equal to prestroke value. Secondary
outcomes included the modified Scandinavian Stroke Scale, the
modified Rankin Scale, death rates at 3 and 12 months, and CT
infarct-volume at day 7.

At 3-month follow-up, functional outcomes in the ancrod and placebo
groups were the same. The authors report that 42% of patients in
both groups had a Barthel index score >95 or had returned to
prestroke values. However, neurological recovery was worse in the
placebo group.

At 20%, 90-day mortality was worse in the ancrod group than in the
placebo group (14%). However, the authors report that 12-month
mortality did not differ significantly between the 2 groups.

Timing (Still) Matters

Symptomatic and asymptomatic ICH at day 28 occurred in 13% of
patients in the ancrod group and 4% in the placebo group. However,
neurological recovery was worse in the placebo group.

"Symptomatic intracranial hemorrhage occurred significantly more
often in patients given ancrod, compared with those given placebo,
and mainly arose within 7 days. Asymptomatic intracranial hemorrhage
also occurred more often in the ancrod group than the placebo
group," the authors write.

However, the authors note that despite the discouraging differences
in death and intracranial hemorrhage rates between the 2 groups, the
overall death rate in ESTAT was lower than in the control groups of
earlier controlled trials, including the Neurological Disorders and
Stroke (NINDS) tPA trial, which reported a death rate of 21% among
controls, and STAT's 23% death rate.

In an accompanying editorial, Markku Kaste, MD, PhD, from Helsinki
University Central Hospital in Finland, notes that "although the
study was unsuccessful, it delivers an important message: that time
from onset of symptoms to treatment matters, and in ESTAT it was too
long."

Accentuate the Negative

As an addendum to the study, the authors note that it is just as
important to report negative results as it is positive results. They
cite the struggle they had to publish the ESTAT trial results, the
preliminary findings of which were originally reported in 2001 at
the World Federation of Neurology Congress in London.

After this conference, they write, the pharmaceutical company that
supported the trial (Knoll AG) was sold. Thereafter, the data from
the study were not fully available to the investigators, making
further analysis difficult.

According to the authors, "only with the support of many dedicated
investigators and after careful reassessment of the material finally
provided" were they able to prepare the current report.

"This situation illustrates the understandable but often regrettable
divergences between sponsor and investigators' interest, leading to
scientific losses and unethical waste of patients' and
investigators' efforts. The bias towards easier publication of
successful trials, sometimes at too early a stage, is another
important issue to consider: the publication of this report is
therefore an important recognition of the scientific and medical
value of all clinical trials," they write.

Lancet 2006; 368:1871-1878.

JAMA 2000; 283:2395-2403.

The first study to examine late-occurring stroke risk in pediatric
cancer survivors has found that children who have been successfully
treated for brain tumors or acute lymphoblastic leukemia — the 2
most common childhood cancers — are at significantly increased risk
of stroke in later life.

Researchers from University of Texas Southwestern Medical Center at
Dallas, Texas, report that among children with brain tumors the
stroke rate was 3.4%, but among patients treated with both cranial
radiotherapy (CRT) and chemotherapy, the rate was as high as 6.5%.
Among children with leukemia, the stroke rate was 0.8%; among their
siblings the rate was 0.2%.

"Many people think, 'You're 5 years out from your cancer, you must
be cured, and you can get on with the rest of your life.' But these
patients suddenly develop a new complication of the cancer and its
treatments," said principal investigator Daniel Bowers, MD, in a
statement.

The study was published in the November 20 issue of the Journal of
Clinical Oncology.

Impact of Cancer Treatment

According to the investigators, the study had 3 aims:

▪ To estimate the incidence rate of stroke among leukemia and brain-
tumor survivors 5 years or more after the diagnosis of cancer (late-
occurring stroke)

▪ To compare the rate of late-occurring stroke between leukemia and
brain-tumor survivors and their siblings

▪ To assess the association of specific treatments of late-occurring
stroke.

Using data from the Childhood Cancer Survivor Study (CCSS),
investigators analyzed stroke as a late effect of cancer treatment
in a large and diverse cohort of cancer survivors, which included
4828 leukemia survivors and 1871 brain-tumor survivors. In addition,
the occurrence of stroke was assessed in a random sample of 3846
cancer survivor siblings.

In total, 37 leukemia and 63 brain-tumor survivors had a late-
occurring stroke, defined as a stroke that occurred 5 years or more
after cancer diagnosis. The rate of late-occurring stroke for
leukemia and brain-tumor survivors was 57.9 per 100,000 person-years
and 267.6 per 100,000 person-years, respectively.

In comparison, the sibling group had a rate of stroke of 8.0 per
100,00 person-years.

When researchers analyzed the cohort according to the type of cancer
treatment individuals received, they found an increased risk of late-
occurring stroke, particularly in children treated with cranial
radiotherapy at dose greater than 30 Gy.

CRT Dose Response

In addition, the authors report that there was a dose-response
relationship between radiation-therapy dose and risk for
stroke. "Survivors treated with CRT greater than 50 Gy had a
significantly greater risk for stroke in comparison with those
treated with 30 to 49 Gy," they write.

In contrast, lower-dose CRT, ranging from 10 to 29 Gy, was not
associated with an increased risk, compared with no CRT.

However, the authors note that among both leukemia and brain-tumor
survivors who did not receive CRT, "the risk of late-occurring
stroke remained significantly increased, albeit modestly, compared
with the sibling comparison group."

According to Dr. Bowers, there is an ongoing trend to try to
minimize the use of radiation therapy, a move designed to lessen the
learning problems associated with radiation therapy.

Dr. Bowers said it would be interesting to determine whether this
initiative would also have an impact on the occurrence of stroke in
this patient population.

This study, the authors write, "justifies efforts to continue to
reduce radiation doses among both leukemia and brain-tumor treatment
regimens whenever practical."

J Clin Oncol. 2006; 24:5277-5282

The range of embryonic stem cells that ultimately develop into the
heart muscle and its conduction system and vasculature might be
narrower in range than once believed, suggest two laboratory studies
published online November 22, 2006 in Cell [1, [2].

Each of the studies identified a single kind of progenitor cell
that, at least in vitro, collectively differentiates into all of the
major cardiac tissues, including myocardium, Purkinje fibers,
vascular endothelium, and smooth muscle. The two progenitors belong
to different embryonic cardiac-cell families, each believed
responsible for the formation of the left and right side of the
heart, respectively.

The research challenges a traditional view of the developmental
origins of the heart's varied tissue types in which each is derived
from a distinct precursor cell with different embryonic origins,
according to the authors of both reports, which are slated for
publication in the journal's December 15, 2006 issue. In place of
the old view is the idea that all of the heart's tissue types are
derived from no more than a few progenitor cell types.

The studies, if verified, point to potential ways around some
current obstacles to using stem cells for cardiac-tissue
regeneration to repair infarct-damaged myocardium or congenital
defects. Although it has been suggested that embryonic stem cells
are "a renewable source of cardiac-muscle cells for transplantation,
this has been problematic, given the difficulty in generating
sufficient amounts of homogenous cardiac myocytes and the dangers
associated with the risk of teratomas," according to Dr Alessandra
Moretti (Massachusetts General Hospital, Boston) and colleagues,
authors of the right-sided progenitor-cell report [1]. Those
problems, they write, might be overcome by the cloning and delivery
of a few specific progenitor cells that might more easily and safely
regenerate different heart tissues.

In a series of mouse and in vitro studies, Moretti et al traced the
differentiation of a specific cardiac precursor cell characterized
by the expression of the transcription factor islet-1 (isl1). They
discovered that a subset of these "multipotent isl1+ cardiovascular
progenitors" (MICPs) can differentiate into myocardial, conduction,
endothelial, and smooth-muscle cell lineages.

"Since MICPs can be isolated and selectively expanded from a
renewable embryonic-stem-cell-based source, the findings point to a
new strategy for cardiovascular tissue regeneration via the directed
differentiation of embryonic-stem-cell-based MICPs into discrete
cardiac, pacemaker, smooth-muscle, and endothelial cell lineages,"
the group writes, "pointing to a new strategy for cardiovascular
tissue regeneration."

Dr Sean M Wu (Children's Hospital, Boston, MA) and associates made
similar observations and arrived at much the same conclusions after
isolating cardiac-specific progenitor cells expressing the
transcription factor Nkx2.5 from a mouse embryo, and following its
developmental pathways [2]. A distinct subset of the Nkx2.5+ cells
showed an unusual capacity in vitro for replication and
differentiation into both myocardial and smooth-muscle cells. "With
further differentiation, these precursor cells become atrial- or
ventricular-specific myocytes or cells of the conduction system,"
they write. They appeared unable to differentiate into
hematopoietic, neuronal, or skeletal muscle cells, "thus, they
represent a population that is restricted with respect to other
lineages.

According to Wu et al, their findings "support a new paradigm for
cardiovascular development involving the divergence of myocardial
and smooth-muscle-cell lineages from a common precursor."

In a press release on the two studies issued by Cell, lead
investigator of the Wu et al study, Dr Stuart H Orkin (Children's
Hospital), is quoted as saying the relationship between the two
studies' key progenitor cells is unknown and a subject of continued
research. "One may be the predecessor of the other, or they may be
quite separate."

Moretti A, Caron L, Nakano A, et al. Multipotent embryonic Isl1+
progenitor cells lead to cardiac, smooth muscle, and endothelial
cell diversification. Cell 2006; doi:10.1016/j.cell.2006.10.029.
Wu SM, Fujiwara Y, Cibulsky SM, et al. Developmental origin of a
bipotential myocardial and smooth muscle cell precursor in the
mammalian heart. Cell 2006; doi:10.1016/j.cell.2006.10.028.

A new study by Mayo researchers suggests that women who develop
hypertension during pregnancy face a higher risk for stroke,
coronary heart disease, hypertension, and microalbuminuria later in
life.

"Even though it's logical, it's common sense, that if someone
becomes hypertensive during pregnancy, they are hypertensive later
in life, there really are no data to support that," lead author
Vesna D. Garovic, MD, from the Mayo Clinic in Rochester, Minnesota,
told Medscape.

She presented their findings at the American Heart Association 2006
Scientific Sessions, in Chicago, Illinois, and then subsequently at
the American Society of Nephrology's 39th Annual Meeting and
Scientific Exposition in San Diego, California.

"We thought it would be nice to show these results to both
cardiologists and nephrologists, because it¡¦s an area of interest
for both specialties," Dr. Garovic, a nephrologist, noted.

History of Hypertension

Hypertension affects about 10% of pregnancies in the United States,
the authors note. In this study, Dr. Garovic and colleagues aimed to
assess whether women who develop hypertension during pregnancy are
at higher risk for cardiovascular and renal outcomes.

To do this, they used data on 4782 women who had participated in the
Family Blood Pressure Program (FBPP), all of whom were considered to
have a higher risk for hypertension owing to family history, which
was defined as belonging to sibships with >2 members who had
hypertension diagnosed prior to age 60.

They were then categorized according to whether they had no history
of pregnancy lasting more than 6 months (718), only normotensive
pregnancies (3421), or at least 1 hypertensive pregnancy (643).

Frequently in young women, pregnancy is the first occasion that
their blood pressure is checked, Dr. Garovic noted, and so a
diagnosis of hypertension during pregnancy cannot rule out the
possibility that the woman was hypertensive prior to that. "To
differentiate between immediate complications of hypertensive
pregnancy disorders and those later in life, all of the analyses for
cardiovascular outcomes in hypertension were done after the age of
40, assuming that pregnancy would have happened earlier," she noted.

Despite their fairly young age, a median of 54 years in this cohort,
women who were diagnosed with hypertension during pregnancy had a
significantly higher risk for stroke, coronary heart disease (CHD)
events, and subsequent hypertension after the age of 40 than those
who had had only normotensive pregnancies. They also had a higher
urine albumin-creatinine ratio (UACR), and a higher body mass index
(BMI) than women with normotensive pregnancies.

Interestingly, women with normotensive pregnancies had lower
creatinine levels than those who had never had a pregnancy lasting
longer than 6 months.

They also looked at the relationship between hypertension in
pregnancy and novel risk factors, such as homocysteine and C-
reactive protein (CRP), in a subset of 1755 women in the FBPP who
participated in the Genetic Epidemiology Network of Arteriopathy
(GENOA). Women with a history of hypertensive pregnancy had higher
CRP and homocysteine levels, both when BMI was included in the
multiple regression models and when it was not. No difference was
seen in levels of lipoprotein (a) or small dense LDL cholesterol
between groups.

Chicken or Egg?

It's not clear at this point whether this relationship can be
explained simply by the fact that risk factors for hypertensive
disorders (including pre-eclampsia), such as higher BMI, diabetes,
and kidney disease, are the same as those for cardiovascular
disease, she said.

A competing theory is that hypertensive pregnancy disorders induce
vascular and metabolic changes that modify a woman's overall risk
profile for these events later in life, Dr. Garovic said.
Preclinical studies, for example, have shown that animals with high
levels of angiotensin 2, when given a high-salt diet, will develop
hypertension. "Pregnancy is a high angiotensin 2 state," she pointed
out, "so these hormonal changes that occur during pregnancy,
specifically those relative to blood-pressure control, may somehow
be modified in a way that changes the overall risk profile. It's a
very intriguing hypothesis and I think we are going to start seeing
more and more research in this area."

More immediately, in practice, Dr. Garovic now asks about pregnancy
outcomes when taking a history and assessing risk factors in her
patients. "If someone has had 1 or 2 hypertensive pregnancies, these
are women who should be advised to check their blood pressure on a
regular basis, work on their diets, on their lipid profile, on their
exercise regimen, on lifestyle modifications that can improve
overall risk profiles and may affect longtime outcomes."

Garovic VD, et al. Hypertension in pregnancy is associated with a
higher incidence of cardiovascular events later in life. American
Heart Association 2006 Scientific Sessions, Chicago, Illinois.
Abstract # 2025.

Garovic VD, et al. Hypertension in pregnancy is associated with
microalbuminuria and cardiovascular events later in life. American
Society of Nephrology 39th Annual Meeting and Scientific Exposition,
San Diego, California. TH-FC050.

The range of embryonic stem cells that ultimately develop into the
heart muscle and its conduction system and vasculature might be
narrower in range than once believed, suggest two laboratory studies
published online November 22, 2006 in Cell [1, [2].

Each of the studies identified a single kind of progenitor cell
that, at least in vitro, collectively differentiates into all of the
major cardiac tissues, including myocardium, Purkinje fibers,
vascular endothelium, and smooth muscle. The two progenitors belong
to different embryonic cardiac-cell families, each believed
responsible for the formation of the left and right side of the
heart, respectively.

The research challenges a traditional view of the developmental
origins of the heart's varied tissue types in which each is derived
from a distinct precursor cell with different embryonic origins,
according to the authors of both reports, which are slated for
publication in the journal's December 15, 2006 issue. In place of
the old view is the idea that all of the heart's tissue types are
derived from no more than a few progenitor cell types.

The studies, if verified, point to potential ways around some
current obstacles to using stem cells for cardiac-tissue
regeneration to repair infarct-damaged myocardium or congenital
defects. Although it has been suggested that embryonic stem cells
are "a renewable source of cardiac-muscle cells for transplantation,
this has been problematic, given the difficulty in generating
sufficient amounts of homogenous cardiac myocytes and the dangers
associated with the risk of teratomas," according to Dr Alessandra
Moretti (Massachusetts General Hospital, Boston) and colleagues,
authors of the right-sided progenitor-cell report [1]. Those
problems, they write, might be overcome by the cloning and delivery
of a few specific progenitor cells that might more easily and safely
regenerate different heart tissues.

In a series of mouse and in vitro studies, Moretti et al traced the
differentiation of a specific cardiac precursor cell characterized
by the expression of the transcription factor islet-1 (isl1). They
discovered that a subset of these "multipotent isl1+ cardiovascular
progenitors" (MICPs) can differentiate into myocardial, conduction,
endothelial, and smooth-muscle cell lineages.

"Since MICPs can be isolated and selectively expanded from a
renewable embryonic-stem-cell-based source, the findings point to a
new strategy for cardiovascular tissue regeneration via the directed
differentiation of embryonic-stem-cell-based MICPs into discrete
cardiac, pacemaker, smooth-muscle, and endothelial cell lineages,"
the group writes, "pointing to a new strategy for cardiovascular
tissue regeneration."

Dr Sean M Wu (Children's Hospital, Boston, MA) and associates made
similar observations and arrived at much the same conclusions after
isolating cardiac-specific progenitor cells expressing the
transcription factor Nkx2.5 from a mouse embryo, and following its
developmental pathways [2]. A distinct subset of the Nkx2.5+ cells
showed an unusual capacity in vitro for replication and
differentiation into both myocardial and smooth-muscle cells. "With
further differentiation, these precursor cells become atrial- or
ventricular-specific myocytes or cells of the conduction system,"
they write. They appeared unable to differentiate into
hematopoietic, neuronal, or skeletal muscle cells, "thus, they
represent a population that is restricted with respect to other
lineages.

According to Wu et al, their findings "support a new paradigm for
cardiovascular development involving the divergence of myocardial
and smooth-muscle-cell lineages from a common precursor."

In a press release on the two studies issued by Cell, lead
investigator of the Wu et al study, Dr Stuart H Orkin (Children's
Hospital), is quoted as saying the relationship between the two
studies' key progenitor cells is unknown and a subject of continued
research. "One may be the predecessor of the other, or they may be
quite separate."

Moretti A, Caron L, Nakano A, et al. Multipotent embryonic Isl1+
progenitor cells lead to cardiac, smooth muscle, and endothelial
cell diversification. Cell 2006; doi:10.1016/j.cell.2006.10.029.
Wu SM, Fujiwara Y, Cibulsky SM, et al. Developmental origin of a
bipotential myocardial and smooth muscle cell precursor in the
mammalian heart. Cell 2006; doi:10.1016/j.cell.2006.10.028.

Compared with traditional on-pump coronary artery bypass grafting
(CABG), off-pump CABG appears to reduce the risk of postoperative
death, MI, and need for reoperation, especially in low-risk
patients, new research suggests.

There is limited data showing a clear-cut advantage for off-pump
versus on-pump CABG. However, many of the studies did not stratify
patients according to their preoperative risk of adverse outcomes.

To address this problem, Dr. Gaieta Permanyer-Miralda, from Vall
d'Hebron Hospital in Barcelona, Spain, and colleagues assessed
preoperative risk in 1585 CABG patients using a validated measure
called EuroSCORE.

The authors report their findings in the October issue of the
European Heart Journal.

Roughly half of the patients had a moderate/high preoperative risk
profile and half had a low risk profile. In each of these groups,
the number that underwent off-pump CABG was similar to the number
that underwent on-pump CABG.

In high-risk patients, off-pump CABG cut the risk of adverse in-
hospital outcomes by up to 60%, which fell short of statistical
significance, the report indicates. The benefit in low-risk
patients, however, reached significance with a reduction in risk of
up to 73% (p < 0.05).

"In real clinical practice, off-pump surgery in those patients
undergoing a primary coronary bypass procedure may be associated
with slightly but definitely better outcomes than on-pump surgery on
a range of clinical important outcomes," the researchers
write. "This advantage may be greater than previously reported and
predominately apparent in low-risk patients."

Eur Heart J 2006;27:2473-2480

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The ACUITY trial, suggesting that bivalirudin is an alternative to
heparin/enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor in
moderate- or high-risk ACS patients undergoing an early invasive
strategy, is published in the November 23, 2006 issue of the New
England Journal of Medicine [1].

The trial--which was first presented, and reported by heartwire,
last March at the American College of Cardiology meeting--showed a
slight nonsignificant increase in ischemic events but a large
reduction in bleeding with bivalirudin, compared with heparin plus a
IIb/IIIa blocker, which translated into a net clinical benefit for
bivalirudin.

Lead investigator Dr Gregg Stone (Columbia University Medical
Center, New York), says: "After testing several different
combinations of drug therapies, we found bivalirudin delivered by
itself is as effective as combination drugs and results in less
bleeding, which may lead to improved outcomes. Use of bivalirudin
alone, rather than the more traditional anticoagulants, in ACS
patients could prevent a significant number of major bleeding
episodes and blood transfusions every year."

In an accompanying editorial [2], Dr John A Bittl (Ocala Heart
Institute, FL) says ACUITY provides "strong support" for the use of
bivalirudin. Two other experts, who were not involved in the trial,
told heartwire that, in their view, bivalirudin did not set a new
standard but was definitely another option for some ACS patients.

In the ACUITY paper, investigators explain that an early invasive
strategy--consisting of angiography followed by PCI, CABG, or
medical management--is recommended for patients with moderate- or
high-risk ACS, but that this strategy requires an intensive
pharmacologic regimen, including aspirin, clopidogrel, a GP IIb/IIIa
inhibitor, and an antithrombotic agent (either unfractionated [UFH]
or low-molecular-weight heparin), which together cause frequent
hemorrhagic complications. They point out that bivalirudin is an
alternative to heparin and that the ACUITY trial was designed to
establish the usefulness of this new agent in this patient group.

The trial randomized 13 819 ACS patients to one of three
antithrombotic regimens: UFH or enoxaparin plus a GP IIb/IIIa
inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin
alone (with provisional use of GP IIb/IIIa blockers only if
required; they were actually used in 9% of this group).

The primary end points were a composite ischemia end point (death,
myocardial infarction, or unplanned revascularization for ischemia),
major bleeding, and the net clinical outcome, defined as the
combination of composite ischemia or major bleeding at 30 days.

Bivalirudin plus a GP IIb/IIIa inhibitor, compared with heparin plus
a GP IIb/IIIa inhibitor, was associated with noninferior 30-day
rates of the composite ischemia end point, major bleeding, and the
net clinical outcome end point.





ACUITY Published: Bivalirudin—An Alternative to Heparin Plus
IIb/IIIa Blocker in ACS Patients Undergoing An Early Invasive
Strategy
from Heartwire ¡X a professional news service of WebMD


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November 22, 2006 (New York, NY) - The ACUITY trial, suggesting that
bivalirudin is an alternative to heparin/enoxaparin plus a
glycoprotein (GP) IIb/IIIa inhibitor in moderate- or high-risk ACS
patients undergoing an early invasive strategy, is published in the
November 23, 2006 issue of the New England Journal of Medicine [1].

The trial--which was first presented, and reported by heartwire,
last March at the American College of Cardiology meeting--showed a
slight nonsignificant increase in ischemic events but a large
reduction in bleeding with bivalirudin, compared with heparin plus a
IIb/IIIa blocker, which translated into a net clinical benefit for
bivalirudin.

Lead investigator Dr Gregg Stone (Columbia University Medical
Center, New York), says: "After testing several different
combinations of drug therapies, we found bivalirudin delivered by
itself is as effective as combination drugs and results in less
bleeding, which may lead to improved outcomes. Use of bivalirudin
alone, rather than the more traditional anticoagulants, in ACS
patients could prevent a significant number of major bleeding
episodes and blood transfusions every year."

In an accompanying editorial [2], Dr John A Bittl (Ocala Heart
Institute, FL) says ACUITY provides "strong support" for the use of
bivalirudin. Two other experts, who were not involved in the trial,
told heartwire that, in their view, bivalirudin did not set a new
standard but was definitely another option for some ACS patients.

In the ACUITY paper, investigators explain that an early invasive
strategy--consisting of angiography followed by PCI, CABG, or
medical management--is recommended for patients with moderate- or
high-risk ACS, but that this strategy requires an intensive
pharmacologic regimen, including aspirin, clopidogrel, a GP IIb/IIIa
inhibitor, and an antithrombotic agent (either unfractionated [UFH]
or low-molecular-weight heparin), which together cause frequent
hemorrhagic complications. They point out that bivalirudin is an
alternative to heparin and that the ACUITY trial was designed to
establish the usefulness of this new agent in this patient group.

The trial randomized 13 819 ACS patients to one of three
antithrombotic regimens: UFH or enoxaparin plus a GP IIb/IIIa
inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin
alone (with provisional use of GP IIb/IIIa blockers only if
required; they were actually used in 9% of this group).

The primary end points were a composite ischemia end point (death,
myocardial infarction, or unplanned revascularization for ischemia),
major bleeding, and the net clinical outcome, defined as the
combination of composite ischemia or major bleeding at 30 days.

Bivalirudin plus a GP IIb/IIIa inhibitor, compared with heparin plus
a GP IIb/IIIa inhibitor, was associated with noninferior 30-day
rates of the composite ischemia end point, major bleeding, and the
net clinical outcome end point.

Major results for bivalirudin + GP IIb/IIIa blocker vs
UFH/enoxaparin + GP IIb/IIIa

End point
  UFH/enoxaparin + GP IIb/IIIa inhibitor
  Bivalirudin + GP IIb/IIIa inhibitor
  Relative risk (95% CI)
  p for superiority
  p for noninferiority

Composite ischemic end point (%)
  7.3
  7.7
  1.07 (0.92¡V1.23)
  0.39
  <0.007

Major bleeding (%)
  5.7
  5.3
  0.93 (0.78¡V1.10)
  0.38
  <0.001

Net clinical outcome (%)
  11.7
  11.8
  1.01 (0.90¡V1.12)
  0.93
  <0.001



Bivalirudin alone, compared with heparin plus a GP IIb/IIIa
inhibitor, was associated with a noninferior rate of the composite
ischemia end point, and significantly reduced rates of major
bleeding and the net clinical outcome end point.

Major results for bivalirudin alone vs UFH/enoxaparin + GP IIb/IIIa

Clopidogrel treatment--the only subgroup that shows an interaction

Stone et al note that subgroup analysis revealed no significant
interactions between the primary study end points and numerous
demographic and treatment variables, with the possible exception of
the administration of clopidogrel before angiography or PCI. They
report that clopidogrel was given to 64% of patients before
angiography or PCI. In these patients, the point estimate for
composite ischemic events was similar with bivalirudin monotherapy
and with heparin plus GP IIb/IIIa inhibitors. In contrast, in
patients who were not pretreated with clopidogrel, the point
estimate for adverse ischemic events was slightly higher with
bivalirudin monotherapy than with heparin plus GP IIb/IIIa
inhibitors. Addressing this difference, Stone et al say: "Given the
borderline statistical significance of the interaction (p = 0.054)
and the risk of a spurious finding from examination of multiple
subgroups, caution against over-interpretation is warranted.
Nonetheless, the administration of a thienopyridine before
angiography may be desirable to optimize outcomes with a regimen of
bivalirudin monotherapy".

Short time to angiography

One point that has been the subject of discussion was the short time
from administration of the study drug to angiography (median: 3.5-4
hours). The authors agree that the time to angiography was
relatively short, but point out that bivalirudin monotherapy was
also associated with a significantly lower risk of bleeding and
similar rates of ischemia in the subgroup of patients for whom the
interval from randomization to angiography or intervention was more
than 24 hours.

Some caveats

The researchers point out that the results of this study do not
apply to ACS patients who are managed solely with a noninvasive
strategy or for a prolonged period (>72 hours) before
catheterization, or to patients with severe renal insufficiency who
were excluded from enrollment.

Another issue that has been raised is the 25% noninferiority margin
used, which is wider than in many other studies. Alhough conceding
that the noninferiority margin might be considered wide, the ACUITY
investigators state: "As the rate of ischemic events in the control
group was 7.3%, an estimated ischemic-event rate as high as 9.1% in
the test groups would have been considered noninferior, even though
it might be regarded as clinically important. However, given the
observed event rates and confidence intervals, there was a 95.0%
likelihood that the incidence of composite ischemia in the
bivalirudin-monotherapy group was less than 20% higher than the
incidence in the control group."

Positive editorial

In the accompanying editorial, Bittl says the main results of the
ACUITY trial are clear. "The nominal 7% decrease in bleeding events
seen with bivalirudin plus a glycoprotein IIb/IIIa inhibitor offset
the nominal 7% increase in ischemic events, which resulted in a near-
perfect balance in the composite event rates? The significant 47%
reduction in bleeding seen with bivalirudin monotherapy offset the
noninferior 8% increase in ischemic events and produced a small
significant 14% reduction in net clinical outcomes at 30 days, which
corresponded to an absolute decrease of 1.6 percentage points from
the control group."

He says the trial provides strong support for the use of bivalirudin
as a substitute for heparin plus GP IIb/IIIa inhibitors in ACS
patients who undergo early invasive management, in particular if
they are pretreated with clopidogrel.

Bittl says that the clopidogrel-subgroup findings suggest, but do
not prove conclusively, that patients treated with bivalirudin
monotherapy should be pretreated with clopidogrel in a dose of 300
mg six hours before PCI, but a dose of 600 mg as early as two hours
before PCI remains controversial. Patients who require urgent PCI
but have not been adequately pretreated with aspirin or clopidogrel
should receive a GP IIb/IIIa inhibitor, he adds.

heartwire asked a few experts in the field for their opinion on the
ACUITY results, now that they are published and, on the whole, the
comments were relatively positive.

Steinhubl--"major step forward"

Dr Steven Steinhubl (University of Kentucky, Lexington), who was
cochair of the ACUITY inflammation substudy, says the trial is
a "major step forward" in improving the treatment of patients with
an acute coronary syndrome in whom invasive management is
planned. "I believe it provides reassurance in the one important
group of patients not well represented in REPLACE-2--the higher-risk
ACS patients--that bivalirudin alone is an effective alternative to
a heparin plus a GP IIb/IIIa antagonist," he told heartwire.

He adds that troponin-positive patients are really the only subgroup
of possible ACS patients in whom antithrombotic therapy has been
shown to make a difference, and although the 1% absolute increase in
ischemic events with bivalirudin in this arm is a concern, the 2.6%
absolute decrease in major bleeding suggests that long-term
cardiovascular outcomes will favor the bivalirudin arm. He thinks
too much is being made of the clopidogrel pretreatment issue. "The
timing, dose, and duration of clopidogrel pretreatment is not well
documented and may be just a chance finding. The ISAR-REACT 4 trial
will help determine if bivalirudin plus P2Y12 blockade have
complementary roles, but until then I will not let the lack of
clopidogrel pretreatment influence my use of bivalirudin".

Harrington/Ferguson more guarded

Drs Robert Harrington (Duke University, Durham, NC) and James
Ferguson (Texas Heart Institute, Houston), neither of whom were
involved in the study, were slightly more guarded in their response
to ACUITY.

Harrington has some reservations about the study, including the fact
that the results apply to just a select group of moderate- to high-
risk patients who are managed in an expedited fashion with an
invasive strategy, and that the noninferiority margin was large. He
says the clopidogrel data are "intriguing" and "yet another factor
that must be considered in selecting an antithrombotic strategy for
these patients." He concluded: "The bottom line for me is that
unfractionated heparin, low-molecular-weight heparin, fondaparinux,
and bivalirudin all appear to have a role as anticoagulants in the
treatment of NSTE ACS. How one chooses is largely dependent on the
local practice style, including the use and timing of an invasive
strategy. There is still much work to be done to determine optimal
combinations of drugs, including antiplatelet therapies, because 30-
day event rates, including bleeding, remain high."

Ferguson, who was the chief investigator of the SYNERGY trial of
enoxaparin in ACS, takes a similar line, saying: "For me, ACUITY
does not define a new standard, but gives us another pharmacological
option that physicians can consider in treating ACS patients". He
notes: "What we saw in ACUITY is pretty much identical to what we
saw in REPLACE-2--less bleeding and generally similar clinical
outcomes. But "generally similar" becomes a somewhat slippery slope,
depending on whether you were a bivalirudin believer or not going
into the trial." On the clopidogrel difference, he
states: "Bivalirudin advocates say this means we need to use more
clopidogrel early, and anybody who has received clopidogrel should
get bivalirudin monotherapy. The bivalirudin skeptics will suggest
that if you have not already loaded with clopidogrel you should not
use bivalirudin alone." Although acknowledging that ACUITY
solidifies the role of bivalirudin in the cath lab, Ferguson feels
that patients with a positive troponin would still benefit from GP
IIb/IIIa antagonists.

"The message for me is not necessarily that bivalirudin needs to be
the drug you start in the ER and carry forward all the way till the
patient comes to the cath lab--instead, what ACUITY tells me is that
bivalirudin monotherapy is a reasonable option to consider when you
have made the decision to go to the cath lab in the very near
future. But ACUITY has also taught me that if you have already
decided to give a GP IIb/IIIa antagonist, there is no advantage
whatsoever in choosing bivalirudin over a heparin," he adds.

Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with
acute coronary syndromes. N Engl J Med 2006; 355:2203-2216.
Bittl JA. Accounting for ACUITY. N Engl J Med 2006;355: 2249-2250.

In patients with an implantable cardioverter defibrillator (ICD),
anger management could go a long way toward reducing ventricular
tachycardia/ventricular fibrillation (VT/VF) events, thus reducing
the number of painful shocks needed to convert the heart to normal
rhythm, a new study has shown.



Presenting data last week at the American Heart Association 2006
Scientific Sessions, lead investigator Dr Christine Albert (Harvard
Medical School, Boston, MA) and colleagues report that acute
episodes of moderate anger were associated with a significantly
greater risk of ICD discharge.



"None of the patients want to be shocked by their defibrillator, so
if they know that something they're doing might precipitate that,
they might try to modify their behavior," said Albert.



The rationale for the study, explained Albert during a briefing for
the media, was to examine the triggers of arrhythmia in patients
with an ICD. In this multicenter, prospective cohort study, 1188
patients with an ICD were asked to report to the hospital any time
the device delivered a shock and to complete a questionnaire about
how they were feeling before the ICD discharge. Information on the
exposure to triggers prior to the ICD shock was collected within 72
hours, and stored electrograms were studied to confirm the cardiac
rhythm underlying each ICD shock.



A total of 199 cases of VT/VF were recorded in the study. The
relative risk of ICD discharge for VT/VF within one hour of exposure
to at least moderate levels of anger was 3.2 as compared with the
risk during periods of lesser or no anger. If patients were very
angry or furious, there was a 16-fold increased risk of ICD
discharge for VT/VF.



Although the study did not address how anger caused the arrhythmia,
Albert told heartwire that previous studies have shown alterations
in T-wave alternans when patients become angry. In addition, the
sympathetic nervous system is thought to be a driver of arrhythmia,
and this system is highly activated during periods of stress and
anger, she said. Albert cautioned, however, about extrapolating the
findings to the general population, because the patients in this
study are high risk and predisposed to arrhythmias. In terms of a
clinical message, it might help to tell ICD patients not to get too
worked up.



"The motivation for a lot of patients in this study was that they
really wanted to understand what kinds of things they could or could
not do. Our patients ask us these questions all the time," said
Albert. "We try everything we can as physicians to minimize the
amount that they get shocked, but often we don't talk to them about
what they can do."

Patients with short QT syndrome (SQTS) are at high risk of sudden
death, even during the first few months of life, and SQTS may be a
cause of sudden infant death syndrome, European researchers report.

The researchers suggest that an implantable cardioverter
defibrillator should be the first-line therapy for patients, and
that hydroquinone be reserved as a possible treatment for children
or in those patients who refuse defibrillator implantation.

In the October issue of the European Heart Journal, Dr. Carla
Giustetto, from Cardinal Massaia Hospital in Asti, Italy, and
colleagues note that they analyzed data from 29 patients with SQTS.
All of the subjects had a personal or family history of sudden death
or aborted sudden death.

Twenty-one patients were male and eight were female. The median age
at diagnosis was 30 years, the report indicates.

Eighteen of the patients had symptoms from their SQTS. A history of
cardiac arrest was noted in nine of the patients, including eight
whose arrest was the first clinical presentation of SQTS. At the
time of arrest, the patients ranged in age from 4 months to 62 years.

Six patients had syncope and one patient had presyncope.
Palpitations were noted in nine patients, usually in conjunction
with atrial fibrillation. On ECG, the patients' QT intervals were no
greater than 320 ms and the QTc was no greater than 340 ms.

Three patients died before evaluation and had not received
treatment. Of the remaining 26 patients, 14 received an implantable
cardioverter defibrillator and 12 did not. These 12 patients
included 2 who were very young and 10 who refused the implant. Ten
patients were ultimately treated with hydroquinidine prophylaxis and
none of them experienced sudden death or syncope.

"The outcome of SQTS patients becomes relatively safe when they are
identified and treated. Unfortunately, without therapy the outcome
is not so good," the authors note. "For this reason today, subjects
with SQTS and family history of sudden death must be treated with
ICD in primary prevention."

Euro Heart J 2006;27:2440-2447

PET imaging with fluorodeoxyglucose (FDG-PET) can be used to
identify noninvasively the degree of inflammation in carotid plaques
in patients, according to a report in the November 7th issue of the
Journal of the American College of Cardiology.

"Plaque biology can be imaged using PET and may prove to be a
stronger predictor of risk than stenosis," Dr. Ahmed Tawakol from
Massachusetts General Hospital and Harvard Medical School, Boston,
told Reuters Health. "I believe that PET imaging of plaque may prove
to be a remarkably powerful way of evaluating the effect of new
therapies targeting atherosclerotic diseases."

Dr. Tawakol and colleagues investigated whether inflammation in
human carotid arteries could be measured noninvasively in vivo using
FDG-PET in 17 adult patients with severe carotid artery stenosis
already scheduled to undergo carotid endarterectomy.

The PET signal correlated significantly with macrophage staining in
the plaques removed at the time of endarterectomy, the team found.

The correlation was even stronger between FDG uptake and mean
inflammation (as measured by mean percentage of CD68 staining), the
results indicate.

In contrast, FDG uptake did not correlate significantly with plaque
thickness or plaque area, the researchers note.

"The findings of the present study suggest that PET studies of the
carotid arteries could aid in the risk stratification of patients
with less stenotic or asymptomatic lesions by identifying inflamed
plaques that may be associated with a higher risk of a clinical
event," the investigators explain.

"Natural history studies are needed to evaluate the clinical
relevance of plaque imaging," Dr. Tawakol said. "We are also
planning several additional pharmacological intervention studies."

J Am Coll Cardiol 2006;48:1818-1824

Variability in blood pressure in patients who have had a previous
transient ischemic attack (TIA) or minor stroke means that single
measurements are unreliable, UK researchers report in the November
issue of Stroke.

Dr. Peter M. Rothwell of the Radcliffe Infirmary, Oxford and
colleagues note that as well as the short-term variability of
systolic and diastolic BP, which can be corrected by 24-hour
monitoring, there may also be variations in the medium-term -- over
week or months.

"The data," Dr. Rothwell told Reuters Health, "show that blood
pressure is so variable in patients with previous TIA or stroke that
individual measurements of blood pressure on a particular day can be
very misleading."

To gauge the effect of this medium-term variability, the researchers
examined data from three large cohorts of patients with TIA or minor
stroke. In all, more than 7600 subjects were involved. The team
found poor correlations between BP at baseline and 3 to 5 months
later.

This resulted in considerable misclassification. For example, in one
of the cohorts, 31.6% of patients who had a systolic BP of less than
140 mm Hg at baseline had a usual systolic BP of at least 140 mm Hg.
Corresponding proportions in the other two cohorts were 48.2% and
57.7%.

The researchers calculate that three consecutive measurements were
required to be more than 90% certain that the subsequent usual
systolic BP would not be 140 mm Hg or more.

Nevertheless, they also point out that in patients with three such
measurements below 140 mm Hg, but with a mean of 130 to 139 mm Hg,
there still was a 25% to 30% chance that the subsequent usual BP
would 140 mm Hg or more.

"In particular," concluded Dr. Rothwell, "several measurements on
several different days are required before one can be confident that
blood pressure is consistently well controlled and not therefore in
need of further treatment ."

Stroke 2006;37:2776-2783

Stem cells can be grown in large numbers from the abdominal fat of
elderly patients with cardiovascular disease, according to new
research. Adipose tissue may be a safe, reliable source of
autologous stem cells for use in elderly patients to repair vascular
tissue.

Previous studies attempting to harvest stem cells from adipose cells
have focused on young, healthy subjects. At the American Heart
Association 2006 Scientific Sessions, researchers announced that
elderly patients with cardiovascular disease can serve as their own
source of stem cells, using the relatively safe, conventional
procedure of liposuction to extract abdominal fat from which large
numbers of stem cells can be harvested.

Researchers at Thomas Jefferson University in Philadelphia,
Pennsylvania, led by Paul J. DiMuzio, MD, associate professor of
surgery, are growing and isolating adipose-derived stem cells in
elderly patients with a variety of manifestations of cardiovascular
disease.

Dr. Muzio presented findings in 25 such patients who were undergoing
elective vascular-related surgery. Approximately 15 g of abdominal
fat were extracted from each patient using liposuction.

Stem cells were cultured from the adipose tissue, and then the
number and quality of the cells was compared with adipose-derived
stem cells taken form young, healthy subjects in previous studies.

Dr. DiMuzio announced finding "no significant difference" between
young and older patients in terms of the number of cells derived per
gram of fat. "They were nearly equivalent," he told meeting
attendees.

The number derived from men and women was "roughly equivalent," with
a marginally larger number of cells per gram of fat in women. The
same was true between obese and leaner patients, who had
statistically equivalent numbers of stem cells.

The group in which there was a difference was patients with
diabetes, who proved to be a poorer source of adipose-derived stem
cells than their nondiabetic counterparts.

Patients with kidney failure showed no disadvantage as a source of
autologous stem cells. "This could be very important for patients
who need tissue-based dialysis grafts," Dr. DiMuzio pointed out.

Surprisingly, patients with cardiovascular disease, in general,
proved to be a better source of stem cells than healthy control
subjects, he said, but the number in this group is too small to make
any real conclusions.

"We are now looking at the quality of the stem cells," Dr. DiMuzio
told Medscape. "So far, we can't tell a difference. The cells grow
and proliferate at the same rate and they have the same markers. But
we don't know if they have the ability to differentiate."

Elliott M. Antman, MD, American Heart Association spokesperson and
professor of medicine at Harvard University in Cambridge,
Massachusetts, commented in an interview with Medscape after Dr.
DiMuzio's presentation, that "this is the least studied of the
possible sources of stem cells.

"If stem cells can be harvested in sufficient numbers from elderly
patients, this research will be very intriguing....," Dr. Antman
said. "And who isn't willing to give up some fat?"

Dr. DiMuzio and Dr. Antman report no relevant financial
relationships.

AHA Scientific Sessions 2006: Abstract 2191. Presented November 15,
2006

A virtual environment can safely reproduce potentially dangerous
tasks as part of stroke rehabilitation, according to a report in the
November issue of Stroke. However, the system needs further work in
order to mimic the real world more closely.

"The use of virtual technologies may be of benefit to stroke
patients and may be a way forward for the future," Dr. Judi A.
Edmans from the University of Nottingham, UK told Reuters Health.

In a study involving 50 stroke patients, Dr. Edmans and colleagues
evaluated a virtual environment developed for the rehabilitation of
the task of making a hot drink.

"The virtual environment was displayed and interacted with using a
laptop computer touch screen and handheld stylus," the investigators
explain. The patients selected and moved images of the required
components (such as a kettle and instant coffee), and were told when
each subtask was performed correctly.

The virtual environment was feasible for use in the stroke
rehabilitation unit, the authors report, and performance of hot
drink-making in the real and virtual worlds were correlated, albeit
not strongly.

Real world performance was associated with arm function and
sequencing ability, the results indicate, whereas virtual
environment was associated with language function and praxis.
Performance scores for both real and virtual environments correlated
with age, Mini-Mental Status Examination scores, Barthel activities
of daily living, and visuospatial perception tests.

Error patterns during attempts to make a hot drink were not
significantly associated between real world and virtual
environments, the researchers note. That is, the patients made
different mistakes when making a real and a virtual hot drink.

"Further design work or alternative strategies using different
technologies might improve the similarity between real and virtual
tasks," the investigators suggest.

"Although further development is needed," they conclude, "our
virtual environment may nevertheless be a valuable rehabilitation
tool for some patients aiming at making a hot drink, because it
retains many of the potential educative benefits of the virtual
environment, such as the ability to practice the task repeatedly and
in safety, and encouraging error-free learning."

Stroke 2006;37:2770-2775.

Dr. Wang-

   Your member "Mot Gro" is using your list to send spam.  I have received five
junk messages from him already.  I hope you will terminate his privileges.

   Michael

dr_allen_wang <no_reply@yahoogroups.com> wrote:
           Lipoatrophy is one of the most stigmatizing effects of
antiretroviral medications. In fact, for some HIV patients the
change in their appearance leads to reduced adherence to
antiretroviral medications or to treatment discontinuation. In a
study published in the October 24 issue of AIDS, Graeme Moyle, MBBS,
MD, from the Chelsea and Westminster Hospital in London, United
Kingdom, and his associates illustrate that switching from a
thymidine nucleoside analogue regimen to either tenofovir DR or
abacavir leads to significant improvements in limb fat mass during a
48-week period.

In a phase 4, open-label, randomized trial, 105 patients were
treated with either 300 mg of tenofovir DF once daily or 300 mg of
abacavir twice a day as a substitution for zidovudine or stavudine.

The participants of the study, sponsored by Gilead Sciences, were
chosen from 10 UK HIV treatment centers. Patients were all aged 18
years or older and had been receiving a stable therapy of zidovudine
or stavudine for more than 16 weeks prior to the beginning of the
study. In addition, all participants had clinically evident moderate
to severe lipoatrophy at one or more body or facial sites as well as
a documented HIV-1 RNA load of less than 50 copies/mL on 2
consecutive visits to the clinic.

Exclusion criteria consisted of previous exposure to tenofovir,
abacavir, adefovir, or resistance to these drugs; the receipt of
dual or monotherapy with nucleoside reverse transcriptase
inhibitors; the diagnosis of active opportunistic disease; or
receipt of chemotherapy, insulin-sensitizing agent, anabolic
steroids, growth hormones, or any drug that was likely to interact
with the study drugs within 16 weeks before the initiation of the
study.

Dr. Moyle and colleagues measured the change in limb fat mass using
dual x-ray absorptiometry (DEXA) at baseline, 24 weeks, and 48 weeks
for each participant. Furthermore, the researchers noted changes in
total body and trunk fat mass; changes in visceral, subcutaneous,
and total adipose tissue; as well as changes in bone mineral
density. Adverse events, virologic rebound, complete blood count,
liver and renal function, insulin, triglyceride, and lipid levels
were also evaluated. Virologic rebound was defined as 2 consecutive
HIV-1 RNA measurements of more than 200 copies/mL.

Virologic control was maintained, and a statistically significant
increase in limb fat mass occurred in both treatment groups. In
fact, patients receiving tenofovir DF and abacavir had a mean 329 g
and 483 g increase, respectively, in limb fat mass at week 48.

Those patients who had switched from stavudine experienced the
greatest increase in limb fat mass. For example, among patients in
the tenofovir DF treatment group, in the patients who had previously
taken stavudine there was a mean increase in limb fat of 499 g
compared with a 195-g increase for those who had received zidovudine
prior to the study. Likewise, among patients in the abacavir
treatment group, the patients who had previously taken stavudine
experienced a mean limb fat increase of 615 g compared with a 253-g
increase for those who had received zidovudine before the study
began.

"I believe that [the clinical implications of these findings] will
encourage physicians to switch [patients] to one of these newer
antiretroviral regimens. Also, I believe that as more data become
available, it will become increasingly more unacceptable to use the
thymidine analogue," study coauthor Philip Hay, MD, QME, from St.
George's Hospital in London, United Kingdom, told Medscape.

Moreover, there appeared to be some promise in the area of
cardiovascular benefits as a result of the change to tenofovir DF.
Mean total cholesterol, low-density lipoprotein cholesterol, and
triglyceride levels all improved modestly among the tenofovir DF
treatment group.

"While one could not really expect to get concrete data from a 48-
week study, one can extrapolate the apparent benefits from the
change in lipid profile," commented Dr. Hay. "Although the
differences are not great, the good news is that there is a
reduction in cardiovascular risk [factors after a switch] to
tenofovir DF."

Some researchers and physicians remain cautiously optimistic.

"This study suggests, but does not prove, that switching off
[zidovudine or stavudine] to abacavir and tenofovir DF allows for
similar rates of improvement over 12 months, " Andrew Carr, MD, from
St. Vincent's Hospital in Sydney, Australia, told Medscape. "It was
not large enough, however, to prove that [these drugs] allow for
identical rates of improvement, although my suspicion is that they
do," he said.

Due to adverse events, 1 patient in the tenofovir DF treatment group
and 3 patients in the abacavir treatment group had to discontinue
the study.

AIDS. 2006;20:2043-2050










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Clinical Context
Thiazide diuretics are some of the most commonly used medications to
lower blood pressure among patients with hypertension, and an
editorial by Phillips, which accompanies the current article,
reviews the history of research into this class of medications.
Initial studies used high-dose thiazide diuretics for treatment of
hypertension, and these dosages were associated with a higher risk
for sudden death among patients with baseline electrocardiogram
abnormalities. These high dosages were not necessary, as the dose-
response curve for thiazide diuretics and blood pressure become
fairly flat at moderate dosages. Lower dosages of thiazide diuretics
have been demonstrated to reduce blood pressure as well as left
ventricular mass among patients with hypertension.

Thiazide diuretics have also been demonstrated to increase levels of
serum glucose. The current analysis of ALLHAT examines this
phenomenon as well as the clinical significance of incident diabetes
linked with antihypertensive therapy.

Study Highlights
Patients eligible for study participation were at least 55 years old
and either had blood pressure values of at least 140/90 mm Hg or
were receiving treatment of hypertension with fewer than 3
medications. Subjects also had at least 1 risk factor for CHD and a
baseline serum glucose level less than 110 mg/dL.
Participants were randomized to receive treatment with
chlorthalidone, amlodipine, or lisinopril to reduce blood pressure
to less than 140/90 mm Hg.
Serum glucose was measured at baseline and at years 2, 4, and 6. The
main study outcome was the relationship between antihypertensive
assignment, serum glucose at follow-up, and the incidence of
diabetes (defined by serum glucose > 125 mg/dL).
18,411 patients in the ALLHAT trial did not have diabetes at
baseline, and 53.2% of these subjects had FG levels examined at
subsequent visits. The mean age of participants was 66 years, and
the mean serum FG level was 93 mg/dL among all treatment groups.
The mean follow-up time was 4.9 years. Rates of maintenance of
blinded medication use at year 4 were 76.3%, 84.7%, and 83.2% among
the lisinopril, amlodipine, and chlorthalidone groups, respectively.
Glucose levels rose in all treatment groups with time. During the
first 2 years, the mean increase is serum glucose levels was 8.5,
5.5, and 3.5 mg/dL among the chlorthalidone, amlodipine, and
lisinopril groups, respectively. The difference between
chlorthalidone and the other antihypertensive drugs in this outcome
was significant and remained relatively stable at 4 years.
Compared with the chlorthalidone group, the odds ratios for
developing diabetes were 0.55 and 0.73 in the lisinopril and
amlodipine groups, respectively.
Despite the increase in serum glucose and risk for diabetes linked
with chlorthalidone therapy, subjects with these outcomes did not
have a significantly increased risk for CHD or mortality vs subjects
receiving chlorthalidone whose glucose remained stable during study
therapy. Conversely, incident diabetes increased the risk for CHD
and heart failure among subjects receiving lisinopril. The overall
risk for CHD was also increased among all subjects who developed
incident diabetes.
Pearls for Practice
High-dose thiazide diuretics can promote sudden death among patients
with hypertension and electrocardiogram abnormalities, but they can
also safely reduce blood pressure and left ventricular mass at lower
dosages among patients with hypertension.
In the current analysis of ALLHAT, chlorthalidone was associated
with a more significant increase in serum glucose level and incident
diabetes than amlodipine and lisinopril. However, incident diabetes
among subjects receiving chlorthalidone did not increase the risk
for CHD or mortality.

Fasting glucose (FG) levels increase in older adults with
hypertension regardless of whether they are treated with
chlorthalidone, amlodipine, or lisinopril, according to the results
of an analysis from the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT) reported in the
November 13 issue of the Archives of Internal Medicine. Although the
risk of developing FG levels higher than 125 mg/dL was modestly
greater with chlorthalidone, there was no conclusive or consistent
evidence that this diuretic-associated increase in risk for diabetes
increased the risk for clinical events.

"Many patients with hypertension eventually develop diabetes,"
Robert Phillips, MD, author of an editorial accompanying the
article, and director of the Heart and Vascular Center of Excellence
at the University of Massachusetts Memorial Medical Center in
Worcester, told Medscape. "Physicians and others interested in the
individual and public health are guided by the principle of primum
non nocere ¡X first, do no harm. The initial reports from the ALLHAT
trial showed that there was more diabetes associated with thiazide-
diuretic treatment, and the authors sought to determine if this was
harmful."

The objective of this analysis was to compare the effect of first-
step antihypertensive drug therapy with thiazide-type diuretic,
calcium-channel blocker (CCB), or angiotensin-converting enzyme
(ACE) inhibitor on FG levels and to determine the risks for
cardiovascular and renal disease associated with elevated FG levels
and incident diabetes mellitus in these 3 treatment groups. The
investigators performed post hoc subgroup analyses from ALLHAT among
nondiabetic participants who were randomized to treatment with
chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n =
5034). Mean follow-up was 4.9 years.

"Mean fasting glucose levels increased during ALLHAT follow-up in
all treatment groups," corresponding author Barry R. Davis, MD, PhD,
of the University of Texas School of Public Health, Coordinating
Center for Clinical Trials in Houston, told Medscape. "There was no
significant association of fasting glucose level change at 2 years
with subsequent coronary heart disease [CHD], stroke, cardiovascular
disease, total mortality, or end-stage renal disease."

At year 2, the chlorthalidone group had the greatest increase in
mean FG levels (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L]
for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The
odds ratios for developing diabetes at 2 years were 0.55 with
lisinopril vs chlorthalidone (95% confidence interval [CI], 0.43 -
0.70), and 0.73 with amlodipine vs chlorthalidone (95% CI, 0.58 -
0.91; P <.01). Incident diabetes at 2 years was not significantly
associated with clinical outcomes, except for CHD (risk ratio [RR],
1.64; P = .006), but RR was lower and nonsignificant in the
chlorthalidone group (1.46; P = .14).

"The diuretic did not appear to be the culprit responsible for the
increased CHD risk associated with new-onset DM [diabetes
mellitus]," Dr. Phillips says. "Rather surprisingly, development of
DM during treatment with ACE inhibitors was associated with an
increased risk of CHD and congestive heart failure, and development
of DM during treatment with CCB was associated with increased
mortality. We need to be cautious about the clinical implications,
but I do believe that they suggest that diuretic-induced
hyperglycemia is relatively benign. Conversely, if diabetes develops
on an ACE or CCB, it suggests that that patient has developed
insulin resistance despite being on drugs that tend to improve
insulin sensitivity, and hence the consequences are more dire."

Strengths of this study, according to Drs. Davis and Phillips, are
the large sample size providing much greater statistical power to
recognize associations and differences between medications and the
relatively long duration of follow-up. Limitations are the
retrospective design, and follow-up possibly insufficient to detect
the adverse effects of thiazide-induced hyperglycemia.

"Considerable attention was paid to quality assurance, and all
laboratory tests were done in a certified central laboratory," Dr.
Davis says. "Limitations of the study are that no FG measurements
during follow-up were available for nearly half of the cohort, owing
primarily to participants not fasting prior to venipuncture. Also,
we did not obtain measures of overall glucose control, such as
glycosylated hemoglobin, and we did not obtain information on
treatment of diabetes."

Dr. Phillips also notes that because of its design, ALLHAT did not
study the typical types of combinations of hypertensive medications
that patients frequently take, limiting generalizability of the
results. However, the International Verapamil-Trandolapril Study
showed that an atenolol-hydrochlorothiazide based strategy was as
effective as the verapamil-trandolapril strategy in preventing death
and cardiovascular outcomes in this high-risk population, even
though there was more incident diabetes associated with the former
regimen.

"I think that [the ALLHAT analysis] will help physicians to feel
more comfortable about using low-dose thiazide therapy as either the
initial drug choice as or part of combination therapy," Dr, Phillips
said. "If hyperglycemia or frank diabetes does develop, many
physicians would stop the diuretic and substitute another agent to
see if the hyperglycemia would resolve. One can't argue with that
approach, but actually we do not know if it is the correct action to
take."

"These results should reinforce the recommendations of the Joint
National Committee on Hypertension that diuretics should be
considered as a first-line treatment of hypertension and should be
part of any multidrug regimen for hypertension," Dr. Davis concluded.

This study was supported by the National Heart, Lung, and Blood
Institute. The ALLHAT investigators disclosed receiving
contributions of study medications from Pfizer (amlodipine and
doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers
Squibb (pravastatin), and financial support from Pfizer. Some of the
authors have disclosed various financial relationships with Takeda,
GlaxoSmithKline, Merck, BioMarin, Proctor & Gamble, Bristol-Myers
Squibb, Pfizer, Abbott Laboratories, AstraZeneca, Boehringer
Ingelheim, Forest Pharmaceuticals, Novartis, Reddy, Sankyo,
SmithKline Beechman/Glaxo Wellcome, Bertek, DepoMed, Medco, and/or
Wyeth. Dr. Phillips has disclosed no relevant financial
relationships.

Arch Intern Med. 2006;2174-2176, 2191-2201.