The overall rate of "definite or probable" stent thrombosis within 30
days of PCI was about 1.4% in a prospectively planned substudy of the
Acute Catheterization and Urgent Intervention Triage Strategy
(ACUITY) trial, which randomized patients with "moderate- or high-
risk" ACS to early invasive management using one of several
antithrombotic regimens, report investigators in the February 10,
2009 issue of Circulation [1].

The early stent-thrombosis risk didn't significantly vary among the
different adjunctive regimens, which consisted of either heparin or
bivalirudin with glycoprotein (GP) IIb/IIIa inhibitors or bivalirudin
without GP IIb/IIIa inhibition. The risk was also unrelated to the
timing of GP-IIb/IIIa-inhibitor administration and to whether
patients received drug-eluting stents (DES), which were used in 90%
of cases, or only bare-metal stents.

Independently significant predictors of stent thrombosis at 30 days
included a lack of preprocedural thienopyridine treatment and reduced
in-stent minimum luminal diameter, according to the authors, led by
Dr Jiro Aoki (Columbia University Medical Center, New York, NY).
Unsurprisingly, poor compliance with postprocedure thienopyridine
therapy was also a risk factor for early stent thrombosis.

"It concerns me that, whether with drug-eluting stents or bare-metal
stents, the stent-thrombosis rates are still relatively high,"
regardless of antithrombin regimen, ACUITY primary investigator Dr
Gregg Stone (Columbia University Medical Center) commented to
heartwire. "So I think we need to, one, modify the risk factors we
can modify, which means pretreat with thienopyridines; two, emphasize
prolonged thienopyridine use as per guidelines, one year or longer of
dual antiplatelet therapy; and three, optimize the angiographic
result with appropriately sized balloons and/or pressure."

In ACS, some PCI operators like to get "in and out," Stone said. "But
to make a good job of stenting we really do need to try to optimize
the result and get as close to a zero percent residual stenosis as
possible, to try to minimize the risk of stent thrombosis. So I think
technique does matter."

Stent thrombosis is certainly worth avoiding; in the current ACUITY
30-day analysis, patients with definite or probable stent thrombosis
had increased rates of death, MI, unplanned revascularization, and
major bleeding.

The complication hasn't recently received the attention it deserves,
contend Drs Stéphane Cook and Stephan Windecker (Swiss Cardiovascular
Center, Bern) in an accompanying editorial [2]. It's been
overshadowed, they write, by the specter of late stent thrombosis
since the first controversial allegations in 2006--covered
extensively since then by heartwire--that it may be more likely after
DES than bare-metal-stent procedures.

The current ACUITY analysis, Cook and Windecker write, "will
reinforce our quest to strive for an optimal postprocedural result"
and "underscores the importance of timely and adequate inhibition of
platelet aggregation in patients with acute coronary syndromes
undergoing PCI." It suggests that supplementary GP IIb/IIIa
inhibition "be strongly considered in the absence of thienopyridine
treatment."

Agreeing, Dr Ron Waksman (Washington Hospital Center, Washington,
DC), who isn't an ACUITY coauthor, said the analysis emphasizes that
in the setting of invasive management of ACS, patients should be
preloaded with clopidogrel. But, he commented to
heartwire, "glycoprotein IIb/IIIa inhibition probably does have a
role in this setting, specifically when patients are not preloaded--
or even if they are preloaded on the table, when they have pills in
their stomach that aren't yet doing anything."

The ACUITY trial's primary outcomes were reported in 2006 [3]. As
covered by heartwire at the time, the trial randomized 13 819
patients invasively managed for ACS to receive one of the three
antithrombin regimens and saw a "noninferior" rate of a composite
ischemia end point--which included death by any cause--for the
bivalirudin regimens compared with heparin plus GP IIb/IIIa
inhibition.

The trial came with its own controversy; also as covered by
heartwire, some observers questioned ACUITY's statistical definition
of noninferiority, alleging that it favored outcomes in the
bivalirudin arms.

The current analysis focused on the trial's 3405 patients implanted
with at least one stent and evaluated by quantitative coronary
angiography according to a prospective protocol. The 30-day rate of
definite or probable stent thrombosis was 1.4% overall and 1.1% for
heparin plus GP IIb/IIIa inhibitors, 1.6% for bivalirudin with GP
IIb/IIIa inhibitors, 1.5% for bivalirudin alone, and 1.4% for both
DES and bare-metal-stent procedures (no significant differences).

The complication was associated with significantly increased rates of
death (27% vs 0.4% for no early stent thrombosis), MI (79% vs 6.7%),
and unplanned ischemia-driven PCI or CABG (67% vs 2.4%); all
differences were significant at p<0.0001.

The timing of clopidogrel initiation in ACUITY was at the operator's
discretion, Waksman observed, but its early-stent-thrombosis outcomes
underscore that preloading should be routine in ACS. In fact, he
said, the importance of thienopyridine preloading likely outweighs
the role of stent placement technique for cutting the early stent-
thrombosis risk.

"Clearly, if you get good [angiographic] results in patients with
unstable angina, you still have a higher risk of MI than in patients
with stable angina," Waksman said. "The more unstable the patient,
the more stent thrombosis. That's why [in ACS] you have to be more
meticulous with antiplatelet therapy."

The ACUITY trial was funded by the Medicines Co and Nycomed;
individual author disclosures are in the report. Windecker reports
consulting for and receiving lecture fees from Abbott, Biosensors,
Biotronik, Boston Scientific, Medtronic, and Johnson & Johnson.


Aoki J, Lansky AJ, Mehran R, et al. Early stent thrombosis in
patients with acute coronary syndromes treated with drug-eluting and
bare metal stents: the Acute Catheterization and Urgent Intervention
Triage Strategy trial. Circulation 2009; 119:687–698. Abstract
Cook S, Windecker S. Early stent thrombosis: past, present, and
future. Circulation 2009; 119:657–659. Abstract
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with
acute coronary syndromes. N Engl J Med 2006; 355:2203–2216.Abstract

"Progress" is the word Dr Patrick W Serruys (Erasmus University
Medical Center, Rotterdam, the Netherlands), coˇVprincipal
investigator for the Synergy Between PCI With Taxus and Cardiac
Surgery (SYNTAX) trial, uses to summarize the landmark study,
published in the February 19, 2009 issue of the New England Journal
of Medicine (NEJM) [1].

Reflecting on over almost 30 years of angioplasty-vs-surgery trials,
Serruys says ever more patients are heading to the cath lab instead
of the OR, and SYNTAX expands the circle still further, suggesting
that at least some patients with left main or three-vessel disease
can safely and feasibly be treated with PCI.

"With every trial, we're taking a step forward. . . . I think we keep
making progress," he said.

It's a somewhat rosy take on what was, after all, a negative trial.
As previously reported by heartwire when the study was presented at
the ESC 2008 meeting, one-year results from SYNTAX showed that PCI
with drug-eluting stents (DES) was statistically inferior to CABG, at
least for the primary composite end point of major adverse cardiac or
cerebrovascular events (MACCE). But for combined "hard" end points--
death, MI, and stroke--event rates were no different between the two
trial groups, and secondaryˇVend-point findings indicated a
statistically higher risk of stroke with CABG and a statistically
higher risk of revascularization with PCI. Further details of the
trial, released at TCT 2008, suggested that in low- or intermediate-
risk patients with left main disease, PCI and CABG are both
reasonable options, at least for hard events at one year. In three-
vessel disease, however, only the lowest-risk patients should be
considered as candidates for PCI instead of surgery. These results,
however, while prespecified analyses, were merely "hypothesis-
generating," since the primary trial results were negative.

Patients deemed during the screening process to be unsuitable for
randomization were instead enrolled in one of two "nested" registries
(1077 to CABG; 198 to PCI). As previously reported by heartwire, CABG-
treated patients did extremely well (even better than CABG patients
in the randomized trial), while PCI-treated patients fared worse than
PCI-treated patients in the randomized arm.

The Essence of SYNTAX

Now published, the SYNTAX results are nearly identical to what
Serruys, with co-PI Dr Friedrich W Mohr (University of Leipzig,
Germany), previously presented (see related links). In the paper, the
authors cautiously conclude that the results of SYNTAX "show that
CABG as compared with PCI is associated with a lower rate of MACCE at
one year among patients with three-vessel or left main coronary
artery disease (or both) and should therefore remain the standard of
care for such patients."

But speaking with heartwire about the SYNTAX publication, Serruys
bluntly stated that he and his coauthors had grappled with that final
sentence: "At the end of the day, we have a study in the NEJM with a
last sentence that's been changed six or seven times during the
writing, because the NEJM wanted something more conservative."

In Serruys's opinion, that final sentence "is not the essence of the
trial."

The essence, he says, is that among the 1800 patients deemed by both
the surgeon and the interventionalist to be eligible for either
treatment, one-third of those patients can safely be treated with
either PCI or CABG. Furthermore, he said, the development of the
SYNTAX score--the other major contribution of the trial--allows
surgeons and cardiologists on the "heart team" to agree on a patient-
by-patient basis as to which therapy is appropriate. Anyone with a
cutoff score of 22, says Serruys, could "legitimately" be treated
with either therapy.

"When you do a trial, you have the rules of engagement, so you apply
one statistical rule to decide whether you have a positive or
negative result," he said. Yes, PCI did not meet the test of
noninferiority against CABG, he affirmed, "but that's why we created
the SYNTAX score, because we had the strong feeling that we had to
differentiate between patients on a case-by-case basis. That's what I
hope we have introduced to the medical field."

Serruys says he has increasingly been approached by cardiologists
interested in learning more about the SYNTAX score; he and his
colleagues will be launching a web-based tool and CD-program at
EuroPCR, he added.

Debating the Message

Mohr, for his part, agrees with Serruys about the critical role of
the "heart team" in the decision-making process, but is content with
the paper's wording, calling it an "honest analysis of the current
practice."

"The study clearly shows that about 65% to 70% of the study patients
with more complex three-vessel and/or left main disease . . . should
be treated by CABG, because the data show superior results: better
survival, lower myocardial infarction, etc," Mohr told
heartwire. "This is a very clear message, also demonstrated by the
8.8% MACCE rate at 12 months in the CABG registry." Moreover, MACCE
rates in the randomized arm will continue to diverge over time in
favor of CABG, Mohr notes.

He also points out that while rates of symptomatic bypass-graft
occlusion and stent occlusion were the same, at 3.5%, they have very
different clinical consequences--high mortality and MI rates for
stent occlusion, vs no mortality with bypass-graft occlusion. "This
will have a continuous impact in the future and puts PCI patients at
an imminent risk," Mohr said.

Informing the Decision

In an accompanying editorial, Drs Richard A Lange and L David Hillis
(University of Texas Health Science Center, San Antonio) describe how
the SYNTAX results can be applied in practice [2]. Patients who
cannot or will not take clopidogrel long term or in whom complete
revascularization is more easily accomplished with surgery "should be
encouraged to undergo CABG," they write. On the flip side, patients
with serious coexisting conditions or vessels not suitable to grafts
are better off with PCI. Patients in whom either strategy is
appropriate "should be presented with the advantages and
disadvantages of each procedure and allowed to choose between them."

According to interventionalist Dr Paul Teirstein (Scripps Clinic, La
Jolla, CA), who commented on the study for heartwire, the notion of
choice centers on the increased risk of stroke with CABG and the
increased risk of repeat procedures with PCI.

"Using the SYNTAX data to advocate CABG as the standard of care for
patients with three-vessel and left main disease is, in my opinion, a
case of 'good data, bad interpretation,' " he said. "If you talk to
most patients who undergo PCI, they tell you they would rather have
three, four, or even five PCI procedures instead of one bypass
surgery."

Crunching the numbers, Teirstein says that the small absolute
difference in revascularization procedures in SYNTAX translates into
a "number needed to prevent" of 14. "Thus, while our patients say
they would rather have several PCIs instead of one bypass, SYNTAX
teaches us we need to do 14 bypasses to prevent one repeat PCI, at a
cost of four times as many strokes. This argument makes no sense at
all and is just the opposite of what our patients want."

The argument is even more compelling in the left main subset, he
points out. "We have to do 19 CABGs to prevent just one repeat left
main PCI. This means 18 of every 19 CABGs we do for left main
patients are completely unnecessary! Certainly, with these new data,
patients with left main disease should be strongly considered for PCI
instead of CABG. I believe the SYNTAX data should be used to
highlight the fact that many bypass surgeries are currently being
performed unnecessarily."

Dr Grayson Wheatley (Arizona Heart Institute, Phoenix), a surgeon,
also commented on SYNTAX for heartwire, noting that the study
reaffirms the "excellence of treatment when a CABG is performed in
the correct patient."

That said, he continued, "PCI is eroding the 'CABG business,' and our
definition of the 'correct patient' for CABG is changing as new PCI
technology evolves. It is only a matter of time before there will be
another iteration of PCI technology that will prove to be superior to
DES."

Wheatley says he's seen an increase in use of PCI for three-vessel
and left main disease in recent months, but likely driven by safety
data supporting DES and not necessarily the SYNTAX results. "There
have been increased discussions between cardiac surgeons and
interventional cardiologists about the meaning of the SYNTAX data,
but little has changed with regard to treatment patterns," he said.
The increased dialogue, he said, is "always a good thing" and
underscores the need to "pause" between the diagnostic angiogram and
the treatment choice. "All too often there is no pause and an
angiogram automatically leads to PCI," Wheatley said. "Although such
a simple step, the introduction of a team discussion with the
patient, would better help define appropriate patient selection."
Everyone who commented on the study for heartwire also pointed to the
need for longer follow-up to tease out the impact of repeat
revascularization. "How significant is it really to reintervene in a
patient with PCI?" Wheatley asked. "The patient has still not had a
sternotomy and may only have had a few days of recovery vs a
significant recovery for CABG. Patients and interventional
cardiologists may feel that reintervention is an 'acceptable' event,
while cardiac surgeons may view reintervention as a failure.  The
answer is not as simple as either side views it, and more attention
needs to be devoted to working through the metrics of reintervention."


Serruys P, Morice MC, Kappetein P, et al. Percutaneous coronary
intervention versus coronary-artery bypass grafting for severe
coronary artery disease. N Engl J Med 2009; 360:961-972.
Lange R, Hillis L. Coronary revascularization in context. N Engl J
Med 2009; 360:1024-1026.

Sudden cardiac death occurs more frequently in young athletes than in
previous estimates, but event rates are still relatively low, a new
study has shown [1]. In the past six years, when reporting has been
the most robust, fewer than 100 athletes in the US have died each
year, according to investigators.

"The low overall event rate reported here should provide a measure of
reassurance regarding sports participation but underscores the need
for mandatory reporting of sudden deaths in young athletes, and it is
also relevant to the question of whether a national screening program
with noninvasive testing should be considered for US athletes," write
lead investigator Dr Barry Maron (Minneapolis Heart Institute
Foundation, MN) and colleagues online February 16, 2009 in
Circulation.

Sudden cardiac death, as the investigators point out, particularly
among young, competitive athletes, are highly visible events that
generate a lot of attention in the media, as well as have a large
impact in the medical and lay communities. Despite the visibility of
these deaths, the magnitude of sudden death in this population is
still unknown, the researchers write.

In this analysis, Maron and colleagues estimated the absolute number
of sudden deaths in US competitive athletes from registry data at the
Minneapolis Heart Institute Foundation.

From 1980 to 2006, 1866 athletes died suddenly in 38 diverse sports.
Of these sudden deaths, 56% were caused by cardiovascular disease,
but 22% also died from blunt trauma causing structural damage, and 3%
from commotio cordis. The most common cardiovascular causes of death
were hypertrophic cardiomyopathy (30%) and congenital coronary artery
anomalies (17%).

On average, there were 66 deaths from cardiovascular causes per year
over the most recent six years. In this period, the incidence of
sudden death was estimated at 0.6/100 000 person-years. Overall,
reports of sudden deaths were less common from 1980 to 1993, with
only 576 reported during this time period, compared with 1290
individuals who died suddenly between 1994 and 2006.

"It is likely that the steady increase in the number of sudden deaths
observed over the 27 years of this registry reflects enhanced public
recognition due to increased media attention and the more robust
search strategies that have become available recently, rather than a
true acceleration in the occurrence of these events," explain the
researchers.

Preparticipation Screening

At present, the American Heart Association (AHA) does not believe it
is practical or financially feasible to support a large-scale
preparticipation screening involving standard 12-lead
electrocardiogram (ECG) testing for cardiovascular abnormalities in
competitive athletes [2].

As reported previously by heartwire, the AHA recommendations contrast
with programs proposed by the European Society of Cardiology (ESC)
and the International Olympic Committee (IOC), which include
combining noninvasive testing, such as a 12-lead ECG, with the
standard history and physical examination. The ESC and IOC
initiatives are based on the long-term Italian experience with a
state-subsidized national screening program. In Italy, all
individuals 12 to 35 years of age participating in organized sports
are required to obtain annual medical clearance by accredited sports-
medicine doctors.

In their paper, Maron and colleagues suggest that the relatively low
absolute number of cardiovascular sudden death events reported in
young athletes raises some doubt regarding the ambitious
considerations for preparticipation cardiovascular screening.
Instead, the investigators call again for a systematic and mandatory
reporting system for sudden cardiac deaths in young competitive
athletes to determine the true absolute number of these events.

In an editorial accompanying the published study [3], Dr Paul
Thompson (Hartford Hospital, CT) writes that athletes deserve better
data and a more thoughtful "consideration of the benefits and
untoward consequences of any recommended screening program." The
Italian results, for example, are from a single center and do not
include a controlled comparison of different screening strategies.
Moreover, there remain questions about whether an asymptomatic
athlete with a cardiac condition detected by screening has the same
prognosis as an athlete with symptoms. A reliable estimate of the
cost of such extensive screening is also unavailable, notes Thompson.

"Experience suggests that when experts disagree, there is a dearth of
reliable data," writes Thompson. "The present data suggest that the
problem, at least in the United States, is not so huge that we must
leap into action."


Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young
competitive athletes. Circulation 2009; 119: 1085-1092. Abstract
Maron BJ, Thompson PD, Ackerman MJ, et al. Recommendations and
considerations related to preparticipation screening for
cardiovascular abnormalities in competitive athletes: 2007 update.
Circulation 2007; 115:1643-455. Abstract
Thompson PD. Preparticipation screening of competitive athletes.
Circulation 2009; 119: 1072-1074.Abstract

A greater proportion of patients who arrive at the hospital in the
first 60 minutes after symptom onset ˇX the so-called "golden hour" ˇX
  receive thrombolytic therapy than those who arrive later, new data
from the Get With The Guidelines-Stroke (GWTG-S) quality-improvement
program shows.

In this analysis, 12% of all ischemic stroke patients seen at 100
GWTG-S hospitals arrived within 1 hour of symptom onset, and 27.1% of
these were treated with tissue plasminogen activator (tPA) vs 12.9%
of those arriving between 1 and 3 hours after onset.

However, Jeffery L. Saver, MD, from the University of California, Los
Angeles Stroke Center, pointed out that golden-hour patients also had
door-to-needle (DTN) times that were about 20 minutes longer than
those arriving later, and only about 20% were treated within 60
minutes of arrival.

"These findings support greater public-education efforts to increase
the proportion of patients arriving in the first 60 minutes after
symptom onset and a revamping of our hospital's performance-
improvement activities to shorten the DTN times in patients who've
done their part in arriving in the first 60 minutes, to make sure we
do our part and get drug started for them in the next 60 minutes,"
Dr. Saver concluded.

He presented their findings here at the American Stroke Association
International Stroke Conference 2009.

Benefit Strongly Time Dependent

The benefit of intravenous (IV) tPA in acute ischemic stroke is
strongly time dependent, Dr. Saver said. Therapeutic yield of
treatment is maximal in the first minutes after stroke and declines
steadily during the first 3 hours. "Every minute that goes by without
treatment, 2 million nerve cells die," he said. "Every 10 minutes
that goes by without tPA, 1 fewer patient experiences benefit from
tPA."

Patients who present within the first 60 minutes after symptom onset
have the greatest opportunity for benefit from treatment, but these
patients have not been well characterized. "That's why we undertook
this study," Dr. Saver said.

They used the GWTG-S registry, a national database of acute strokes
treated at participating hospitals in the United States. From 905
participating hospitals, a total of 517,000 stroke and transient
ischemic attack patients were entered in the database between April
2003 and December 2007. After excluding those who did not arrive
directly at the emergency department by ambulance or private vehicle,
those having hemorrhagic strokes, and patients for whom a time of
symptom onset could not be documented, they were left with 106,924
patients for this analysis.

Of these, 28.3% arrived at the hospital within 60 minutes of symptom
onset; the mean onset-to-door time for these patients was 39.9
minutes.

Although most patient characteristics examined were to some extent
statistically significant, 2 factors stood out; National Institutes
of Health Stroke Scale (NIHSS) score, which was higher in those
arriving earlier (8 for those arriving within 60 minutes vs 4 in
those arriving after 3 hours), and arrival by ambulance, which was
the case in 79% of those arriving in the golden hour, vs 55% of those
arriving after 3 hours.

Overall, 11.8% of all ischemic stroke patients arriving directly at
the hospital with a documented onset time were treated with IV tPA,
vs 5% of those without a documented onset of symptoms. The mean onset-
to-door time in patients who received tPA was 56 minutes, and the
mean DTN time was 84 minutes.

Those arriving within the golden hour were much more likely than
those arriving later to receive thrombolysis, Dr. Saver said.

The frequency of delivery of tPA was 27.1% of the golden-hour
patients vs 12.9% in the 1-to-3 hour patients (P < .0001).

However, those arriving earlier also had longer DTN times. Patients
who arrived at the hospital within the first hour had a mean DTN time
of 90.6 minutes, compared with 76.7 minutes for those arriving
between 1 and 3 hours after symptom onset. Only 18.3% of these
patients who arrived within 60 minutes of symptom onset had a DTN
time under the recommended target of 60 minutes.

There was a "modest increase" of about 1.2% per year over time in the
number of golden-hour patients being treated within 60 minutes, from
12.8% in 2003 to 19.5% in 2007; this improvement did not appear to be
related to length of participation in the GWTG-S program, he noted.

Having More Time Should Not Mean Taking More Time

After his presentation, Dr. Saver was asked about what might explain
the longer times to treatment among those who arrived earlier.
Although they plan to look at this issue further in this data set, he
pointed out that doctors might take the opportunity for a longer
informed-consent process when they have more time.

Furthermore, during a press conference here, Dr. Saver speculated
that this potential problem of using the time for deliberation may
worsen over time, given the results of ECASS 3 reported last fall
that showed thrombolytic therapy was safe and effective up to 4.5
hours after symptom onset.

"I think for the providers, focusing the attention on how well your
health system is performing by focusing on door-to-needle time for
treatment, rather than the onset-to-treatment time or the maximal
permitted time, is the way to go," Dr. Saver said. "We're trying to
emphasize a door-to-needle time of 60 minutes."

Arthur Pancioli, MD, professor and vice chair of emergency medicine
at the University of Cincinnati, in Ohio, moderated a press
conference here where this paper was presented. He pointed out that
while there is a benefit to treatment, there are also serious risks
associated with thrombolytic therapy, including a 6.4% risk of
hemorrhage, "even if you're doing it right."

While it is still clearly the right thing to do, he said, "that would
give you pause . . . but what you cannot do is pause, and that's the
hard part.

"We're caught in a situation where you have to be fast, and you have
to do it well."

It is not uncommon for young adults with stroke to be misdiagnosed
during initial presentation to the emergency department, particularly
if they experience an infarct in their posterior circulation.

New research presented here at the American Stroke Association
International Stroke Conference 2009 shows an overall misdiagnosis
rate of 14% among adults under the age of 50 years.

"In these individuals, we also found there was a strong trend among
the very youngest patients ˇX those under age 35 ˇX to have an even
greater chance of misdiagnosis," principal investigator Seemant
Chaturvedi, MD, from Wayne State University, in Detroit, Michigan,
told Medscape Neurology.

Dr. Chaturvedi said his own anecdotal experience and that of some of
his colleagues led them to look into the issue of misdiagnosis in
young stroke patients.

"I think we've all seen young patients who, even though they have
presented to the emergency department early after symptom onset, do
not receive the proper diagnosis. When that happens, patients are
deprived of the opportunity to receive [tissue plasminogen activator]
tPA or interventional stroke therapy, so we decided to look at this
issue in a more systematic way," he said.

Inner-Ear Disorder Diagnosed in 50%

The researchers reviewed data on 57 patients aged 16 to 50 years
enrolled since 2001 in the Young Stroke Registry at the Comprehensive
Stroke Center at Wayne State University.

With an average age of 34 years, 8 patients ˇX 4 males and 4
females ˇX were misdiagnosed with conditions including alcohol
intoxication, migraine, vertigo, and inner-ear disorder.

Of these, half were diagnosed with an inner-ear disorder, including
labyrinthitis or peripheral vertigo, and subsequently ended up being
diagnosed with stroke in the brain stem or cerebellum. One 18-year-
old patient diagnosed with alcohol intoxication also ended up with a
diagnosis of posterior cerebral artery stroke.

Of the misdiagnosed cases, 7 of the 8 presented within 3 hours to the
emergency department. Of these, said Dr. Chaturvedi, 3 would have
been considered good candidates for thrombolysis.

A Diagnostic Challenge

Diagnosing posterior stroke can be challenging, said Dr. Chaturvedi.

"There are a number of neural pathways in the brain stem that can
affect different functions, including strength, coordination, speech,
eye movements, hearing, and swallowing. So to a nonspecialist, it can
be challenging to tease out which of these are serious and which are
benign," he said.

Nevertheless, he added, the presenting signs and symptoms in these
misdiagnosed patients were not atypical.

"It may be that physicians are just not expecting stroke [in these
young patients]. A lot of the presentations were classic for stroke,
but for whatever reason, they just weren't recognized as such," he
said.

Dr. Chaturvedi said the study highlights the need for efforts to
increase awareness among the public and clinicians that stroke can
occur in young people. He estimated that in the United States there
are approximately 10,000 to 15,000 strokes in individuals under the
age of 45 years annually.

"I think I would recommend that doctors consider a diagnosis of
stroke in patients who present with acute neurologic deficits,
regardless of age. It is particularly important in patients who
present with dizziness to evaluate patients' gait, speech, and eye
movements before concluding their condition is benign."

Dr. Chaturvedi said his future research will examine potential
differences between misdiagnosis rates in designated and undesignated
stroke centers.

International Stroke Conference 2009: Abstract 33. Presented February
18, 2009.

The debate over whether the nucleoside reverse-transcriptase
inhibitor abacavir increases the risk for myocardial infarction (MI)
continues, with 4 presentations on the topic presented here at the
16th Conference on Retroviruses and Opportunistic Infections (CROI).

Data from the SMART and D:A:D studies presented last summer at the
International AIDS Conference in Mexico City suggested that the use
of abacavir heightened the risk for cardiovascular disease (CVD), a
contention that the drug's manufacturer, GlaxoSmithKline, disputed
with their own reanalysis of their clinical-trials data.

Here in Montreal, Jens Lundgren, MD, from the University of
Copenhagen, in Denmark, presented an additional analysis from D:A:D,
showing no statistically significant associations between recent or
cumulative use of tenofovir, zalcitabine, zidovudine, stavudine, or
lamivudine and risk for MI. Antiretroviral drugs associated with a
statistically significantly increased risk for MI were abacavir,
didanosine, indinavir, and lopinavir/ritonavir.

A separate caseˇVcontrol study from France (268 case patients, 865
control patients) found that the risk for MI was increased by
cumulative exposure to lopinavir and amprenavir or fosamprenavir.
More curiously, initiating abacavir also carried that increased risk,
but longer exposure to it did not.

But a third study, an analysis of the MACS and WIHS cohort data,
concluded that abacavir was not associated with elevated levels of
high sensitivity C-reactive protein, interleukin-6, or D-dimer levels.

Finally, Carl Grunfeld, MD, from the University of California, San
Francisco, reported on a cross-sectional study that compared scans
for carotid intima medial thickness in HIV-infected patients (n =
433) and control subjects (n = 5748). After adjustment for
demographic factors and CVD risk factors, he found that HIV infection
independently conferred a risk for greater intima medial thickness,
which is similar to other traditional CVD risk factors, such as
smoking.

"When you advise patients in your office, you can say, here is your
standard risk [for CVD], but because you have HIV, you are at higher
risk," he later told reporters. "It is the equivalent of being male,
smoking, or having diabetes. I believe that the effect of HIV is much
larger than the small signal seen with those drugs," such as abacavir.

Dr. Grunfeld acknowledged that 1 of the limitations in studying this
effect is that "97% of [HIV] patients have been treated, and 94%
[are] on HAART," so they can only compare with matched controls in
other CVD studies.

It was left to Peter Reiss, MD, from the University of Amsterdam, in
the Netherlands, to try to pull together these and other
presentations at CROI in a summary session on what it all means. He
said: "In a simplistic way, 4 studies basically give a signal of an
increased risk" of MI with abacavir, "and 3 do not."

He noted that the studies showing a signal generally were prospective
and more robust in size, and the study population also was 7 to 10
years older. "Age is a very important cardiovascular disease risk
factor. You could speculate that maybe it is just harder to pick up a
signal in that younger population."

Dr. Reiss said that inflammation really underlies all of the
processes of plaque formation and growth. He reviewed how untreated
HIV "is associated with upregulation of endothelial activation,
inflammation, and coagulation," markers that lead to CVD.

He said there is not that much evidence for an effect of
abacavir. "Once HIV is suppressed or the virus is replicating at low
levels, there is no consistent pattern emerging; there are still
question marks, but there is a hint that in that particular
circumstance, some of the inflammatory markers may be upregulated."

He acknowledged that if abacavir is proinflammatory, "against a
background of a very high inflammatory state" induced by HIV, it may
be difficult to discern such an additional signal. "By treating HIV
and downregulating the inflammatory state, maybe you have a better
opportunity for picking up a signal" from abacavir.

"The clinical data with this on/off phenomenon suggests a subacute
and reversible process rather than an aggressive progressive
pathogenic mechanism," Dr. Reiss said.

Clinically, Dr. Reiss urged a common-sense approach of identifying
and modifying underlying risk factors for CVD in individual
patients. "In those who are at high risk, and where there are clear
alternatives for abacavir, I think you just take the abacavir away.
But if there is no alternative, you continue on abacavir." For
someone who is at very low risk for CVD, abacavir only modestly
increases that risk; the absolute risk will be very low, he said.

A 10-year analysis of offspring patients in the Framingham Heart
Study suggests improvements in lipid profiles, particularly
beneficial changes in triglyceride and HDL-cholesterol levels [1].
During the most recent examination periods, HDL-cholesterol levels
rose and triglycerides decreased, despite an overall increase in body-
mass index (BMI), report investigators in the February 9, 2009 issue
of the Archives of Internal Medicine.

"If you ask any cardiologist what is the likelihood that a patient
with increasing body weight would also have their triglycerides go
down and their HDL-cholesterol levels go up, I would bet that almost
100% of them would tell you it's very unlikely this would happen,"
senior investigator Dr Sander Robins (Boston University, MA) told
heartwire. "Maybe you'd find one exercise nut or something like that.
The findings are counterintuitive, or counterscience, at least in
terms of the science we think we know."

The findings, which come as a surprise, also contrast with other
cross-sectional studies, including a recent National Health and
Nutrition Examination Survey (NHANES), which reported that plasma
levels of HDL and triglycerides were unchanged from 1988 to the most
recent examination period in 2002, despite increasing rates of
obesity in the US.

In this analysis, the researchers assessed lipid levels of 1666 men
and women participating in the three most recently completed
examinations of the Framingham Offspring Study. These examinations,
which took place between 1991 and 2001, were selected to correspond
roughly with the last two NHANES assessments. All individuals were
without cardiovascular disease and not currently prescribed lipid
and/or hormone-replacement therapy.

Over the three exams, total cholesterol levels were unchanged in men
and women, although BMI increased significantly. Despite the increase
in body mass, triglyceride levels declined and HDL-cholesterol levels
increased in both men and women. Consistent with these findings,
there was a significant decrease in the proportion of patients with
low HDL cholesterol and those with elevated triglyceride levels.

"Over this 10-year period, over three sequential exams, men and women
alike have had an increasing level of HDL cholesterol in concert with
a decreasing level of triglycerides," said Robins. "When you have
this reciprocal relationship between HDL and triglycerides, it is
much more apt to be a physiologically linked phenomenon than just two
separate measurements being affected independently. Our presumption
is that we're looking at something that's real, that's biologic,
because of this linked phenomenon."

Researchers say they have no certain explanation for these beneficial
changes in blood lipid levels in a "fairly large segment of the
Framingham Heart Study population," but Robins said one theory might
be based on changes in patterns of food consumption in the US. Recent
dietary surveys suggest increased consumption of carbohydrates and a
decrease in the consumption of fats, particularly saturated fats.
This would lead to more active and complete hydrolysis of
triglyceride-rich lipoproteins and would result in the increased
formation of HDL cholesterol.

"In this way, you do have the opportunity for invoking change in both
the triglycerides and HDL cholesterol in a reciprocal way," said
Robins. The dietary information available to the Framingham
investigators, however, is too crude to be able to detect changes in
the type of fat consumption, so further studies will be needed,
particularly in terms of having the results confirmed in other
studies, he added.


Ingelsson E, Massaro JM, Sutherland P, et al. Contemporary trends in
dyslipidemia in the Framingham Heart Study. Arch Intern Med 2009;
169:279-286. Abstract

A polymorphism in one of the genes responsible for metabolizing
clopidogrel to its active form has been shown to be associated with
an increased risk of stent thrombosis in patients undergoing PCI [1].

The study, published online February 4, 2009 in the European Heart
Journal, was conducted by a group led by Dr Dirk Sibbing (Deutsches
Herzzentrum, Munich, Germany).

Sibbing told heartwire that the mutant *2 allele of the CYP2C19 gene
occurs with a frequency of about 15%. In the current study, 25% of
patients had one copy of the genotype (ie, were heterozygous) and 2%
of the group were homozygous. "We clearly saw a gene dose effect, so
that patients who were heterozygous had an increased risk of stent
thrombosis compared with those without this genotype, and those who
were homozygous had a higher risk again. We are the first group to
describe this," Sibbing said.

A previous study by a group from Harvard has shown similar results,
but that study was smaller than this one and had a less specific end
point. "Our study is larger and used definite stent thrombosis as the
end point, whereas the Harvard study had definite or probable stent
thrombosis as the end point. We also did a multivariate analysis
showing that this genotype is an independent predictor of stent
thrombosis."

In the current study, 2485 consecutive patients undergoing coronary
stent placement after pretreatment with 600 mg of clopidogrel were
genotyped. The primary end point of the study was the incidence of
definite stent thrombosis within 30 days following PCI. Of the
patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes
(*1/*1), 633 (25%) were CYP2C19*2 heterozygotes (*1/*2), and 47 (2%)
were homozygous (*2/*2) for the mutant CYP2C19*2 allele. The
cumulative 30-day incidence of stent thrombosis was significantly
higher in CYP2C19*2 allele carriers compared with those without this
polymorphism. In addition, the incidence of ST-segment-elevation MI
(STEMI) and ischemic stroke was significantly higher in CYP2C19*2
allele carriers vs CYP2C19 wild-type homozygotes.

The risk of stent thrombosis was highest (2.1%) in patients carrying
two of the mutant CYP2C19 alleles (*2/*2 genotype), and the p value
for this trend was significant (p=0.002).

The authors conclude: "The results of the present study identify
patients at high risk for stent thrombosis and provide a rationale
for administration of an intensified antiplatelet treatment in
patients scheduled for coronary stent placement. Genetic
determination of the CYP2C19 loss-of-function polymorphism may be
beneficial in this setting, as high-risk patients can be identified
prior to the planned procedure. High clopidogrel maintenance dosing
or the use of novel and more potent P2Y12-receptor antagonists, such
as prasugrel, may be potential treatment options for tailored
antiplatelet therapy in CYP2C19*2 carriers."

To heartwire, Sibbing noted that they do not routinely test for this
genotype at present, as there is not yet a point-of-care assay that
would give a quick result. "But if such an assay became available, we
would test all our patients and intensify treatment in those who
tested positive," he said.

He added that the next step would be to conduct a randomized trial in
which patients with this genotype are randomized to clopidogrel at
the regular dose or to a more potent regimen such as clopidogrel at a
higher maintenance dosage or prasugrel. He says he hopes such a study
will be done.

The study was funded by Deutsches Herzzentrum, Munich, Germany.
Sibbing reports receiving speaker fees from Dynabyte. Other authors
involved in the study report receiving speaker fees from Eli Lilly,
Sanofi-Aventis, and Bristol-Myers Squibb, and fees for advisory-board
activities from Eli Lilly and Sanofi-Aventis


Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-
function polymorphism and stent thrombosis following percutaneous
coronary intervention. Eur Heart J 2009;
DOIi:10.1093/eurheartj/ehp041. Available at:
http://eurheartj.oxfordjournals.org. 19193675

Data from a national registry suggest that outcomes at 30 days are
better with carotid endarterectomy (CEA) than with carotid artery
stenting (CAS) [1]. Investigators report that the combined rate of
death, stroke, and MI was significantly lower with the surgical
approach vs the less invasive interventional technique.

"The debate about the interpretation of the results of this study as
well as results of other CAS studies will continue until randomized
trials such as International Carotid Stenting Study (ICSS) in Europe
and [the Carotid Revascularization Endarterectomy vs Stenting Trial]
CREST in North America are reported," note lead investigator Dr Anton
Sidawy (Washington Veterans Affairs Medical Center, DC) and
colleagues in the January 2009 issue of the Journal of Vascular
Surgery.

The data, from the Society for Vascular Surgery (SVS), are the latest
in a number of head-to-head comparisons between CEA and CAS that have
often shown conflicting results. Two carotid-artery stenting studies--
Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus
Endarterectomy (SPACE) [2] and Endarterectomy versus Angioplasty in
Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) [3]--were
published in 2006, and both showed stenting to be inferior to
endarterectomy.

Those findings contrasted with data from the Stenting and Angioplasty
with Protection in Patients at High Risk for Endarterectomy
(SAPPHIRE) trial, a study that compared carotid stenting using distal
embolic protection with carotid endarterectomy in patients at high
surgical risk [4]. Based on the findings from SAPPHIRE, the Food and
Drug Administration approved the use of carotid stenting in patients
with high-grade symptomatic stenosis who are at high operative risk.

In this analysis, the researchers obtained data from the SVS vascular
registry for carotid procedures. Rates of death, stroke, and MI were
significantly higher among patients who underwent stenting compared
with those had an endarterectomy. Both symptomatic and asymptomatic
patients had significantly higher 30-day procedure rates of death,
stroke, and MI compared with CEA patients. Similarly, in an analysis
of only patients with atherosclerosis, the death, stroke, and MI
combined end point was significantly lower among those who underwent
CEA.

Highlighting the inconsistencies in the field, the 5.72% event rate
among CAS patients is consistent with outcomes observed in the BEACH
and MAVERIC studies, higher than that observed in SAPPHIRE and other
studies, and lower than that observed in the ARCHER and CAPTURE
trials.

More data are expected sometime this year with the results of CREST,
a study of 2511 asymptomatic and symptomatic patients who are not at
high risk for surgery. The ICSS study is a head-to-head comparison of
carotid stenting and endarterectomy in approximately 1700
asymptomatic patients with carotid stenosis.

The researchers note that the SVS registry could possibly supplement
randomized trials "by providing real-world comparisons of CAS and
CEA," especially in important patient subsets.


Sidawy AN, Zwolak RM, White RA, et al. Risk-adjusted 30-day outcomes
of carotid stenting and endarterectomy: results from the SVS vascular
registry. J Vasc Surg 2009; 49:71-79. Abstract
Space Collaborative Group. 30-day results from the SPACE trial of
stent-protected angioplasty versus carotid endarterectomy in
symptomatic patients: a randomised non-inferiority trial. Lancet
2006; 368:1239-1247. Abstract
Mas JL, Chatellier G, Beyssen B. Endarterectomy versus stenting in
patients with symptomatic severe carotid stenosis. N Engl J Med 2006;
355:1660-1671. Abstract
Yadav JS, Wholey MH, Kuntz RE. Protected carotid-artery stenting
versus endarterectomy in high-risk patients. N Engl J Med 2004;
351:1493-50. Abstract

Several research groups have identified new genomic markers in
various cohorts that have an association--albeit small--with MI or
coronary artery disease (CAD). The work appears as five papers online
February 8, 2009 in Nature Genetics, and some of the discoveries are
somewhat surprising, say experts.

Dr Nilesh Samani (University of Leicester, UK), who was involved in
three of the papers, told heartwire: "The bottom line is that if we
take this new research [on top of existing work], we now have at
least 10 loci that clearly affect the risk of heart attacks and CAD.
This is from a position where, two years ago, we didn't really have
any loci we were completely comfortable with. And most of these are
[associated with genes] we wouldn't hitherto have suspected of being
involved, so this provides new evidence, new pathology, that may be
involved in causing heart disease."

Dr Eric Topol (Scripps Translational Research Institute, La Jolla,
CA), who was not involved in any of this new research, told
heartwire: "Using various cohorts, several new genomic markers have
been found without any particular theme on type of gene; the only
common thread is that the effect is small: 1.1 to 1.2 odds ratio."

Haplotype Association Study Among Papers Identifying New Loci for
MI/CAD

Samani was involved in the work by Dr David-Alexandre Tregouet
(University Pierre and Marie Curie, Paris, France) and his team, who
have discovered a new gene cluster--SLC22A3-LPAL2-LPA--as a strong
susceptibility locus for CAD [1]. The novelty of this paper, says
Samani, is that they used "a slightly different technique to look at
the data that come out of genomewide association studies [GWAS]."
Rather than looking at individual differences in DNA sequence--single
nucleotide polymorphisms (SNPs)--the researchers looked at groups of
SNPs that are inherited together, known as haplotypes.

"Tregouet has slowly walked across the chromosomes identifying these
haplotypes to see whether the signal was better when looking at the
haplotype rather than individual SNPs . . . and one region showed
very strong evidence, which was apparent in the individual SNP
analysis but wasn't strong enough to be definite. By analyzing it in
this way [by haplotype], we found evidence that this locus is
strongly associated with CAD. So the findings are twofold: first, we
identified a new locus; and second, it shows we can extract more
information out of GWAS by doing a slightly more sophisticated
analysis," Samani asserts.

We can extract more information out of GWAS by doing a slightly more
sophisticated analysis.

The second paper that Samani is involved in is by Dr Jeanette Erdmann
(University of Lubeck, Germany) and colleagues, who identify a new
susceptibility locus for CAD on chromosome 3q22.3 following a three-
stage analysis of genomewide data in 1222 German individuals with MI
and 1298 controls [2].

Samani explains: "When we did the original genomewide scans, we
really looked at the low-hanging fruit--the signals that were very
strong--but we knew that, because of the nature of these studies,
there was a strong possibility that among the signals that were of
moderate significance, there must be some that were definitely
genuine. In this new Erdmann paper, we saw some signals that appeared
to be stronger when we combined everything together and then took it
through to replication in these populations, and we confirmed that
this locus was true."

Largest GWAS for MI to Date; No Association of MI With CNVs

Samani is also involved in the international Myocardial Infarction
Genetics Consortium research, a GWAS testing SNPs and copy number
variants (CNVs) for association with early-onset MI in 2967 cases and
3075 controls and replicated in an independent sample of 19 492 [3].

Corresponding author on the paper, Dr Sekar Kathiresan (Massachusetts
General Hospital, Boston, MA), told heartwire: "Our study is the
largest GWAS for MI conducted to date [and] the first to
comprehensively test whether CNVs are associated with MI."

Kathiresan explained that CNVs are large chunks of DNA that are
either deleted or duplicated, and it has been hypothesized that they
might be responsible for some of the inherited component of common
diseases. They found no evidence in this new study, however, that any
CNVs were associated with MI.

They did find that SNPs at nine loci reached significance, three of
which were new: 21q22, 6p24, and 2q33. The remaining six had
previously been observed, including one at 9p21, which is recognized
to be the strongest genetic predictor of early MI discovered to date.

"These nine variants in aggregate identify 20% of the population at
2.25-fold increased risk for MI," says Kathiresan.

Surprising Link Between Eosinophil Count and MI; New Data in Asian
Subjects

Probably the most surprising of the new reports is from Dr David F
Gudbjartsson (deCODE Genetics, Reykjavik, Iceland) and colleagues,
who find a link between a high-eosinophil-count gene and MI [4]. They
looked for sequence variants affecting eosinophil counts in the blood
of 9392 Icelanders and, using the most significant SNPs identified,
they studied them further in 12 118 Europeans and 5212 East Asians.

A variety of the SNPs were associated with asthma and one--a
nonsynonymous SNP at 12q24--was significantly associated with MI in
six different populations (6650 cases and 40 621 controls).

Topol says the Icelandic paper is "curious," with "the surprise link
of a high-eosinophil-count gene and MI. This wasn't at all surprising
for atopic asthma, but we would not have expected it to be the case
for MI."

Finally, Japanese researchers extend on prior work they have
conducted. Dr Kouichi Ozaki (Center for Genomic Medicine, RIKEN,
Yokohama, Japan) and colleagues have previously reported an
association of variants in LGALS2, encoding galectin-2, with MI
susceptibility in a case-control association in a Japanese
population.

Now, they identify BRCA-1 associated protein (BRAP) as a galectin-2
binding protein and report an association of SNPs in BRAP with MI
risk in a large Japanese cohort (OR 1.48, 2475 cases and 2778
controls), with replication in additional Japanese and Taiwanese
cohorts [5].

Topol says, "This has been a very interesting series of findings from
the group of Ozaki and [Dr Toshihiro] Tanaka over several years."

In conclusion, Topol says that he now believes "there are several
pathways that set up a genomic susceptibility to MI. Some are
ancestry-specific (such as galectin2-BRAP) and some are unanticipated
(eg, eosinophilia). While we see the common phenotype of MI, [it
appears] there are many ways to get there at the molecular level."


Tregouet D-A, Konig IR, Erdmann J, et al. Genome-wide haplotype
association study identifies the SLC22A3-LPAL2-LPA gene cluster as a
risk locus for coronary artery disease. Nat Genet 2009; DOI:
10.1038/ng.314. Available at: http://www.nature.com/ng.
Erdmann J, Grosshennig A, Braund PS, et al. New susceptibility locus
for coronary artery disease on chromosome 3q22.3. Nat Genet 2009;
DOI: 10.1038/ng.307. Available at: http://www.nature.com/ng.
Myocardial Infarction Genetics Consortium. Genome-wide association of
early-onset myocardial infarction with single nucleotide
polymorphisms and copy number variants. Nat Genet 2009; DOI:
10.1038/ng.327. Available at: http://www.nature.com/ng.
Gudbjartsson DF, Bjornsdittir US, Halapi E, et al. Sequence variants
affecting eosinophil numbers associate with asthma and myocardial
infarction. Nat Genet 2009; DOI: 10.1038/ng.323. Available at:
http://www.nature.com/ng.
Ozaki K, Sato H, Inoue K, et al. SNPs in BRAP associated with risk of
myocardial infarction in Asian populations. Nat Genet 2009; DOI:
10.1038/ng.326. Available at: http://www.nature.com/ng.

Further evidence that even commonly used nonsteroidal anti-
inflammatory drugs (NSAIDs) are harmful to heart-failure patients has
come from a new study [1].

The study, published in the January 26, 2009 issue of the Archives of
Internal Medicine, shows dose-related increases in risk of death and
rehospitalization for heart failure or MI with all COX-2 inhibitors
or other NSAIDs.

Lead author Dr Gunnar Gislason (Gentofte University Hospital,
Hellerup, Denmark), commented to heartwire: "Although our study is
observational, and you can never exclude all confounding factors, we
have very consistent results estimated using two different
statistical methods. And these results are similar to many other
previous studies. In addition, we see a strong dose-related response.
I think the data are very convincing."

And it is not just the COX-2 inhibitors that are the problem, as
diclofenac showed a similar risk. "This is very disturbing, as this
drug is so widely used and is available off prescription in many
countries," Gislason noted.

He described the effect as "quite considerable." For example, for
rofecoxib (Vioxx, Merck), the number of patients needed to treat for
one year to cause one death was just nine, and the corresponding
number for celecoxib (Celebrex, Pfizer) was 14 and diclofenac
11. "These numbers are very low," Gislason said, noting that for
antihypertensive drugs, the number needed to treat for one year to
save one life is in the range of 50 to 100. "Everyone agrees that it
is worth treating hypertension. So the harmful effect of some NSAIDs
is much greater than the beneficial effect of antihypertensive
treatment."

Even Naproxen Risky at High Dose

"Our results suggest that all NSAIDs have harmful effects in heart-
failure patients, even naproxen at high doses. Naproxen is probably
the best of the bunch, but it still increases fluid retention, which
is bad news for heart-failure patients," Gislason added.

But he points out that these drugs are still being used in this
population. "I don't think doctors are aware of this problem. We need
to raise awareness. I think the main culprits are primary-care
doctors, as these drugs are so widely prescribed in general
practice," he commented. "The fact that some of these drugs are
available over the counter makes the situation much worse, as anyone
can buy them without advice from a doctor. All NSAIDs should be
prescription-only drugs. Making them available in petrol stations and
supermarkets gives the impression that they are not harmful. Many
heart-disease patients will not be aware that they shouldn't take
them."

In the current study, Gislason and colleagues used Danish national
records of hospitalizations and pharmacy drug dispensing to identify
107 092 patients surviving their first hospitalization due to heart
failure between 1995 and 2004 and their subsequent use of NSAIDs.

They found that 36 354 patients (33.9%) claimed at least one
prescription of an NSAID after discharge; 60 974 patients (56.9%)
died, and 8970 (8.4%) and 39 984 (37.5%) were rehospitalized with MI
or heart failure.

After adjustment for age, sex, calendar year, comorbidity, medical
treatment, and severity of disease, the authors found a clear dose-
related increase in risk with the drugs.

The authors conclude that patients with heart failure should, if
possible, avoid using NSAIDs, and if they do need to use one, they
should take an agent that is more COX-1 selective, in as low a dosage
and for as short a period as possible. "I know NSAIDs are useful
drugs, and they will always be used to some extent, but we need to be
careful about which drug is selected and which dosage used. More
thought should go into trying to combine them with other agents so
that a lower dose could be used," Gislason added.


Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality
and cardiovascular morbidity associated with use of nonsteroidal anti-
inflammatory drugs in chronic heart failure. Arch Intern Med 2009;
169:141-149. Abstract

Hypertensive disorders during pregnancy are associated with an
increased risk for subsequent chronic hypertension, thromboembolism,
and type 2 diabetes, according to the findings of a large cohort
study.

Gestational hypertension and pre-eclampsia have already been
associated with a high risk for maternal ischemic heart disease and
mortality, but little research has been done on their relation to
other types of cardiovascular outcomes and diabetes, Jacob Alexander
Lykke, MD, an obstetrician at the Rigshospitalet, in Copenhagen,
Denmark, explained in an oral presentation here at the annual meeting
of the Society for Maternal-Fetal Medicine 29th Annual Meeting.

"To our knowledge, this is the first study to describe the risk
gradient of subsequent thromboembolic events" in women who experience
hypertension during pregnancy, said Dr. Lykke.

He and his colleagues conducted a registry-based retrospective cohort
study of nearly 1.4 million women who had delivered 1 (n = 782,287)
or 2 (n = 536,419) singleton children in Denmark between 1978 and
2007. The women were followed for 13 to 15 years. Women with a
history of diabetes (type 1 or 2) were excluded from the analysis.

The presence of gestational hypertension did not significantly
increase the risk for subsequent thromboembolism. However, even mild
pre-eclampsia was associated with a hazard ratio for thromboembolism
of 5.1. With severe pre-eclampsia, the hazard ratio was 6.9 (P < .001
for both). When it came to type 2 diabetes, gestational hypertension
and mild and severe pre-eclampsia were all associated with a
significant increase in risk. The hazard ratio associated with each
condition was 3.32, 3.53, and 3.68, respectively, compared with women
who did not develop any hypertensive disorder (P < .001 for each).

When it came to chronic hypertension, pre-eclampsia alone was
associated with a hazard ratio of 4.07, which more than doubled to
8.72 when preterm delivery (PTD) was added to the mix. However, the
risk for hypertension associated with pre-eclampsia plus a small-for-
gestational-age (SGA) baby was no greater than that observed with pre-
eclampsia alone (4.17). The hazard ratio associated when all 3
conditions were calculated together was no larger than that observed
for pre-eclampsia plus preterm delivery (7.68). Pre-eclampsia raised
the risk for subsequent thromboembolism, with a hazard ratio of 1.61.
Adding preterm delivery to the calculation did not change that ratio,
but pre-eclampsia plus SGA was associated with a hazard ratio of
2.74. The risk was no higher when all 3 conditions were combined.

Among multiparous women, the number of pregnancies marked by pre-
eclampsia of any severity influenced the risk for subsequent chronic
hypertension. Pre-eclampsia during the first pregnancy was associated
with a hazard ratio for hypertension of 2.90. Women who experienced
pre-eclampsia during the second but not the first pregnancy had a
hazard ratio of 4.80, and if pre-eclampsia occurred during both
pregnancies, the hazard ratio was 7.31 (P < .001 for each group,
compared with women who did not develop pre-eclampsia).

Although he did not present the data, similar patterns occurred in
the risk for thromboembolism and type 2 diabetes, Dr. Lykke said.

"This was a beautiful study," said Marshall Lindheimer, MD, professor
emeritus of Obstetrics and Gynecology in Medicine at the University
of Chicago, in Illinois. Dr. Lindheimer, who was not involved in this
study, cited research conducted by Leon C. Chesley, PhD, in the
1970s, showing an association between pre-eclampsia and subsequent
cardiovascular events. However, among women who developed
hypertension only during their first pregnancy, the rate of
cardiovascular outcomes was no different than in the general
population.

Nevertheless, Dr. Lykke concluded that "hypertensive pregnancy
disorders are strongly associated with subsequent hypertension,
thromboembolism, and type 2 diabetes," with severity, parity, and
recurrence all affecting the degree of risk. He recommended
that "physicians and other healthcare professionals be encouraged to
include earlier pregnancy outcomes when calculating the risk of
cardiovascular events in their pregnant patients."

Society for Maternal-Fetal Medicine (SMFM) 29th Annual Meeting:
Abstract 10. Presented January 29, 2009.

Computed tomography angiography (CTA) is an effective tool to
determine the presence and severity of peripheral arterial disease
(PAD) in patients with intermittent claudication, according to the
results of a systematic review and meta-analysis reported in the
January 28 issue of the Journal of the American Medical Association.

"...CTA is an increasingly attractive imaging modality for assessing
lower extremity...PAD," write Rosemarie Met, MD, from Academic
Medical Center in Amsterdam, the Netherlands, and colleagues. "The
purpose of this systematic review and meta-analysis was to determine
the diagnostic performance of CTA compared with intra-arterial DSA
[digital subtraction angiography] for grading disease severity in
patients with PAD."

The reviewers searched MEDLINE from January 1966 through August 2008,
EMBASE from January 1980 through August 2008, and the Database of
Abstracts of Reviews of Effectiveness to identify studies that
compared the accuracy of CTA vs intra-arterial DSA to differentiate
the extent of PAD.

Inclusion criteria were comparison of multidetector CTA vs intra-
arterial DSA; study sample of at least 10 patients with intermittent
claudication or critical limb ischemia; testing looking for more than
50% stenosis or arterial occlusion; and presentation of either 2 x 2
or 3 x 3 contingency tables (ˇÜ 50% stenosis vs > 50% stenosis or
occlusion), or provision of data allowing construction of these
tables.

Two reviewers screened studies to determine if they met inclusion
criteria and independently extracted study data. They also evaluated
methodologic quality using the quality assessment tool for diagnostic
accuracy studies (QUADAS) instrument.

Twenty (2.2%) of 909 studies identified met inclusion criteria;
median sample size in these was 33 (range, 16 - 279), and
methodologic quality was moderate. Of the total number of 957
patients enrolled, 68% had intermittent claudication.

For detection of more than 50% stenosis or occlusion, the overall
sensitivity of CTA was 95% (95% confidence interval [CI], 92% - 97%),
and specificity was 96% (95% CI, 93% - 97%). CTA accurately
identified occlusions in 94% of segments, the presence of more than
50% stenosis in 87% of segments, and the absence of significant
stenosis in 96% of segments. However, CTA overstaged 8% of segments
and understaged 15%.

"...CTA is an accurate modality to assess presence and extent of PAD
in patients with intermittent claudication; however, methodological
weaknesses of examined studies prevent definitive conclusions from
these data," the study authors write. "Nonetheless, CTA was a
reliable imaging modality with high sensitivity and specificity for
differentiating extent of disease in patients with predominantly
intermittent claudication compared with intra-arterial DSA."

Limitations of this study include exclusion of 12 studies because
they did not provide data allowing construction of 2 x 2 tables; the
possibility that important publications were missed; likely
publication bias; nonconsecutive recruitment and inclusion of only a
subset of stages of disease, resulting in possible spectrum bias;
only 4 studies clearly describing the selection criteria; incomplete
description of the patient population in many studies; most studies
including predominantly patients with intermittent claudication, who
are generally treated conservatively and do not typically require a
CTA; only 1 study including a large proportion of patients with
critical limb ischemia; and problems with the data analysis method in
the individual studies.

"Our meta-analysis also reveals that the diagnostic performance of
CTA for patients with critical limb ischemia has been poorly
investigated thus far," the review authors conclude. "More rigorous
evaluations of CTA in patients with critical limb ischemia are
needed."

The review authors have disclosed no relevant financial relationships.

JAMA. 2009;301:415-424.

Adding to a mixed evidence base regarding the use of natriuretic-
peptide levels as a treatment target in heart failure, a randomized
trial has suggested that the appealing but unproven strategy has
little or no effect on survival overall but also hinted at a possible
benefit in patients younger than 75 [1].

In the Trial of Intensified versus Standard Medical Therapy in
Elderly Patients With Congestive Heart Failure (TIME-CHF), drug
therapy guided by N-terminal brain-type natriuretic-peptide (NT-
proBNP) levels, as compared with conventional symptom-guided
management, made no significant difference to the primary end point
of hospitalization-free survival at 18 months.

The TIME-CHF results now published in the January 28, 2009 Journal of
the American Medical Association are virtually the same as those
presented in August at the European Society of Cardiology Congress
2008, reported then by heartwire.

A handful of prior studies exploring the biomarker-guided approach
produced mixed results, some showing it can improve clinical outcomes
and others showing no such advantages. A few suggested that biomarker-
guided management may tilt toward a clinical benefit in younger
patients, especially in preventing some HF hospitalizations.

That experience is somewhat consistent with TIME-CHF, which
secondarily showed across-the-board improvements in several clinical
end points with NT-proBNP guidance among its younger patients, those
no older than 75 years. Biomarker-guided management also appeared to
improve survival free of heart-failure hospitalization over the
entire study population.

In addition, write the authors, led by Dr Matthias Pfisterer
(University Hospital Basel, Switzerland), "both treatment strategies
improved symptoms and quality of life and reduced [NT-proBNP] levels
similarly over time, although these effects tended to be lower in
patients aged 75 years or older." There were also hints that
biomarker-guided therapy may have caused more "serious adverse
events" in the older group.

The current trial "is quite unique in that we looked at real-world
patients," its principal investigator, Dr Hans-Peter Brunner-La Rocca
(University Hospital Basel), told heartwire. It's the first study of
the natriuretic-peptide-guided strategy in a broad spectrum of heart-
failure patients, including the very elderly and those with multiple
comorbidities, he said. The other trials included patients who
were "at least 10 years younger, on average, than those in TIME-CHF."

The trial and clinical experience suggest that patients younger than
75 can benefit from intensified drug management, whether driven by
natriuretic peptide targets or not, according to Brunner-La
Rocca. "But in the very elderly, especially those with many
comorbidities, it's important to use the medications recommended in
the guidelines without pushing them to the highest level."

TIME-CHF entered 499 patients >60 years of age with heart failure of
at least NYHA class 2, an LVEF <45%, an HF hospitalization within the
previous year, and an NT-proBNP level >400 pg/mL for those <75 years
old or >800 pg/mL for those >75 years despite medical therapy. They
were randomized either to drug therapy aimed at pushing natriuretic-
peptide levels below those thresholds and achieving a NYHA class of 2
or better or to symptom-guided management according to US and
European guidelines and with the same functional-class goal.

Across all patients, the two groups fared similarly with respect to
the primary end point. But those younger than 75 showed a consistent
benefit from the natriuretic-peptide-guided approach. Their hazard
ratios were improved by 30% (p=0.05) for hospitalization-free
survival, 59% (p=0.02) for overall survival, and 58% (p=0.002) for HF-
hospitalization-free survival for biomarker-guided vs symptom-guided
therapy. Patients 75 or older showed no such difference for any of
the end points.

An accompanying editorial agrees that the biomarker-guided
approach "may have limited value" in the oldest patients, whereas--as
TIME-CHF suggests--it may reduce the risk of heart-failure
hospitalization in younger patients who are already well managed
pharmacologically by conventional standards [2].

"Medical therapy, therefore, can usually be further optimized and
uptitrated even in the absence of worsening symptoms--an important
clinical point," write Dr Ileana L Pińa (Case Western Reserve
University, Cleveland, OH) and Dr Christopher O'Connor (Duke
University, Durham, NC).

TIME-CHF, according to the editorialists, "points to the fact that
symptom-guided medical therapy can be improved in most patients."
Indeed, "persistence in intensifying medical therapy seems to be the
key for an optimal clinical outcome in patients aged 60 to 74 years."

The reports states that TIME-CHF was 55% sponsored by the nonprofit
Horten Research Foundation; the remainder was supported by
AstraZeneca, Novartis, Menarini, Pfizer, Servier, Roche Diagnostics,
Roche Pharma, and Merck.


Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided
heart failure therapy: The Trial of Intensified vs Standard Medical
Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF)
randomized trial. JAMA 2009; 301:383-392.
Pińa IL, O'Connor C. BNP-guided therapy for heart failure. JAMA 2009;
301:432-434.

Background: Cigarette smoking is an important risk factor for
cardiovascular disease, but it is unknown whether it also contributes
to the risk of atrial fibrillation.
Methods and results: The study is part of the Rotterdam Study, a
population-based cohort study among subjects aged ˇÝ55 years. The
association between cigarette smoking and the risk of atrial
fibrillation was examined in 5,668 subjects without atrial
fibrillation at baseline. During a median follow-up of 7.2 years, 371
cases of atrial fibrillation were identified. Relative risks (RR)
were calculated with 95% CIs using the Cox proportional hazards
model, adjusted for age, gender, body mass index, hypertension,
systolic blood pressure, serum cholesterol level, diabetes mellitus,
left ventricular hypertrophy on the electrocardiogram, prevalent and
incident myocardial infarction, prevalent heart failure, and the use
of pulmonary medication.
After multivariate adjustment, current smokers and former smokers had
increased risks of atrial fibrillation as compared to never smokers
(RR 1.51, 95% CI 1.07-2.12; and RR 1.49, 95% CI 1.14-1.97,
respectively). No differences were found between men and women.
Conclusions: The results of this prospective, population-based study
show that current and former smoking of cigarettes are associated
with increased risk of atrial fibrillation.

Am Heart J.  2008;156(6):1163-1169

New guidelines on the management of aneurysmal subarachnoid
hemorrhage (aSAH) have been released by the American Heart
Association/American Stroke Association.

Among recommendations based on newly available evidence are that
these patients be treated at high-volume centers where endovascular
interventions as well as neurosurgical services are available.
Guideline authors also caution that despite having generally among
the most dramatic presentations in medicine, these hemorrhages can
present as a milder sentinel headache, and aSAH should be considered
in the differential diagnosis of all patients with new headache.

Joshua B. Bederson MD, professor and chair of the department of
neurosurgery at Mount Sinai Medical Center, in New York, and chair of
the writing group for the new guidelines, told Medscape Neurology &
Neurosurgery that aSAH is a complex process, from the initial bleed
to the devastating delayed effects of rupture.

"What has changed over the past 15 or 16 years is a gradual
improvement in understanding of many of the separate processes that
constitute the disease, as well as the evolution of some new
technologies such as endovascular treatment of aneurysms that were
really just beginning at the time of the first guidelines," Dr.
Bederson said in an interview.

The guidelines are published online January 22 in Stroke.

Improving Outcomes by Many Paths

Mortality associated with aSAH is high, about 45% in the first 30
days after a rupture, Dr. Bederson said. Still, he notes, "The
majority of aneurysms do not rupture, and as much as 1% of the
population dies of old age with a small, unruptured aneurysm."

When they do rupture, the focus of treatment has to be on both
prevention of rebleeding and management of the pathological adverse
effects that the bleed has in the brain. However, he said, "We still
have very few treatments for the hit that the brain takes during the
first seconds after the hemorrhage. Most of our progress has been in
secondary things like preventing the aneurysm from rebleeding, which
can occur in 20% of patients in the first 2 weeks."

The last guidelines document was released in 1994, and 1 of the main
changes since then has been the development of endovascular
approaches to obliteration of aneurysms. Development since that time
of the subspecialty of neurocritical care, with its own fellowships
and certification, may also have improved outcomes, Dr. Bederson
noted.

"The current standard of practice calls for microsurgical clipping or
endovascular coiling of the aneurysm neck whenever possible," the
writing group concludes. "Treatment morbidity is determined by
numerous factors, including patient, aneurysm, and institutional
factors. Favorable outcomes are more likely in institutions that
treat high volumes of patients with SAH, in institutions that offer
endovascular services, and in selected patients whose aneurysms are
coiled rather than clipped."

Other major conclusions in the new guidelines include:

SAH is frequently misdiagnosed, in up to 12% of cases. For the
initial evaluation of headache, CT scanning for suspected SAH
is "strongly recommended," followed by lumbar puncture if the CT is
negative. A standard management protocol for the evaluation of
patients with headaches and other symptoms that may potentially
relate to SAH does not currently exist and should be developed.
Early vs later treatment of the aneurysm reduces the risk for
rebleeding after SAH, and so early surgery is "reasonable and
probably indicated in the majority of cases," the authors write.
Medical measures to prevent rebleeding include blood-pressure
monitoring and control and bed rest, although these should be part of
a broader strategy with more definitive measures. A short course of
antifibrinolytics may be considered prior to definitive treatment.
To reduce poor outcomes associated with vasospasm, the
authors "strongly recommend" use of oral nimodipine. The value of
other calcium antagonists remains uncertain, they note. Treatment
begins with early management of the ruptured aneurysm, they add; "in
most cases maintaining normal circulating blood volume and avoiding
hypovolemia is probably indicated."
Another "reasonable" approach to symptomatic vasospasm is volume
expansion with induction of hypertension and hemodilution, so-
called "triple-H therapy," the authors note. "Alternatively, cerebral
angioplasty and/or selective intra-arterial vasodilator therapy may
also be reasonable, either following, or together with, or in the
place of, triple-H therapy, depending on the clinical scenario."
The relationship between hypertension and aSAH is "uncertain," they
conclude, but management of blood pressure to prevent other clinical
problems is recommended. Quitting smoking is "reasonable," they
note, "although the evidence for this association is indirect."
Screening for unruptured aneurysms in high-risk populations is
of "uncertain value," they conclude. Noninvasive imaging may be used
for such screening, "but catheter angiography remains the 'gold
standard' when it is clinically imperative to know if an aneurysm
exists."
Other recommendations in the document focus on the management of
hydrocephalus, hyponatremia, and volume contractions, as well as
seizures.

The management of aSAH is so complex that "people have really been
clamoring for recommendations or guidelines," Dr. Bederson said. The
final document is large, with over 85 pages and more than 400
references, but basically summarizes the current literature into
recommendations on each of the complex processes that run their
separate course after aSAH.

"Even if there isn't 1 major new earthshaking change, putting it all
together for the practitioner may be the most valuable part of this,"
he said.

Dr. Bederson reports he has no conflicts of interest. Disclosures for
other members of the writing group appear in the paper.

Stroke. Published online January 22, 2009.

Diastolic dysfunction is independently and strongly related to
reduced exercise capacity, a new cross-sectional study has shown [1].
And unlike many other factors associated with reduced exercise
capacity, diastolic dysfunction is modifiable and so may be a
preventable factor in the development of exercise intolerance, the
researchers point out.

Dr Jasmine Grewal (Mayo Clinic, Rochester, MN) and colleagues report
their findings in the January 21, 2009 issue of the Journal of the
American Medical Association. "This is the first time this has been
studied in a large number of patients, and it's the first time
[diastolic dysfunction] has been attempted to be related to exercise
capacity and age-related changes," senior author Dr Patricia A
Pellikka (Mayo Clinic, Rochester, MN) told heartwire.

Although she says the results need to be confirmed in prospective
trials, she says that they found "that even mild abnormalities of
diastolic function seemed to be related to a lower exercise capacity
and that the magnitude of the effect of diastolic abnormalities
became greater in older patients." This points to a potentially
modifiable factor that might be a target for interventions that could
maintain exercise capacity with aging, she says.

Diastolic Dysfunction Strongest Echocardiographic Correlate of
Exercise Tolerance

Grewal et al explain that many factors, such as advancing age, female
sex, greater body-mass index (BMI), and coexisting medical conditions
are known to be associated with a decrease in exercise capacity, but
elucidating the mechanisms of cardiac-related exercise limitation has
been technically difficult to date. Prior research has suggested that
measurements of left ventricular systolic function do not predict
maximal exercise time in people with normal or impaired left
ventricular systolic function.

Doppler echocardiography can now characterize left ventricular
diastolic function through a combination of measurements, they note,
and a few previous small studies have shown this to be correlated
with exercise capacity.

In their study, they assessed 2867 patients undergoing exercise
echocardiography with routine measurements of left ventricular
systolic and diastolic dysfunction by two-dimensional and Doppler
techniques. Analyses were conducted to determine the strongest
correlates of exercise capacity and the age and sex interactions of
these variables with exercise capacity. The main outcome measure was
exercise capacity in metabolic equivalents (METs).

Diastolic dysfunction was strongly and inversely correlated with
exercise capacity. Compared with normal function, after multivariate
adjustment, those with moderate/severe resting diastolic dysfunction
(-1.30 METs; p<0.001) and mild resting diastolic dysfunction (-0.70
METs; p<0.001) had substantially lower exercise capacity. Left
ventricular filling pressures were similarly associated with a
reduction in exercise capacity, each in separate multivariate
analyses.

Individuals with impaired relaxation (mild dysfunction) or left
ventricular filling pressure of E/e' 15 or greater had a progressive
increase in the magnitude of reduction in exercise capacity with
advancing age (p<0.001 and p=0.02, respectively). Other independent
correlates of exercise capacity were age, female sex, and BMI >30.

In this large consecutive population free of valvular heart disease
or exercise-induced ischemia referred for exercise echo, "we found
resting diastolic function to be the strongest echocardiographic
correlate of exercise tolerance," the researchers say. "This was
superseded only by the clinical factors of advancing age, female sex,
and increased BMI."

Forum moderator of theheart.org, Dr Melissa Walton-Shirley (TJ Samson
Hospital, Glasgow, KY), said: "Historically, our main focus as
cardiologists has been upon systolic dysfunction, and rightly
so . . . but this study highlights the importance of a new emphasis
on diastology and its implied role in both quality- and quantity-of-
life issues.

"When physicians have a better understanding of the physiology of
exercise intolerance, we can then translate that understanding to our
patients in the office setting or at the bedside. One of our greatest
responsibilities as healthcare providers is to convey the secrets of
wellness, longevity, and prevention to our patient population. Adult
cardiologists and pediatricians alike should take the time on a daily
basis to have these conversations that explain the negative effects
of obesity and inactivity to our patients and, more important, the
potential for reversibility of these entities," she adds.

ARBs May Have a Therapeutic Role To Play

"In identifying diastolic function parameters as strong correlates of
exercise capacity, we have identified potentially modifiable and
preventable factors in the development of exercise intolerance," the
researchers say. "It is well-known that exercise training improves
diastolic function in healthy individuals, [but] the effects of
training on diastolic dysfunction are less clear," they add.

Pellikka expanded upon this for heartwire: "Work needs to be done to
see if we can modify this age-related decline in exercise capacity.
We know certain risk factors--such as uncontrolled hypertension and
untreated coronary disease--will lead to diastolic dysfunction, so we
need to make sure we're treating those conditions aggressively.

"Patients with unexplained limitations of exercise capacity or
patients with exertional symptoms should have their diastolic
function assessed, and fortunately that is something that is widely
available and can be achieved with echo Doppler completely
noninvasively," she notes.

One possible therapy is angiotensin-receptor blockers (ARBs), she
says, which appear promising because they block the angiotensin II
action that is thought to be responsible for slowed left ventricular
relaxation during exercise.

"Although these data require confirmation in prospective studies,
they point to a potentially modifiable factor that might be a target
for interventions that could maintain exercise capacity with aging."


Grewal J, McCully RB, Kane GC, et al. Left ventricular function and
exercise capacity. JAMA 2009; 301:286-294.

In the alternative, it tells us the entire preoccupation with cholesterol is
nonsense.

   ----- Original Message -----
   From: dr_allen_wang
   To: heart119@yahoogroups.com
   Sent: Thursday, January 22, 2009 11:21 PM
   Subject: [Heart119] Majority of Patients Hospitalized With CAD at
Guideline-Recommended LDL Targets


   A majority of patients hospitalized with coronary artery disease
   (CAD) have LDL-cholesterol levels considered normal by current
   guidelines, a new study has shown [1]. The findings suggest that
   current lipid targets are not low enough to prevent risk in patients
   who would benefit, say researchers.

   "There have been modest improvements in LDL-cholesterol levels over
   time," lead investigator Dr Gregg Fonarow (University of California
   Los Angeles Medical Center) told heartwire. "One of the major
   findings of this study that should serve as a wake-up call for anyone
   interested in reducing death and disability due to cardiovascular
   disease is that nearly 75% of patients having first ACS events had
   LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
   mg/dL."

   The study is published in the January 2009 issue of the American
   Heart Journal with lead investigator Dr Amit Sachdeva (University of
   California, Los Angeles Medical Center).

   GWTG Database

   The new data, obtained from a national database sponsored by the
   American Heart Association Get With the Guidelines program, includes
   admission lipid levels on 137 000 individuals from more than 500
   hospitals who were admitted with CAD. Admission diagnoses were most
   commonly related to acute coronary syndromes.

   Before admission to the hospital, 21% of patients were taking lipid-
   lowering medications. Among patients with a medical history of CAD,
   other atherosclerotic vascular disease, or diabetes, just 29.4% were
   taking lipid-lowering therapy prior to hospital admission, compared
   with 14% of patients without a history of CAD.

   The mean LDL-cholesterol level among hospitalized patients was 104.9
   mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
   <100 mg/dL, with 17% of patients having LDL levels lower than the
   more stringent target of <70 mg/dL. In the total cohort, roughly 75%
   of patients had levels <130 mg/dL.

   Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
   levels <40 mg/dL and only 7.8% of patients had levels that exceeded
   60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
   levels of LDL and HDL cholesterol.

   "The conventional cholesterol guidelines are missing the majority of
   patients having cardiovascular events," said Fonarow. "While
   certainly there are other risk factors beyond LDL, there are hundreds
   of thousands of potentially preventable cardiovascular events
   occurring because the LDL levels for primary prevention are missing
   too many individuals."

   Among patients without established vascular disease or diabetes, 42%
   of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
   <130 mg/dL. On the other hand, 52% of patients without established
   disease had HDL cholesterol levels <40 mg/dL.

   Low HDL was observed in a majority of patients presenting with first
   and recurrent cardiovascular events, noted Fonarow. "Finding safe,
   well-tolerated, and effective therapies to raise cardioprotective HDL
   appears to be very important," he added. "However, it is essential
   that large-scale trials be conducted to demonstrate reduction in
   clinical events incremental to LDL lowering with statin therapy and
   that the benefits of treating HDL outweigh potential risks."

   The group also points out that a large proportion of patients
   included in the present study could reach the standard or optional
   National Cholesterol Education Program (NCEP) LDL goals without
   statin therapy or with a statin dose lower than used in clinical
   trials.

   Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
   hospitalized with coronary artery disease: an analysis of 136,905
   hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
   117. Abstract





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

A majority of patients hospitalized with coronary artery disease
(CAD) have LDL-cholesterol levels considered normal by current
guidelines, a new study has shown [1]. The findings suggest that
current lipid targets are not low enough to prevent risk in patients
who would benefit, say researchers.

"There have been modest improvements in LDL-cholesterol levels over
time," lead investigator Dr Gregg Fonarow (University of California
Los Angeles Medical Center) told heartwire. "One of the major
findings of this study that should serve as a wake-up call for anyone
interested in reducing death and disability due to cardiovascular
disease is that nearly 75% of patients having first ACS events had
LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
mg/dL."

The study is published in the January 2009 issue of the American
Heart Journal with lead investigator Dr Amit Sachdeva (University of
California, Los Angeles Medical Center).

GWTG Database

The new data, obtained from a national database sponsored by the
American Heart Association Get With the Guidelines program, includes
admission lipid levels on 137 000 individuals from more than 500
hospitals who were admitted with CAD. Admission diagnoses were most
commonly related to acute coronary syndromes.

Before admission to the hospital, 21% of patients were taking lipid-
lowering medications. Among patients with a medical history of CAD,
other atherosclerotic vascular disease, or diabetes, just 29.4% were
taking lipid-lowering therapy prior to hospital admission, compared
with 14% of patients without a history of CAD.

The mean LDL-cholesterol level among hospitalized patients was 104.9
mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
<100 mg/dL, with 17% of patients having LDL levels lower than the
more stringent target of <70 mg/dL. In the total cohort, roughly 75%
of patients had levels <130 mg/dL.

Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
levels <40 mg/dL and only 7.8% of patients had levels that exceeded
60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
levels of LDL and HDL cholesterol.

"The conventional cholesterol guidelines are missing the majority of
patients having cardiovascular events," said Fonarow. "While
certainly there are other risk factors beyond LDL, there are hundreds
of thousands of potentially preventable cardiovascular events
occurring because the LDL levels for primary prevention are missing
too many individuals."

Among patients without established vascular disease or diabetes, 42%
of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
<130 mg/dL. On the other hand, 52% of patients without established
disease had HDL cholesterol levels <40 mg/dL.

Low HDL was observed in a majority of patients presenting with first
and recurrent cardiovascular events, noted Fonarow. "Finding safe,
well-tolerated, and effective therapies to raise cardioprotective HDL
appears to be very important," he added. "However, it is essential
that large-scale trials be conducted to demonstrate reduction in
clinical events incremental to LDL lowering with statin therapy and
that the benefits of treating HDL outweigh potential risks."

The group also points out that a large proportion of patients
included in the present study could reach the standard or optional
National Cholesterol Education Program (NCEP) LDL goals without
statin therapy or with a statin dose lower than used in clinical
trials.


Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
hospitalized with coronary artery disease: an analysis of 136,905
hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
117. Abstract

A majority of patients hospitalized with coronary artery disease
(CAD) have LDL-cholesterol levels considered normal by current
guidelines, a new study has shown [1]. The findings suggest that
current lipid targets are not low enough to prevent risk in patients
who would benefit, say researchers.

"There have been modest improvements in LDL-cholesterol levels over
time," lead investigator Dr Gregg Fonarow (University of California
Los Angeles Medical Center) told heartwire. "One of the major
findings of this study that should serve as a wake-up call for anyone
interested in reducing death and disability due to cardiovascular
disease is that nearly 75% of patients having first ACS events had
LDL levels below 130 mg/dL, and nearly 50% had LDL levels below 100
mg/dL."

The study is published in the January 2009 issue of the American
Heart Journal with lead investigator Dr Amit Sachdeva (University of
California, Los Angeles Medical Center).

GWTG Database

The new data, obtained from a national database sponsored by the
American Heart Association Get With the Guidelines program, includes
admission lipid levels on 137 000 individuals from more than 500
hospitals who were admitted with CAD. Admission diagnoses were most
commonly related to acute coronary syndromes.

Before admission to the hospital, 21% of patients were taking lipid-
lowering medications. Among patients with a medical history of CAD,
other atherosclerotic vascular disease, or diabetes, just 29.4% were
taking lipid-lowering therapy prior to hospital admission, compared
with 14% of patients without a history of CAD.

The mean LDL-cholesterol level among hospitalized patients was 104.9
mg/dL. Of these, almost 50% of patients had LDL-cholesterol levels
<100 mg/dL, with 17% of patients having LDL levels lower than the
more stringent target of <70 mg/dL. In the total cohort, roughly 75%
of patients had levels <130 mg/dL.

Regarding HDL-cholesterol levels, 54.6% of patients hospitalized had
levels <40 mg/dL and only 7.8% of patients had levels that exceeded
60 mg/dL. Just 1.4% of patients hospitalized with CAD had ideal
levels of LDL and HDL cholesterol.

"The conventional cholesterol guidelines are missing the majority of
patients having cardiovascular events," said Fonarow. "While
certainly there are other risk factors beyond LDL, there are hundreds
of thousands of potentially preventable cardiovascular events
occurring because the LDL levels for primary prevention are missing
too many individuals."

Among patients without established vascular disease or diabetes, 42%
of patients had LDL-cholesterol levels <100 mg/dL and 72% had levels
<130 mg/dL. On the other hand, 52% of patients without established
disease had HDL cholesterol levels <40 mg/dL.

Low HDL was observed in a majority of patients presenting with first
and recurrent cardiovascular events, noted Fonarow. "Finding safe,
well-tolerated, and effective therapies to raise cardioprotective HDL
appears to be very important," he added. "However, it is essential
that large-scale trials be conducted to demonstrate reduction in
clinical events incremental to LDL lowering with statin therapy and
that the benefits of treating HDL outweigh potential risks."

The group also points out that a large proportion of patients
included in the present study could reach the standard or optional
National Cholesterol Education Program (NCEP) LDL goals without
statin therapy or with a statin dose lower than used in clinical
trials.


Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients
hospitalized with coronary artery disease: an analysis of 136,905
hospitalizations in Get With the Guidelines. Am Heart J 2009; 157:111-
117. Abstract

New data from a single center suggest that transradial-access PCI can
be performed successfully in complex patients and complex lesions,
such as in acute-MI patients and those older than 80 years of age
[1].

Presenting the data at the International Symposium of Endovascular
Therapy, researchers also showed that radial-access interventions can
be successfully performed in patients with complex lesions, including
chronic total occlusions and bifurcated branches.

"We feel very strongly that the radial approach is the way to go,"
lead investigator Dr Ramon Quesada (Baptist Cardiac and Vascular
Institute, Miami, FL) told heartwire. "It is good for the patient,
results in fewer complications, decreases hospital length of stay,
and the patients love it. Importantly, with these subgroups, we're
showing that everything we do with the femoral approach can also be
done radially."

Presenting data this week on their experience with transradial
interventions at Baptist Cardiac and Vascular Institute, Quesada
noted that the group has performed nearly 700 complex transradial
interventions since 2003. The procedural success rates range from as
high as 98.5% in patients with complex B2-C lesions to 78.9% in
patients with chronic total occlusions. Among acute-MI patients, the
procedural success rate is 97%.

Bleeding risks also remained low, said Quesada, with resolved radial-
access site hematomas occurring in 2.2% of patients with complex
lesions and 5.6% of patients with bifurcated branches. Of the 134
acute-MI patients treated with radial access since 2003, there were
three small hematomas that were resolved.

The group also notes that octogenarians also fare well with the
transradial approach, although tortuosity of the vessels is the
biggest complication in this patient population. Among these
patients, vascular complications declined from 15% via the femoral
approach to less than 2% with radial-access PCI, Quesada told
heartwire.

Proponents of the transradial approach, like Quesada, who has been
performing radial-access PCI for 10 years and who now does 80% of his
cases via the radial artery, point to recent studies and meta-
analyses showing that the technique is associated with equivalent
procedural success to femoral access. Along with the equivalent
success, however, are lower rates of bleeding and vascular
complications, even among high-risk patients.

Still, despite the arguments in favor of the approach, radial-access
PCI is rarely performed. One of the largest and most recent studies
identified nearly 600 000 patients who underwent PCI between January
2004 and March 2007, with only 1.32% treated using radial-artery
access. Despite the limited use of radial PCI, the approach was
associated with a similar rate of success and a 58% lower risk of
bleeding complications.

"The biggest drawback to the procedure is the learning curve," said
Quesada. "It's a more difficult technique to master, but when you get
it down you are able to have the same success as when you use the
femoral approach. We're not saying that every interventionalist
should rush out and start doing these, or start doing them on MI
patients. That would be stupid. Start with a diagnostic and work your
way from there."


Quesada R. Complex transradial interventions for CTOs and STEMI.
International Symposium on Endovascular Therapy; January 19, 2009;
Hollywood, FL.

The severity of incident MIs has dropped significantly in the US over
a 15-year period, a new analysis of the Atherosclerosis Risk in
Communities Study (ARIC) has shown [1]. This has likely contributed
to a decline in populationwide death rates for coronary heart disease
(CHD), say Dr Merle Myerson (St Luke's Roosevelt Hospital, New York,
NY) and colleagues in their report published online January 19, 2009
in Circulation.

"Our severity indicators all seemed to indicate that MIs were less
severe, the cardiac enzymes did not go as high, and there were fewer
Q waves on ECG. This is very good, because if people have less severe
heart attacks, the chances are less that they'll die," Myerson told
heartwire.

"Although this study was not particularly designed to tell us exactly
why heart attacks are less severe, it certainly appears that better
in-hospital care and better prevention beforehand may have played a
role," she added. One thing that has not improved, however, is the
time it takes people to get to the hospital. "We were surprised to
find this, because efforts have been made through public-education
programs. But we didn't see any improvement, and this is in agreement
with several other studies," she noted.

Consistent Picture Showing Clear Decline in MI Severity

The new study by Myerson et al extends previous findings from ARIC,
an ongoing epidemiologic trial that includes data from four areas--
Forsythe County, NC, including Winston-Salem; Washington County, MD,
including Hagerstown; and the suburbs of Minneapolis, MN and Jackson,
MS.

In the previous analysis, focusing on 1987 to 1994, researchers found
a decrease in many but not all indicators of severity. This new study
includes an extra eight years of data, covering 10 285 patients, ages
35 to 74, who were discharged from the hospital diagnosed with a
definite or probable first-time heart attack from January 1, 1987
through December 31, 2002.

"We wanted to explore why mortality from CHD has declined, to see
whether we can discover what's working and what's not working,"
Myerson explained to heartwire. The new findings show a more
consistent picture, with a clear decline in severity of heart
attacks, she says.

MI classification was assigned according to an algorithm consisting
of chest pain, ECG evidence, and cardiac biomarkers. The number of MI
cases with major ECG abnormalities declined as shown by a 1.9%/year
decline (p=0.002) in the proportion of those with initial ST-segment
elevation, a 3.9%/year drop (p<0.001) in those with subsequent Q
waves, and a 4.5%/year reduction (p<0.001) in those with any major Q
wave. Maximum creatinine kinase and creatinine kinase-MB values also
fell (by 5.2% and 7.6%; p<0.001 and p<0.001 per year, respectively),
although in later years maximum troponin I values remained stable.

But the percentage of patients who arrived at the hospital less than
two hours after symptom onset remained unchanged over the course of
the study, at approximately 33%.

Study Findings Generalizable

Myerson says one of the key strengths of ARIC is its
generalizability.

"We had four geographic areas--including urban, rural, and suburban--
and we have men and women and blacks and whites in this study," she
says. "And while we certainly can't say we captured everybody in this
country, the beauty and strength of the ARIC study is that we can
say, 'Hey, we're finding it in each of these populations.' "

The results likely indicate that risk factors, such as blood pressure
and cholesterol, are being better controlled, says Myerson, and that
when people do get to the hospital there has been an improvement in
care there. "Attributing the reduction in severity to specific causes
will be an important next step, so that effective strategies can be
reinforced and public-health policies can be better directed," she
concludes.


Myerson M, Coady S, Taylor H, et al. Declining severity of myocardial
infarction from 1987 to 2002. The Atherosclerosis Risk in Communities
(ARIC) Study. Circulation 2009; 119:503-514. Abstract

A series of papers in a special issue of Circulation is highlighting
new data on cardiovascular disease in Asians specifically. The
researchers stress that the presentation of disease there is often
different from that seen in the West, and responses to treatment can
also differ, necessitating separate study in Asian populations. And
given that it is now widely acknowledged that 85% of cardiovascular
deaths worldwide will soon occur in low- and middle-income countries,
there is a pressing need for such research, they note.

Dr Hirotsugu Ueshima (Shiga University of Medical Science, Otsu,
Japan) and colleagues review the whole subject of cardiovascular
disease and risk factors in Asia in the December 16, 2008 issue of
Circulation [1]. They note that many countries in Asia have greater
mortality and morbidity from stroke than from coronary heart disease
(CHD), "whereas the opposite is true in Western countries," and they
emphasize the high prevalence of hypertension in some Asian nations.
They also point out that, in most Asian countries, mean levels of
total cholesterol are lower than those found in Western countries.

In fact, a new report from the INTERHEART study, published separately
in the January 20, 2009 issue of the Journal of the American College
of Cardiology, has found that the low-density lipoprotein cholesterol
(LDL-C) threshold for treatment may be lower in Asians, perhaps
necessitating a rethinking of treatment targets there [2].

In an editorial accompanying the Circulation papers [3], Dr Shigetake
Sasayama (Doshisha University, Kyoto, Japan) says: "It is our hope
that this issue provides a clear exposition of the current state of
cardiovascular disease in Asia and provides readers with a better
understanding of some of these diseases, with an emphasis on therapy
and insight into specific problems that face patients suffering from
cardiovascular disease in Asia."

Stroke on the Rise in India, on the Wane in Japan

Two of the new papers in Circulation detail the current picture on
stroke in India and Japan, respectively, and another discusses the
situation with regard to hypertension in China.

In their paper [4], Indian physicians Drs Shyamal Kumar Das and Tapas
Kumar Banerjee (Bangur Institute of Neurosciences and Psychiatry,
Kolkata, India) say, "The data accumulated so far are sufficient for
us to declare that stroke in India is very much on the rise," and
they note that in the past decade in particular, some critical data
on stroke in India have become available.

"Management of hypertension, the most important risk factor in the
community, is far from satisfactory," they point out, noting that a
high prevalence of cerebral hemorrhage has been documented in eastern
India. "Similar studies need to be conducted in different parts of
India to develop a national stroke registry . . . that would define
criteria, dietary, and risk factors because India is a multiethnic
and multicultural country."

Data on long-term outcome of stroke, the influence of socioeconomic
factors on its occurrence, and an estimate of the economic burden of
the condition are also essential to allow for adequate allocation of
resources by healthcare planners, they note.

And finally, there is "an urgent need for undertaking health
education . . . about the awareness of risk factors and early warning
signs of stroke in the community," they stress.

Meanwhile, in Japan, new data show that the incidence of ischemic
stroke has declined significantly over the past 40 years, say Dr
Michiaki Kubo (Center for Genomic Medicine, RIKEN, Yokohama,
Kanagawa, Japan) and colleagues [5].

They examined three cohorts of people over the age of 40 in 1961,
1974, and 1988 in the Japanese community of Hisayama. Morphological
exams by autopsy or brain imaging were performed on most of the
ischemic-stroke cases in these cohorts. When 13-year follow-up data
were compared, the age-adjusted incidence of ischemic stroke and
lacunar infarction declined significantly from the first to the third
cohort for both sexes, whereas the incidences of atherothrombotic and
cardioembolic infarction did not change during this period.

They believe that improved control of hypertension would largely have
influenced this declining trend: the age-adjusted and sex-adjusted
hazard ratio of hypertension decreased from 3.25 in the first cohort
to 1.83 in the third cohort.

But they warn that hypertension "still makes a large contribution to
the development of ischemic stroke, [and] there is a need for greater
primary-prevention efforts in the treatment of hypertension and
metabolic disorders."

Hypertension Remains a Huge Problem in China

Meanwhile, Dr Yanfeng Wu (Peking University of Public Health,
Beijing, China) and colleagues, in their report [6], attempt to
provide accurate estimates of the prevalence, awareness, and control
of hypertension in adults in China. Despite evidence to the contrary,
the figures suggest that the ratio of controlled to treated
hypertension has remained largely unchanged, at 1:4, over the past
decade, they note.

Using data obtained from the China National Nutrition and Health
Survey 2002, they discovered that around one in six Chinese is
hypertensive, equating to around 153 million adults, but only one-
quarter are aware of their condition.

The prevalence of hypertension was higher among men than women (20%
vs 17%; p<0.001) and was higher in successive age groups. The
prevalence of hypertension was also higher in urban compared with
rural areas for both sexes.

"National hypertension programs must focus on improving awareness in
the wider community, as well as treatment and control, to prevent
many tens of thousands of cardiovascular-related deaths," they
conclude.

Reduce Salt Consumption, Smoking in Asia

In wrapping up the Circulation issue, Ueshima and colleagues make
some important observations. While total cholesterol intake has
traditionally been low in Asia, the recent Westernization in many
countries there is beginning to change this, resulting in the
prevalence of obesity and diabetes increasing, they note. As in the
West, management of the traditional risk factors for CVD is just as
important for prevention in Asian nations, they stress.

And specifically, "reduction in salt consumption in East Asian
countries . . . is important for the reduction of CVD, especially
stroke. Prevention of smoking is also an important strategy for
reducing CVD in most Asian countries, especially for men," they
conclude.

New INTERHEART Analysis Shows Mean LDL-C Lower in Asians

The new analysis from the INTERHEART study may help illuminate the
picture further with regard to cholesterol and Asian populations.

Dr Ganesan Karthikeyan (McMaster University, Hamilton, ON) and
colleagues recruited 5731 cases of a first AMI and 6459 control
subjects from 65 centers in Asia. They obtained plasma levels of
lipids and apolipoproteins in the different Asian subgroups (South
Asians, Chinese, Southeast Asians, and Japanese) and correlated these
with the risk of AMI.

Among both cases and controls, mean LDL-C levels were about 10-mg/dL
lower compared with non-Asians, and HDL-C levels were slightly lower
among Asians compared with non-Asians.

But despite these differences in absolute levels, the risk of AMI
associated with increases in LDL-C and decreases in HDL-C was similar
for Asians and non-Asians. And in South Asians in particular, changes
in apolipoprotein predicted risk better than HDL-C (South Asians were
much more likely than other Asians to have low HDL-C).

"Although Asian patients are likely to benefit from lowering LDL-C,
the threshold for treatment initiation and the treatment targets are
conceivably lower than for Caucasians. These thresholds and targets
need to be determined in future studies," say Karthikeyan et al.

Also, in South Asians--given their lower levels of HDL-C--approaches
to increasing HDL-C may also be beneficial, they conclude.

The INTERHEART study was funded by unrestricted grants from several
pharmaceutical companies, which are listed in the paper.


Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and
risk factors in Asia. A selected review. Circulation 2008; 118: 2702-
2709. Abstract
Karthikeyan G, Teo KK, Islam S, et al. Lipid profile, plasma
apolipoproteins, and risk of a first myocardial infarction among
Asians. An analysis from the INTERHEART study. J Am Coll Cardiol
2009; 53: 244-253.
Sasayama S. Heart disease in Asia. Circulation 2008; 118: 2669-2671.
Abstract
Das SK and Banerjee TK. Stroke. Indian scenario. Circulation 2008;
118: 2719-2724. Abstract
Kubo M, Hata J, Doi Y, et al. Secular trends in the incidence of and
risk factors for ischemic stroke and its subtypes in Japanese
population. Circulation 2008; 118: 2672-2678. Abstract
Wu Y, Huxley R, Li L, et al. Prevalence, awareness, treatment and
control of hypertension in China. Data from the China National
Nutrition and Health Survey 2002. Circulation 2008; 118: 2679-2686.
Abstract

Results of 2 new MRI analyses from the Women's Health Initiative
Memory Study (WHIMS) show that hormone therapy (HT) is associated
with increased brain atrophy, but not with subclinical
cerebrovascular disease.

The findings suggest that brain atrophy, not ischemic brain lesions,
may underlie the increase in dementia and decrease in global
cognitive functioning with HT seen in the WHIMS study.


Laura H. Coker, PhD, from Wake Forest University, in Winston-Salem,
North Carolina, took the lead on the paper looking at subclinical
cerebrovascular disease, which was actually the primary analysis. The
results were surprising, the authors note.

"We saw very little difference in brain-lesion volumes between women
who had taken the estrogen-based hormone therapy and women who had
taken placebo," Dr. Coker told Medscape Neurology & Neurosurgery.

Susan M. Resnick, PhD, from the Biomedical Research Center, National
Institute on Aging, in Baltimore, Maryland, was lead author on the
brain-volumes study. "Overall, women who had been randomized to
receive hormone therapy had slightly smaller hippocampal and frontal
volumes, both structures critical in maintaining normal memory
function," Dr. Resnick told Medscape Neurology & Neurosurgery. The
greatest negative effects were found among women with the lowest
cognitive function at baseline, prior to the start of hormone
therapy.

Both papers are published in the January 13 issue of Neurology.

Brain Lesions

WHIMS was an ancillary study to the landmark Women's Health
Initiative trial that showed, contrary to previous observational
evidence, that conjugated equine estrogens (CEE), alone and in
combination with medroxyprogesterone acetate (MPA), increased the
risk for heart disease, stroke, and breast cancer in postmenopausal
women.

WHIMS looked specifically at dementia and global cognitive decline in
women 65 years of age and older and found increases in both of these
end points with CEE treatment, again with or without MPA.

The WHIMS-MRI study was undertaken to explore these results further,
looking at potential mechanisms of the adverse effects using magnetic
resonance imaging (MRI). The most likely suspect was subclinical,
or "silent," strokes, the authors reasoned, since clinical stroke was
also increased with hormone therapy in the main WHI trial.

A subset of 1403 women underwent MRI an average of 3 years after the
trial for those in the CEE-plus-MPA trial and 1.4 years for the CEE-
alone trial participants. Average follow-up during the trials
themselves were 4 and 5.6 years, respectively.

The primary outcome measure of the WHIMS-MRI study was total ischemic-
lesion volume, reported in the paper by Dr. Coker and colleagues.
Results showed mean ischemic lesion volumes were slightly larger for
the CEE-plus-MPA group vs placebo, except for the basal ganglia, but
the differences were not significant. Lesion volumes for those on CEE
alone were similar to those on placebo.

"This finding was consistent within each trial and in pooled analyses
across trials," the authors conclude.

Lesion volumes did correlate with age, smoking, a history of
cardiovascular disease, hypertension, lower posttrial global
cognition scores, and increased incident cases of mild cognitive
impairment or probable dementia either during or after the trial.

Brain Volumes

In the same subset of 1403 women, Dr. Resnick and colleagues looked
at total brain, ventricular-, hippocampal-, and frontal-lobe volumes,
after adjustment for age, clinic site, estimated intracranial volume,
and dementia risk factors.

The authors found that the covariate-adjusted mean frontal-lobe
volume was 2.37 cubic cm lower among women assigned to HT compared
with placebo (P = .004). Mean hippocampal volume was slightly lower,
they note (0.10 cubic cm, P = .05), and the difference between groups
in total brain volume approached statistical significance (P = .07).
The results were similar whether women received CEE plus MPA or CEE
alone.

The loss in hippocampal volume was greatest in women who had the
lowest Mini-Mental State Examination scores at baseline, Dr. Resnick
noted, "suggesting that the therapy may have accelerated a
neurodegenerative process that had already begun."

The hormone regimens selected were the most widely used at the time
these trials were begun, Dr. Resnick noted. Since then, other studies
have been undertaken looking at the effects of estradiol, the natural
form of the hormone, as well as the effects of treatment in women who
begin hormone therapy closer to menopause.

In WHIMS, all the women were 65 years of age and older when they
began HT, which may have been too late. However, Dr. Resnick
noted, "it didn't really make sense to look at dementia in 50-year-
olds."

Women who were 50 years at baseline were included in the overall WHI
study, Dr. Resnick said. "One of the things that Dr. [Sally] Shumaker
and Dr. Coker and their colleagues are going to do is go back and
look at those women who were treated when they were 50 to 65 ˇX it's
10 years later ˇX and look at their cognitive function now.

"It's really a hypothesis, but there may be a window of opportunity
such that if women are treated early you may have a different outcome
than you would if you're treated later," she said.

In the meantime, Dr. Coker said, "these findings provide more
evidence to help women make decisions about HT." Those 65 years of
age and older should not begin HT, because the risks outweigh
possible benefits, she said. However, "these findings do not inform
the guidelines for newly menopausal women. The current
recommendations are that HT be used only if needed to treat
menopausal symptoms and be taken at the lowest dose and for the
shortest time possible."


The Women's Health Initiative and the WHIMS-MRI study were funded by
the National Heart, Lung, and Blood Institute, US Department of
Health and Human Services. WHIMS was funded in part by Wyeth
Pharmaceuticals. Dr. Resnick reports no disclosures; disclosure
information for coauthors appears in the paper. Dr. Coker reports no
disclosures.

Neurology. 2009;72:125-134 Abstract,135-142. Abstract

A scientific statement from the American Heart Association (AHA)
outlines what is known and what is yet to be learned regarding a
familiar array of cardiometabolic risk factors manifested in children
and adolescents, emphasizing, in particular, that its clinical
implications are poorly understood in that population, especially
compared with what is known about it in adults [1].

Whether combinations of obesity, insulin resistance, lipid
abnormalities, and hypertension in the young actually predict
cardiovascular disease during the adult years is not known, in part
because of a dearth of longitudinal data and some unique challenges
in even defining those conditions in children, according to the
report's writing group, chaired by Dr Julia Steinberger (University
of Minnesota, Minneapolis).

"In adults, we refer to this clustering of risk factors as the
metabolic syndrome, but it hasn't been clear to us that it could be
called the metabolic syndrome in children," Steinberger, a pediatric
cardiologist, told heartwire.

She described the report as an update to a 2003 statement from the
AHA on obesity, insulin resistance, and diabetes in the young [2],
and a "pediatric companion document" to the organization's Diagnosis
and Management of the Metabolic Syndrome consensus statement from
2005 [3]. The report was published online January 12, 2009 by
Circulation and is scheduled for the February 3 issue.

It has been common in pediatric studies to characterize the metabolic
syndrome in terms of definitions used for adults, observed
Steinberger. But that approach, as well as some attempts to create
child-specific definitions, has been limited, among other reasons, by
a lack of outcomes data and variability in the measures of the
different risk factors. It isn't practical to track children long
enough for some of them to develop cardiovascular disease and
experience clinical events, and what's "abnormal" for some will
be "normal" for others.

"In adults, we can use cut points for defining normal and abnormal
levels of the components of the metabolic syndrome," Steinberger
said. "In children itˇ¦s a lot more vague because we're talking about
children of different ages and in different stages of development.
Waist circumference, triglycerides, HDL-cholesterol, blood pressure,
fasting glucose--in children these are moving targets, there really
aren't very well established criteria for what is normal or
abnormal."

So the challenge in kids, as reflected in the AHA scientific
statement, is to define who is at risk for disease in adulthood in
terms of the different risk factors, with less attention paid to
establishing criteria for defining a specific syndrome, according to
Steinberger. Whereas in adults there is a focus on the treatment of
disease resulting from the metabolic syndrome, she said, in kids the
focus is on prevention and management of obesity and the other risk
factors.

"Because specific treatment aimed at the underlying pathophysiology
of the metabolic syndrome does not yet exist, other than reducing
adiposity and increasing physical activity, therapy targeted at each
of the risk factors present is of importance. This treatment strategy
would not be improved by labeling a patient dichotomously as having
the metabolic syndrome," according to the statement.

"What is probably needed is not a dichotomous definition but a more
complex weighted scoring system that takes into account the magnitude
of all of the risk factors, their interaction, and other important
patient characteristics, including family history."

Steinberger reports receiving research grants from Pfizer and Sankyo.
Disclosures for other members of the statement's writing group are in
the report.

Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges
in metabolic syndrome in children and adolescents. A scientific
statement from the American Heart Association Atherosclerosis,
Hypertension, and Obesity in the Young Committee of the Council on
Cardiovascular Disease in the Young; Council on Cardiovascular
Nursing; and Council on Nutrition, Physical Activity, and Metabolism.
Circulation; published online before print January 12, 2009. Abstract
Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes and
cardiovascular risk in children: an American Heart Association
scientific statement from the Atherosclerosis, Hypertension, and
Obesity in the Young Committee (Council on Cardiovascular Disease in
the Young) and the Diabetes Committee (Council on Nutrition, Physical
Activity, and Metabolism). Circulation 2003; 107:1448 ˇV1453.
Abstract
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of
the metabolic syndrome: an American Heart Association/National Heart,
Lung, and Blood Institute Scientific Statement. Circulation 2005;
112:2735ˇV2752. Abstract

Early postnatal prophylactic granulocyte-macrophage colony
stimulating factor (GM-CSF) corrects neutropenia but does not lower
risk for sepsis or improve survival and short-term outcomes in
extremely preterm neonates, according to the results of a single-
blind, multicenter, randomized controlled trial reported in the
January 17 issue of The Lancet.

"Systemic sepsis is a major cause of death in preterm neonates,"
write Robert Carr, from the Department of Haematology, Guy's and St
Thomas' Hospital, King's College, London, United Kingdom, and
colleagues. "There are compelling theoretical reasons why treatment
with haemopoietic [CSFs] might reduce sepsis and improve outcomes,
and as a consequence these agents have entered into use in neonatal
medicine without adequate evidence. We assessed whether [GM-CSF]
administered as prophylaxis to preterm neonates at high risk of
neutropenia would reduce sepsis, mortality, and morbidity."

The trial of GM-CSF administered as prophylaxis for reduction of
sepsis in extremely preterm neonates who were small for gestational
age (the PROGRAMS trial) took place in 26 centers between June 2000
and June 2006. Within 72 hours of birth, 280 neonates of 31 weeks'
gestation or less and below the 10th percentile for birth weight were
randomly assigned either to treatment with GM-CSF, 10 µg/kg per day
subcutaneously for 5 days, or to standard care.

The treating clinicians completed a detailed clinical record form
daily from recruitment to day 28. The main study endpoint was sepsis-
free survival to 14 days from trial entry, and analysis was by
intention to treat.

During the first 11 days, infants treated with GM-CSF had a
significantly more rapid increase in neutrophil counts after trial
entry than did control infants (difference between neutrophil count
slopes, 0.34 ˇŃ 109/L/day; 95% confidence interval [CI], 0.12 ˇX
0.56). However, sepsis-free survival was not significantly different
for all infants (93 of 139 treated infants, 105 of 141 control
infants; difference, −8%; 95% CI, −18 to 3). A meta-analysis
including data from this study and from previous published
prophylactic trials showed no benefit in survival.

"Early postnatal prophylactic GM-CSF corrects neutropenia but does
not reduce sepsis or improve survival and short-term outcomes in
extremely preterm neonates," the study authors write.

Study limitations include time to enrollment delayed by the need for
informed parental consent and inability to determine the effect of GM-
CSF as adjuvant treatment for established sepsis.

"We believe that, before embarking on future single agent clinical
trials, we should consider if this is too simplistic an approach to
sepsis prevention in the preterm infant, whose immune system appears
compromised in many different ways," the study authors
conclude. "Knowledge of the functional characteristics of neonatal
innate immunity remains limited and needs continued research effort.
Successful future stratagems will need a wider view of their
antibacterial defences."

In an accompanying comment, Frank Shann, MD, from the Intensive Care
Unit, Royal Children's Hospital, in Melbourne, Australia, notes that
about 90% of babies receive at least 1 off-label or unlicensed drug
during a stay in intensive care, and that some of these untested
treatments are ineffective or even harmful.

"Although leucopheresis is far more difficult than giving injections
of G-CSF or GM-CSF, the procedure is much easier to do than in the
early 1980s; perhaps the time is right for a large randomised trial
in neonates," Dr. Shann writes. "G-CSF and GM-CSF should no longer be
used routinely in neonatal intensive care without further evidence
from randomised trials. Unfortunately, funding is difficult to get
for trials of treatments that will be used in very few patients, or
that are not under patent."

Action Medical Research supported the trial. The authors and Dr.
Shann have disclosed no relevant financial relationships.

Lancet. 2009;373:188ˇV190, 226ˇV233.

Elderly patients hospitalized with heart failure who go on beta
blockers for the first time and continue them after discharge can
expect prolonged survival and fewer rehospitalizations, unless they
are one of the many with preserved systolic function, suggests an
analysis based on a large prospective registry [1]. The findings,
which appear in the January 13, 2009 issue of the Journal of the
American College of Cardiology, are consistent with the few other
studies of beta blockade in comparable patients and highlight how
poorly understood preservedˇVejection-fraction heart failure is
compared with systolic heart failure.

The adjusted one-year mortality for patients in the analysis who
were discharged on beta blockers was reduced by a significant 23%
among those with systolic dysfunction but not at all, statistically,
among patients with preserved systolic function. There was also a
significant drop in readmissions on beta blockade in the former
group but not the latter. All of the >7000 patients in the analysis,
from the Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, had
been eligible for beta blockade but weren't on them when
hospitalized.

The patients averaged about 80 years in age, slightly younger for
the group discharged on beta blockers.

Clearly, there is powerful evidence for significant benefit from
certain beta blockers in systolic heart failure, observed lead
author Dr Adrian F Hernandez (Duke Clinical Research Institute,
Durham, NC). But based on this analysis and some other data, he told
heartwire, beta blockers are not the answer for heart failure with
preserved systolic function--although such patients may find them
beneficial if they also have diabetes, hypertension, or other
indications for the drugs.

"Certainly our findings are disappointing and, on the heels of I-
PRESERVE, clearly demonstrate that for half the population with
heart failure, we need, one, to understand more about their
pathophysiology, and two, to develop different targets for their
treatment," according to Hernandez.

The I-PRESERVE trial, as recently reported by heartwire, found no
effect on mortality or CV events from the angiotensin-receptor
blocker irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Synthelabo)
over a four-year follow-up of patients with heart failure and
preserved systolic function.

Such patients typically account for about half of all heart failure
in most reports. In the current analysis, they represented closer to
60%. Systolic dysfunction was defined as an LVEF <40% or qualitative
documentation of systolic dysfunction, while preserved systolic
function meant LVEF >40% or qualitative documentation of preserved
systolic function.

Importantly, the analysis also underscores the poor prognosis faced
by preservedˇVsystolic-function heart-failure patients, according to
Hernandez. Their one-year mortality was about 32%, and
rehospitalization rate was about 65%. "They're still the elephant in
the room. We still don't know what to do with them."

The ongoing, government-funded Treatment of Preserved-Cardiac-
Function Heart Failure (TOPCAT) trial, Hernandez observed, is
exploring whether the aldosterone inhibitor spironolactone will
improve their outcomes.

The study was supported by GlaxoSmithKline.


Hernandez AF, Hammill BG, O'Connor CM, et al. Clinical effectiveness
of beta-blockers in heart failure. Findings from the OPTIMIZE-HF
(Organized Program to Initiate Lifesaving Treatment in Hospitalized
Patients With Heart Failure) registry. J Am Coll Cardiol 2009;
53:184-192).

More evidence is available supporting the preemptive use of statins
in patients undergoing cardiac surgery, only this time the benefit
extends to patients without existing coronary artery disease [1].

A new retrospective review, published in the December 2008 issue of
the Journal of Thoracic and Cardiovascular Surgery, has shown that
the preoperative use of statins is associated with lower mortality
among patients undergoing valve surgery.

"Clinically, this study implies that a preemptive use of
preoperative statins may improve operative outcomes in patients
undergoing cardiac valve surgery who do not have a history of
coronary artery disease," write lead investigator Dr Minoru Tabata
(Brigham and Women's Hospital, Boston, MA) and colleagues. "Our
cohort includes concomitant aortic, congenital, and other cardiac
procedures. Combined with previous findings in coronary artery
bypass graft and patients with coronary artery disease, the
beneficial effects of preoperative statins may be generalizable to
most patients undergoing cardiac surgery."

Patients Without a History of Coronary Artery Disease

The use of preoperative statin therapy among patients undergoing
CABG surgery has been shown to improve operative outcomes in other
studies, including a large 30 000-patient meta-analysis published in
the June 2008 issue of the European Heart Journal [2]. In that
study, previously reported by heartwire, preoperative statins
reduced the risk of 30-day mortality from any cause by 40%, as well
as significantly reduced the risk of stroke and atrial fibrillation.

As Tabata and colleagues point out, however, the role for
preoperative statins in patients without coronary artery disease is
less defined.

In this review, the investigators analyzed data from 1389 patients
undergoing cardiac valve surgery, excluding those undergoing
concomitant CABG surgery and those with a history of MI. Of these
patients, 363 were treated with a statin, including 197 who were
taking atorvastatin and 126 who were taking simvastatin. More than
half of the atorvastatin patients were taking the 10-mg dose,
whereas most simvastatin patients were taking either the 20-mg or 40-
mg dose.

Patients pretreated with statins prior to surgery had a lower rate
of operative mortality--defined as death within 30 days after
surgery--than those not taking statins. The rate of death was 0.8%
among the statin-treated patients compared with 2.3% for the nonˇV
statin-treated group, a difference that translated into a 75% lower
risk of death within 30 days. Statin pretreatment had no effect on
the risk of stroke or perioperative MI rates.

The pleiotropic effects of statins, including improved endothelial
function, enhanced stability of atherosclerotic plaque, decreased
oxidative stress and inflammation, and an inhibited thrombogenic
response are possible biological mechanisms underlying the
beneficial effect, suggest the authors.

"These effects may attenuate the proinflammatory effects of surgical
invasiveness and cardiopulmonary bypass," write Tabata and
colleagues. Further study, however, is needed to confirm the
benefit, as well as to confirm the biological mechanism providing
the reduction in mortality, they add.

Statin Pretreatment Reduces Myocardial Damage

Another study, also appearing in the December 2008 issue of the
Journal of Thoracic and Cardiovascular Surgery, has shown that
pretreatment with statins, specifically rosuvastatin (Crestor,
AstraZeneca), reduces myocardial damage following cardiac surgery
[3].

In total, 200 patients, including those with coronary artery
disease, were randomized to rosuvastatin 20 mg or placebo one week
before coronary surgery. Troponin I, myoglobin, and creatine kinase-
MB mass levels--all markers of myocardial injury--were lower after
surgery among patients pretreated with rosuvastatin. High-
sensitivity C-reactive protein (hs-CRP) levels were also
significantly less elevated; CRP increased 58% in the pretreated
statin-therapy arm and 88% in those randomized to placebo.

In their paper, lead investigator Dr Vito Mannacio (University of
Naples Federico II, Italy) and colleagues point out that large event-
driven studies are needed to assess the advantages of preoperative
statin therapy and that other populations, including those with
diabetes, unstable patients, and patients with extensive coronary
artery disease and decreased left ventricular function, need to be
included in future trials.


Tabata M, Khalpey Z, Cohn LH, et al. Effect of preoperative statins
in patients without coronary artery disease who undergo cardiac
surgery. J Thorac Cardiovasc Surg 2008: 136: 1510-1513. Abstract
Liakopoulos OJ, Choi YH, Haldenwang PL, et al. Impact of
preoperative statin therapy on adverse postoperative outcomes in
patients undergoing cardiac surgery: a meta-analysis of over 30 000
patients. Eur Heart Journal 2008; 29:1548-1559. Abstract
Mannacio V, Iorio D, De Amicis V, et al. Effect of rosuvastatin
pretreatment on myocardial damage after coronary surgery. J Thorac
Cardiovasc Surg 2008: 136:1541-1548. Abstract

A new study suggests that between 1998 and 1999, Medicare managed-
care plans did not have a positive effect on the appropriate use of
carotid endarterectomy (CEA) or outcomes, failing to deliver on
their promise, the researchers say.

"We were surprised that Medicare patients with managed-care
insurance didn't seem to have any benefit as far as lower rates of
overuse of carotid surgery or better outcomes, and in fact, it
looked like they were less likely to be referred to high-volume
providers," lead author Ethan A. Halm, MD, from the Mount Sinai
School of Medicine, in New York, told Medscape Neurology &
Neurosurgery.

"The managed-care plans had the motive, the means, and the
opportunity to try to prevent overuse and selectively refer to high-
quality providers, but they didn't do it," he said.

Their analysis appears in the December issue of the American Journal
of Medical Quality.

CEA a Good Marker

Managed care became the dominant form of healthcare insurance during
the 1990s, with advocates saying that these organizations would
improve quality of care and outcomes while reducing costs. The
improvements would be obtained by, among other interventions,
precertifying elective procedures for their appropriateness and
selective referral of patients to high-quality doctors and
hospitals.

In this analysis, Dr. Halm and colleagues looked to see whether the
promise of managed care had been fulfilled by focusing on its effect
on the use of CEA among Medicare beneficiaries in New York State
between January 1, 1998 and June 30, 1999.

"One of the reasons that we thought this was a good procedure to
look at the impact of managed care is that there have been
randomized, controlled trials outlining who benefits and in what
situations for carotid surgery that have been published for years,
and both the American Heart Association and the American Stroke
Association had set guidelines on what is considered appropriate or
inappropriate patients to have carotid surgery," Dr. Halm said.

In addition, it is "widely known" that high-volume surgeons and
hospitals have better outcomes for carotid surgery, and the managed-
care plans would have access to this information, he pointed out.

In the current study, the researchers looked at whether Medicare
patients who were enrolled in Medicare Choice (MC) managed care
plans (the precursor to Medicare's current MC plans) had lower rates
of inappropriate CEA, had their operations performed more frequently
by high-volume surgeons or hospitals, or had better perioperative
outcomes than those enrolled in fee-for-service (FFS) plans.

Clinical data were abstracted from medical records for 8691 FFS
patients and 897 MC patients undergoing CEA to assess
appropriateness and outcomes, including death and stroke within 30
days of surgery. Patients in both groups had similar indications for
surgery, perioperative risk, and comorbidities, they note.

In the end, there were no differences in inappropriateness between
FFS and MC patients, and MC patients were in fact less likely to be
referred to either a high-volume surgeon or a high-volume hospital
than FFS patients (P < .05).

Nor were there differences between groups in risk-adjusted rates of
death or stroke (OR 0.97; 95% CI, 0.69 ˇV 1.37).

Because CEA is always elective and there are good published data
upon which to make informed decisions, the conclusion must be that
these plans did not, for whatever reason, avail themselves of them,
Dr. Halm said. "This is something they were really set up to do,
that they had access to do, and they just failed to do it."


The researchers also carried out a follow-up survey of plan medical
directors to see whether they had missed plans that were actively
trying to use evidence-based criteria to send patients to high-
quality providers or prevent overuse through utilization-review
mechanisms. "None of them had any procedure-specific utilization
review guidelines they were using," he added.

Instead, he noted, "they seemed largely to be focusing on
contracting based on negotiated cost, not really based on either the
quality of the docs or the hospitals that were delivering the care.
Unfortunately, even though they had financial incentives to prevent
overuse of inappropriate care, they weren't using the second
utilization review mechanism actually set up to do that in a
structured or guideline-driven way."

"Managed Care Lite"


"It's worth saying that this time period represents close to the
apex of managed care's intrusiveness and choice restriction, when
the managed-care backlash was happening," Dr. Halm added. "This
wasn't a test of the 'managed care lite' that we have now, so if
they would have been able to do something, they should have been
doing it back then, but they didn't."

They plan to do some further analyses in this area, he said. "One is
to try to come up with an algorithm that will help neurologists,
surgeons, and referring docs to evaluate which patients are the best
candidates for carotid surgery and to help individualize the short-
term risk of complications for a given patient to help inform
decisions about who should go to surgery and who might be too high
risk."

They are also looking at differences by race in outcomes and
appropriateness, he noted.

The study was supported by the Agency for Healthcare Research and
Quality, the Center for Medicare and Medicaid Services, and by the
Robert Wood Johnson Foundation.

Am J Med Qual. 2008;23:448-456. Abstract

The medical treatment of inoperable chronic thromboembolic pulmonary
hypertension (CTEPH) looks set to be confined to off-label therapy
for the foreseeable future, because the only rigorously conducted
trial of any drug in this specific indication has failed to show a
clear benefit [1].

That trial--Bosentan Effects in Inoperable Forms of Chronic
Thromboembolic Pulmonary Hypertension (BENEFIT)--conducted with the
dual endothelin antagonist bosentan (Tracleer, Actelion
Pharmaceuticals), produced mixed results, with a positive treatment
effect of bosentan on hemodynamics but no improvement in exercise
capacity. The BENEFIT results were first reported at the European
Society of Cardiology (ESC) meeting in Vienna in 2007 and appear in
the December 16, 2008 issue of the Journal of the American College
of Cardiology, by Dr Xavier Jais (Antoine Beclere Hospital, Clamart,
France) and colleagues.

Coauthor Dr Irene M Lang (Medical University of Vienna, Austria),
told heartwire that the published results do not differ from those
she presented at the ESC meeting, but she believes they could be
sufficient for bosentan to be approved for CTEPH. However, the
drug's manufacturer told heartwire it has no plans to pursue an
approval for this indication.

Inoperable CTEPH: A Chronic, Devastating Disease

CTEPH is a form of pulmonary hypertension (PH); PH affects more than
2.5 million people worldwide and is characterized by hypertension in
the pulmonary artery, vein, or capillaries, leading to shortness of
breath, dizziness, fainting, and other symptoms, all of which are
worsened by exertion and can lead to markedly decreased exercise
tolerance, heart failure, and death. The only approved therapies
currently available are for a different form of PH, pulmonary
arterial hypertension, which comprises only a small proportion of PH
cases, so the majority of patients are without approved treatment.

When the BENEFIT results were reported at the ESC meeting, the
discussant, Dr Nazzareno Galie (University of Bologna, Italy), said
this was the first time a randomized controlled study has shown
favorable hemodynamic effects of a targeted therapy in this group of
patients (inoperable CTEPH), but he noted the obvious discrepancy: a
clear decrease in pulmonary vascular resistance was demonstrated,
but there was no change in six-minute walking distance.

Lang told heartwire: "Some people think there is a signal there and
that [bosentan] should be approved for inoperable CTEPH because
there is a bad need for medical treatments for this indication. This
is a chronic, very devastating disease that hits elderly people, and
it's an important problem."

Was the Follow-Up Too Short in BENEFIT?

There are a couple of possible explanations for the discrepancies in
BENEFIT, Galie said in Vienna. First, CTEPH patients are older and
have more comorbidities than patients with PAH, in whom bosentan is
already approved. In addition, the short duration of the study--just
three months of follow-up--may have played a role, he said,
explaining that improvements in exercise capacity can sometimes take
as long as a year to manifest.

Lang takes this up, explaining to heartwire that there is to be
a "statistical look" at the open-label phase of the BENEFIT trial,
but that she does not yet know the results of this phase. She added
that she was not sure whether Actelion Pharmaceuticals would file
for approval of bosentan for inoperable CTEPH on the basis of
BENEFIT, stating that this is a matter "of some debate."

However company spokesperson Roland Haefeli, vice president for
investor relations and public affairs, told heartwire: "In terms of
[inoperable] CTEPH, we currently have no plans for regulatory
proceedings [with bosentan]."

Much Off-Label Use of Bosentan, Sildenafil

Lang told heartwire that whether or not bosentan is actually
approved for inoperable CTEPH, the drug would still be used for this
indication. "I estimate that around 60% of patients with inoperable
CTEPH are treated medically off-label, mainly with sildenafil and
bosentan, which is a very bad situation," she said.

In many countries, sildenafil is the preferred option, she added,
because it is available generically and therefore considerably
cheaper than bosentan. Sildenafil, a phosphodiesterase inhibitor
best known as the erectile-dysfunction therapy Viagra, is approved
for PAH as Revatio (Pfizer). Lang added that there has never been an
appropriately powered trial to assess sildenafil for the CTEPH
indication, "but it appears to do something."

Another new drug is also being investigated for inoperable CTEPH as
well as other forms of PH, she adds. Bayer's riociguat, a soluble
guanylate cyclase stimulator, is about to begin two phase 3 trials:
one in CTEPH and the other in PAH [2]. And phase 2 studies of
riociguat are under way in patients suffering from other forms of PH.

The BENEFIT trial was funded by Actelion Pharmaceuticals. Lang
reports receiving honoraria from Actelion, Bayer-Schering, Pfizer,
AstraZeneca, GlaxoSmithKline, AOP Orphan Pharmaceuticals, the
European Union, and the Austrian government. Disclosures for other
BENEFIT authors are listed in the paper.


Jais X, D'Armini AM, Jansa P, et al. Bosentan for treatment of
inoperable chronic thromboembolic pulmonary hypertension. BENEFIT
(bosentan effects in inoperable forms of chronic thromboembolic
pulmonary hypertension) a randomized, placebo-controlled trial. J Am
Coll Cardiol 2008; 52:2127-2134. Abstract
Bayer Schering Pharma. Bayer reports progress in clinical program
for riociguat [press release]. October 6, 2008. Available at:
http://www.press.bayer.com/baynews/baynews.nsf/id/A2F9D590C44A5879C12
574DA001A936C?Open.