May 2010 Vol. 16 No.

5
From the publishers of
The New England Journal of Medicine

CA RDI OLOGY
Outcomes of Endovascular vs. secondary rupture) were three to four What About
Surgical Repair of AAA times higher in the endovascular-repair Endovascular Repair of
For many patients, an increased risk for late group than in the surgical-repair group, AAA in Inoperable Patients?
complications and higher costs may be a contributing to the increase in late mortality Although endovascular repair reduced the
price worth paying to avoid surgery. and to a higher average total cost of endo- number of aneurysm-related deaths in the
In a new report, investigators for EVAR 1, vascular repair ($23,682) compared with long term, it did not affect overall mortality.
a randomized multicenter trial, provide surgery ($19,010).
In this companion to the EVAR 1 report
the first assessment of both acute and COMMENT (see previous story), investigators exam-
long-term outcomes of endovascular ver- These findings confirm the early superi- ined outcomes in patients with abdominal
sus open surgical repair of abdominal ority of endovascular over open surgical aortic aneurysms (AAAs) ≥5.5 centimeters
aortic aneurysm (AAA). Of 1252 partici- repair of AAA observed in registries and in diameter (mean diameter at baseline,
pants (mean age, 74 years), 91% were smaller randomized trials. They also dem- 6.7 cm) who were considered ineligible for
men. Aneurysms were at least 5.5 centi- onstrate that, compared with surgical re- open surgical repair. The investigators
meters in diameter (mean diameter at pair, endovascular repair is associated with randomized 404 patients (mean age, 77;
baseline, 6.4 cm). more late complications, higher late mor- 86% men) to undergo endovascular repair
Thirty-day mortality was significantly tality, and higher cost. Despite these draw- or no repair. Midterm results were pub-
lower in the endovascular-repair group backs, I believe that the early mortality lished after 4 years of follow-up (JW
(1.8%) than in the surgical-repair group benefit and strong patient preferences for Cardiol Sep 2005, p. 71, and Lancet 2005;
(4.3%; odds ratio, 0.39). However, at a me- the less-invasive procedure will propel 365:2179); this report presents findings
dian follow-up of 6 years, neither overall further growth of endovascular AAA up to 8 years.
nor aneurysm-related mortality differed repair as an alternative to surgery. Reasons for surgery ineligibility in-
between the two groups because of an in- — Howard C. Herrmann, MD cluded coexisting cardiac, renal, or pul-
crease in aneurysm-related deaths after The United Kingdom EVAR Trial Investigators. monary illness. Nonetheless, 70 of the 207
4 years in the endovascular-repair group. Endovascular versus open repair of abdominal patients assigned to no repair eventually
The findings were consistent in analyses aortic aneurysm. N Engl J Med 2010 Apr 11; underwent repair. Thirty-day mortality in
adjusted for age, sex, and aneurysm size. [e-pub ahead of print]. (http://dx.doi.org/10.1056/ the endovascular-repair group was 7.3%.
NEJMoa0909305)
Graft-related complications (including In long-term follow-up, the aneurysm-
related mortality rate was significantly
lower in the endovascular-repair group
CONTENTS (3.6 deaths per 100 person-years) than
in the no-repair group (7.3 deaths per
Outcomes of Endovascular vs. Triple Antiplatelet Therapy After
Surgical Repair of AAA ........................................... 37 Acute Myocardial Infarction .................................. 41 100 person-years). However, total mortal-
What About Endovascular Repair Do Vitamin D and Calcium Supplements ity was high and similar in the two groups
of AAA in Inoperable Patients? ............................. 37 Prevent Cardiovascular Events? ........................... 41 (21–22 deaths per 100 person-years;
Carotid Stenting vs. Endarterectomy: Chromosome 9p21 SNPs estimated survival at 8 years, <30%).
Coming into Focus .................................................... 38 and Heart Disease Risk ........................................... 41
Transcatheter Aortic Valve Implantation: Does Absence of CAC Exclude COMMENT
The Canadian Experience....................................... 38 Obstructive CAD? ..................................................... 42
These findings indicate that in patients
Surgery for Native Valve Endocarditis: Sharing Cardiovascular Risk
considered ineligible for surgery, endovas-
New Data ....................................................... 39 Information with Patients........................................ 42
Clopidogrel and Proton-Pump Inhibitors: A New Agent for Lowering Lipid Levels?................ 42
cular repair of AAA is associated with
More Good News ..................................................... 39 Women from JUPITER . . . .......................................... 43
high early mortality but reduces the risk
Platelet Function Tests and Outcomes Neurohormone-Driven Treatment
for long-term aneurysm-related mortality
After Coronary Stenting .......................................... 40 for Heart Failure ........................................................ 43 compared with no repair. However, the
Intracoronary vs. Intravenous Awareness and Treatment of Atrial Fibrillation ...... 44 high crossover rate in the no-repair group
Eptifibatide for PCI.................................................... 40
is an important study limitation. The

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AN EDITORIALLY INDEPENDENT LITERATURE-SURVEILLANCE NEWSLETTER SUMMARIZING ARTICLES FROM MAJOR MEDICAL JOURNALS. ©2010 MASSACHUSETTS MEDICAL SOCIETY.
ALL RIGHTS RESERVED. DISCLOSURE INFORMATION ABOUT OUR AUTHORS CAN BE FOUND AT http://cardiology.jwatch.org/misc/board_disclosures.dtl
38
EDITOR-IN-CHIEF
Harlan M. Krumholz, MD, SM, Harold H. Hines, Jr.,
Professor of Medicine, Section of Cardiovascular
Medicine, Yale University School of Medicine,
New Haven
EXECUTIVE EDITOR
Kristin L. Odmark
Massachusetts Medical Society
DEPUTY EDITOR
Howard C. Herrmann, MD, Professor of Medicine,
Director, Interventional Cardiology and Cardiac
Catheterization Laboratories, University of
Pennsylvania Medical Center, Philadelphia
ASSOCIATE EDITORS
JoAnne M. Foody, MD, Director, Cardiovascular
Wellness Center, Brigham and Women’s Hospital,
Boston
Joel M. Gore, MD, Edward Budnitz Professor
of Cardiovascular Medicine, University of
Massachusetts, Worcester
Mark S. Link, MD, Associate Professor of Medicine,
New England Medical Center and Tufts University
School of Medicine, Boston
Frederick A. Masoudi, MD, MSPH, Division of
Cardiology, Denver Health Medical Center and
Associate Professor of Medicine, University of
Colorado at Denver
Beat J. Meyer, MD, Associate Professor of
Cardiology, University of Bern; Chief, Division of
Cardiology, Lindenhofspital, Bern, Switzerland
CONTRIBUTING EDITORS
William T. Abraham, MD, Professor of Medicine,
Chief, Division of Cardiovascular Medicine,
The Ohio State University Heart Center, Columbus
Hugh Calkins, MD, Professor of Medicine and
Director of Electrophysiology, The Johns Hopkins
Hospital, Baltimore
FOUNDING EDITOR
Kim A. Eagle, MD, Albion Walter Hewlett Professor
of Internal Medicine and Chief of Clinical
Cardiology, Division of Cardiology, University of
Michigan Medical Center, Ann Arbor
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CARDIOLOGY
lack of a reduction in long-term overall
mortality suggests that practitioners con-
templating endovascular repair in these
patients must carefully weigh not only the
procedural risk but also comorbid condi-
tions that limit overall life expectancy.
— Howard C. Herrmann, MD
The United Kingdom EVAR Trial Investigators.
Endovascular repair of aortic aneurysm in patients
physically ineligible for open repair. N Engl J Med
2010 Apr 11; [e-pub ahead of print]. (http://dx.doi
.org/10.1056/NEJMoa0911056)
Carotid Stenting vs.
Endarterectomy:
Coming into Focus
New findings strengthen the case for endar-
terectomy as the preferred treatment for
carotid artery stenosis.
Although the use of percutaneous stenting
for carotid artery stenosis is increasing,
the procedure is FDA-approved only in
patients at high risk for surgical complica-
tions. In direct comparisons with endar-
terectomy, stenting was associated with
increased rates of periprocedural stroke,
but questions remain about surgical com-
plications, patient selection, timing of in-
tervention, and operator experience. To
address these issues, investigators from
50 centers in Europe, Australia, New
Zealand, and Canada randomized 1713
patients with recently symptomatic carotid
stenosis to undergo stenting or endar-
terectomy. Planned follow-up is 3 years;
we now have results of an interim safety
analysis.
At 120 days after randomization, the
rate of disabling stroke or death was 4.0%
in the stenting group and 3.2% in the end-
arterectomy group, a nonsignificant dif-
ference. However, the incidence of the pri-
mary endpoint — any stroke, death, or
myocardial infarction (MI) — was 8.5%
in the stenting group and 5.2% in the end-
arterectomy group (hazard ratio, 1.69;
95% confidence interval, 1.16–2.45;
P=0·006). Cranial nerve palsy occurred in
1 patient in the stenting group compared
with 45 in the endarterectomy group, and
significantly fewer hematomas occurred
in the stenting group than in the endar-
terectomy group.
In a substudy, 231 patients underwent
preprocedural and postprocedural diffusion-
weighted magnetic resonance imaging
Vol. 16 No. 5
(DWI) to detect ischemic brain lesions.
New postprocedural lesions were found in
50% of patients randomized to stenting
and in 17% of those randomized to endar-
terectomy (odds ratio, 5.21; 95% CI, 2.78–
9.79; P<0.001). Increasing DWI lesion vol-
ume was associated with subsequent
symptomatic stroke. Moreover, DWI lesion
rates were higher in centers where filter-
based cerebral protection devices were used
routinely during stenting than in centers
where these devices were not routinely
used.
COMMENT
Although longer-term follow-up results
of this trial are yet to come, the evidence
increasingly supports endarterectomy as
the first choice for patients with symp-
tomatic carotid stenosis who are suitable
candidates for surgery. The elevated
stroke risk associated with stenting is
underlined by the striking increase in
new ischemic lesions on DWI that ap-
peared to be somewhat related to the use
of cerebral protection devices. Whether
periprocedural strokes have a greater im-
pact on a patient’s quality of life than
periprocedural MIs remains to be seen.
Investigators from a U.S. trial (CREST)
reported at a recent stroke meeting that
stenting and endarterectomy were compa-
rable in their trial, but we reserve judg-
ment until their full published analysis is
available. — Beat J. Meyer, MD
ICSS Investigators. Carotid artery stenting compared
with endarterectomy in patients with symptomatic
carotid stenosis (International Carotid Stenting
Study): An interim analysis of a randomised con-
trolled trial. Lancet 2010 Mar 20; 375:985.
Bonati LH et al. New ischaemic brain lesions on
MRI after stenting or endarterectomy for sympto-
matic carotid stenosis: A substudy of the Interna-
tional Carotid Stenting Study (ICSS). Lancet
Neurol 2010 Apr; 9:353.
Rothwell PM. Carotid stenting: More risky than
endarterectomy and often no better than medical
treatment alone. Lancet 2010 Mar 20; 375:957.
Transcatheter Aortic
Valve Implantation:
The Canadian Experience
New data hone the criteria for evaluating
a new procedure’s risks and benefits.
Transcatheter aortic valve implantation
(TAVI), an emerging alternative to sur-
gery in high-risk patients, is approved for
use in Europe. Now, investigators at six
May 2010
Canadian centers report their pooled
clinical experience implanting the Sapien
transcatheter aortic valve in 339 consecu-
tive patients via either a transfemoral (TF)
or transapical (TA) approach (each used
in ≈50% of procedures). The study was
not industry-funded, although seven of
the authors served as consultants for the
valve manufacturer.
The rate of successful implantation
was 93%, and procedural and 30-day
mortality rates were 2% and 10%, respec-
tively. The mean aortic pressure gradient
decreased from 46 mm Hg to 10 mm Hg,
and mean aortic valve area increased from
0.6 cm2 to 1.6 cm2. Access-site complica-
tions were the most frequent adverse pro-
cedural event, occurring in about 13% of
procedures in both the TF and TA groups.
No structural valve dysfunction occurred
during a median of 8 months of follow-
up. Estimated survival rates at 1 and 2
years were 76% and 64%, respectively, and
were similar in the TF and TA groups.
Predictors of late mortality included post-
procedural sepsis, need for periprocedural
hemodynamic support, pulmonary hyper-
tension, and chronic renal or pulmonary
disease.
COMMENT
This early — but large — multicenter ex-
perience with TAVI provides baseline data
to help clinicians assess potential risks
and outcomes of both TF and TA implan-
tation of the Sapien transcatheter aortic
valve. The findings demonstrate low mor-
tality that is mostly related to comorbid
conditions. Ongoing randomized trials
will help clarify the relative roles of TAVI
and open-heart surgery in high-risk
patients.
— Howard C. Herrmann, MD
Dr. Herrmann has received research support from
Edwards Lifesciences, the manufacturer of the valves
studied in this article.
Rodés-Cabau J et al. Transcatheter aortic valve im-
plantation for the treatment of severe symptomatic
aortic stenosis in patients at very high or prohibitive
surgical risk: Acute and late outcomes of the multi-
center Canadian experience. J Am Coll Cardiol
2010 Mar 16; 55:1080.
Iung B et al. A step forward in the evaluation of
transcatheter aortic valve implantation. J Am Coll
Cardiol 2010 Mar 16; 55:1091.
JWatch.org
Surgery for Native Valve
Endocarditis: New Data
For many patients, early surgery may be
a better strategy than medical therapy.
The current evidence base supporting sur-
gical therapy for infectious endocarditis
consists of observational studies, which are
prone to confounding by both measured
and unmeasured factors and to survival
bias (i.e., the longer patients survive, the
more likely they are to undergo surgery).
In this prospective study involving 1552
patients with native valve endocarditis, in-
vestigators used propensity scores to ac-
count for measured confounders; an in-
strumental variable intended to account for
unmeasured confounders; and survival
time matching to account for survival bias.
The analyses were limited to first epi-
sodes of definite native valve endocarditis
(according to modified Duke criteria) in
either right- or left-sided valves. Intra-
venous drug users were excluded. In the
propensity-matched cohort (mean age,
53.3; 72% men), the most common organ-
isms responsible for infection were Staphy-
lococcus aureus (20%), viridans group
streptococci (19%), enterococcus species
(13%), and coagulase-negative staphylo-
coccus species (13%); 13% were culture
negative. The estimated absolute risk for
in-hospital death was 5.9% lower in early-
surgery recipients than in medical-therapy
recipients after propensity matching and
adjustment for survivor bias and was 11.2%
lower after instrumental-variable analysis.
In subgroup analyses, the estimated ben-
efits of early surgery were significant in pa-
tients with high propensity to receive sur-
gery, paravalvular complications, systemic
embolization, stroke, or S. aureus infection.
In-hospital mortality did not differ signifi-
cantly between patients with and without
heart failure or between patients with and
without valve perforation.
COMMENT
These findings support an early surgical
approach in patients with infectious endo-
carditis similar to those enrolled in the
study — particularly patients with paraval-
vular involvement, stroke, or S. aureus in-
fection. Despite the authors’ best study-
design efforts, the observed benefits of
surgery could reflect selection bias and
confounding. Nonetheless, a randomized
trial of early surgery versus initial medical
39
therapy in patients with endocarditis is
impractical, so more-rigorous evidence is
unlikely to be available anytime soon.
— Frederick A. Masoudi, MD, MSPH
Lalani T et al. Analysis of the impact of early sur-
gery on in-hospital mortality of native valve endo-
carditis: Use of propensity score and instrumental
variable methods to adjust for treatment-selection
bias. Circulation 2010 Mar 2; 121:1005.
Clopidogrel and Proton-Pump
Inhibitors: More Good News
Concurrent use of clopidogrel and PPIs was
safe and effective for patients at high risk for
gastrointestinal bleeding.
Recent prospective trials have shown that
concomitant use of clopidogrel and proton-
pump inhibitors (PPIs) is not associated
with significant adverse cardiovascular
outcomes (Lancet 2009; 374:989). Despite
such findings, warnings that these agents
should not be used in combination persist
from government authorities such as the
U.S. Food and Drug Administration.
To further examine outcomes associ-
ated with concurrent use of these drugs,
investigators conducted a retrospective
cohort study of 20,596 patients (age, ≥30)
who received clopidogrel after being hos-
pitalized for myocardial infarction, coro-
nary revascularization, or unstable angina;
of these patients, 7593 (37%) received
concurrent PPI therapy. The primary
endpoints were hospitalization for gastro-
intestinal (GI) bleeding or serious cardio-
vascular disease complications (myocar-
dial infarction or sudden cardiac death,
stroke, or other cardiovascular-related
death) during the 7-year study period.
The adjusted incidence of hospitali-
zation for GI bleeding was lower for
JOURNAL WATCH ONLINE
• When do you start screening
for Type 2 diabetes? Listen to
the author of a Lancet paper that
analyzes this issue.
• A patient with newly diagnosed
AIDS and suspected Pneumocystis
jirovecii pneumonia develops
renal failure. How would you
manage the case?
JWatch.org/online
40
Correction
In the first sentence of the summary,
“Diabetes and Cardiovascular Events:
Not a Straight Course,” published
in the April 2010 issue of Journal
Watch Cardiology (p. 30), the word
“postprandial” should have been
“preprandial.” We apologize for
the error. — The Editors
patients who received clopidogrel with PPI
therapy than for those who received clopid-
ogrel without PPI therapy (hazard ratio,
0.50; 95% confidence interval, 0.39–0.65).
Also, concurrent PPI therapy was not asso-
ciated with significant excess risk for ad-
verse cardiovascular effects. Of note, for
patients considered to be at highest risk for
GI bleeding, concurrent PPI therapy was
associated with an absolute reduction of
28.5 (95% CI, 11.7–36.9) hospitalizations
for bleeding per 1000 patient-years.
COMMENT
Although limited by its retrospective de-
sign, this study provides further evidence
that the combined use of PPIs and clopid-
ogrel is safe and effective for patients with
heart disease who are deemed to be at high
risk for GI complications and is not associ-
ated with potentially more-formidable car-
diovascular complications. Even though
all PPIs were analyzed for potential risk-
associated events, the majority of patients
(62%) received pantoprazole. Given the
small event rates for the other PPIs,
weighted recommendations for specific
PPIs would not be appropriate.
— David A. Johnson, MD,
Journal Watch Gastroenterology
Ray WA et al. Outcomes with concurrent use of
clopidogrel and proton-pump inhibitors: A cohort
study. Ann Intern Med 2010 Mar 16; 152:337.
Platelet Function Tests and
Outcomes After Stenting
Results of current platelet function tests are
of little value in predicting adverse events.
The efficacy of dual antiplatelet therapy
with aspirin and clopidogrel in patients
undergoing percutaneous coronary inter-
vention is well established. However,
patient response varies widely, and insuffi-
cient platelet inhibition is associated with
increased risk for adverse coronary events.
CARDIOLOGY
Several platelet function assays are avail-
able, but no consensus exists on whether or
how to use them to quantify on-treatment
platelet reactivity in stent recipients.
In a Dutch single-center, prospective
cohort study, investigators compared the
performance of platelet function assays in
1069 patients (mean age, 64; 75% men)
who began dual antiplatelet treatment be-
fore elective stent implantation. If possible,
on-treatment platelet reactivity was meas-
ured by all of the following tests:
• Standard light transmission
aggregometry (LTA)
• VerifyNow P2Y12
• Plateletworks
• Impact-R
• PFA-100 system
The researchers used receiver operating
characteristic analysis to establish cutoff
values for high platelet reactivity.
At 1-year follow-up, the composite rate
of all-cause death, myocardial infarction,
stent thrombosis, and stroke was signifi-
cantly higher in patients with high platelet
reactivity than in those with normal reac-
tivity as assessed by standard LTA (11.7%
vs. 6.0%, P<0.001), VerifyNow (13.3% vs.
5.7%, P<0.001), and Plateletworks (12.6%
vs. 6.1%, P=0.005). Platelet function meas-
ured by the Impact-R and PFA-100 assays
showed no association with outcomes.
However, none of the five tests yielded ac-
curate prognostic information, nor did any
test identify patients at risk for bleeding.
Just over 82% of patients adhered to clopid-
ogrel therapy after 1 year.
COMMENT
In this thorough observational study,
three out of five platelet function tests
identified high on-treatment platelet
reactivity that was associated with adverse
coronary events. Whether tailoring indi-
vidual therapy based on results of these
tests would improve outcomes is un-
known, but this is the focus of several
ongoing clinical trials. Until the results
of these trials are available, monitoring
platelet function seems of little value in
clinical practice. — Beat J. Meyer, MD
Breet NJ et al. Comparison of platelet function tests
in predicting clinical outcome in patients undergoing
coronary stent implantation. JAMA 2010 Feb 24;
303:754.
Vol. 16 No. 5
Intracoronary vs. Intravenous
Eptifibatide for PCI
Intracoronary infusion was better at achieving
GP IIb/IIIa receptor occupancy and, ulti-
mately, post-PCI microvascular perfusion.
Myocardial infarction sometimes compli-
cates percutaneous coronary intervention
(PCI) despite intravenous infusion of a gly-
coprotein (GP) IIb/IIIa inhibitor. To ex-
plore whether intracoronary delivery of the
GP IIb/IIIa inhibitor improves myocardial
perfusion, researchers randomized 43 pa-
tients undergoing PCI for acute coronary
syndromes (ACS) at a single center to
either intravenous or intracoronary admin-
istration of two boluses of eptifibatide
10 minutes apart. Both groups received a
standard maintenance dose intravenously
for 18 hours. Platelet GP IIb/IIIa receptor
occupancy and platelet aggregation were
assessed using blood samples from the
coronary sinus and the femoral artery.
Receptor occupancy, measured 30 to
60 seconds after administration, was sig-
nificantly higher in the intracoronary
group than in the intravenous group, after
both the first bolus (94% vs. 51%) and the
second bolus (99% vs. 91%). Inhibition of
platelet aggregation, measured at 15, 30,
and 60 minutes after the first bolus, was
similar in the two groups. Post-PCI micro-
vascular perfusion, according to a corrected
Thrombolysis in Myocardial Infarction
(TIMI) frame count after administration
of adenosine, improved significantly more
in the intracoronary group than in the
intravenous group. No adverse events were
attributable to intracoronary eptifibatide
administration.
COMMENT
In this small randomized study of ACS
patients, significantly higher GP IIb/IIIa
receptor occupancy was achieved with
intracoronary than with intravenous ad-
ministration of eptifibatide, resulting in
greater post-PCI microvascular perfusion
without compromising safety. According to
editorialists, high local eptifibatide concen-
trations after intracoronary administration
may promote platelet disaggregation. I be-
lieve that if larger trials confirm these find-
ings, intracoronary eptifibatide adminis-
tration will become standard.
— Howard C. Herrmann, MD
May 2010
Deibele AJ et al. Intracoronary eptifibatide bolus
administration during percutaneous coronary
revascularization for acute coronary syndromes
with evaluation of platelet glycoprotein IIb/IIIa
receptor occupancy and platelet function: The
Intracoronary Eptifibatide (ICE) trial. Circulation
2010 Feb 16; 121:784.
Gurbel PA and Tantry US. Delivery of glycoprotein
IIb/IIIa inhibitor therapy for percutaneous coronary
intervention: Why not take the intracoronary high-
way? Circulation 2010 Feb 16; 121:739.
Triple Antiplatelet Therapy After
Acute Myocardial Infarction
Adding cilostazol to clopidogrel plus aspirin
improved biomarkers of platelet inhibition
at 30 days in stent recipients.
High residual platelet reactivity after acute
myocardial infarction (AMI) is associated
with ischemic events, including stent
thrombosis, prompting the development of
new clopidogrel dosing regimens and
more-potent antiplatelet agents. In this
Korean study, 90 AMI patients underwent
coronary stenting and were then random-
ized to receive aspirin plus either standard
clopidogrel therapy (75 mg/day), high-
maintenance-dose clopidogrel therapy
(150 mg/day), or triple therapy consisting
of standard clopidogrel therapy plus the
phosphodiesterase III inhibitor cilostazol
(100 mg twice daily).
The level of platelet inhibition before
hospital discharge was similar in all three
treatment groups. However, at 30-day
follow-up, maximal platelet aggregation
(assessed by light transmission aggregome-
try) was lowest in the triple-therapy group
(33%), compared with the high- and
standard-dose clopidogrel groups (55%
and 60%, respectively). Similarly, platelet
inhibition (assessed by the VerifyNow
P2Y12 assay) was 55% in the triple-therapy
group, 42% in the high-dose clopidogrel
group, and 26% in the standard-dose
clopidogrel group. No major cardiovascu-
lar or bleeding events occurred in any
group.
COMMENT
As evidence of variability in patient re-
sponse to clopidogrel mounts, the race in-
tensifies to find more-effective antiplatelet
regimens with acceptable rates of adverse
effects in patients who receive stents after
acute coronary syndromes. In this study,
the addition of cilostazol to a standard
aspirin–clopidogrel regimen resulted in
JWatch.org
greater platelet inhibition at 30 days than
either a standard-dose or a high-dose
clopidogrel regimen. As an editorialist
notes, we need larger studies (1) to explore
whether this heightened antiplatelet effect
translates into a reduction in ischemic
events, an increase in bleeding events, or
both; and (2) to compare triple antiplatelet
therapy with newer agents, including pra-
sugrel and ticagrelor.
— Howard C. Herrmann, MD
Jeong Y-H et al. Adding cilostazol to dual antiplate-
let therapy achieves greater platelet inhibition than
high maintenance dose clopidogrel in patients with
acute myocardial infarction: Results of the Adjunc-
tive Cilostazol versus High Maintenance Dose Clopid-
ogrel in Patients with AMI (ACCEL-AMI) study.
Circ Cardiovasc Interv 2010 Feb 1; 3:17.
Croce K. Antiplatelet therapy after percutaneous
coronary intervention: Should another regimen be
“TAPT?”. Circ Cardiovasc Interv 2010 Feb 1; 3:3.
Do Vitamin D and Calcium
Supplements Prevent
Cardiovascular Events?
Existing data are insufficient to support
using supplements to prevent cardiovascular
events in the general population.
A growing number of U.S. adults take
vitamin D supplements, calcium supple-
ments, or both. What do we know about
the risks and benefits of these supple-
ments with regard to cardiovascular
disease (CVD) endpoints? To find out,
researchers synthesized data from 17 rel-
evant English-language articles (9 pro-
spective observational studies and 8 ran-
domized trials) that were published from
1966 through July 2009.
Five of the observational studies fo-
cused on kidney-dialysis patients; in these,
CVD mortality rates were consistently lower
among patients who received vitamin D
supplements than among those who did
not. In the other four observational studies,
which focused on healthy people, calcium
supplements showed no benefit with regard
to preventing CVD events. One of these
studies also included data on vitamin D
supplements, which were significantly
associated with reduced coronary heart
disease mortality.
None of the eight randomized trials
was designed specifically to evaluate the ef-
fect of vitamin D or calcium supplementa-
tion on CVD as a primary endpoint. That
said, neither combined calcium and vita-
41
min D supplementation nor calcium sup-
plements alone showed any effect on CVD
incidence. However, in pooled secondary
analyses of the randomized-trial data,
high-dose vitamin D supplements alone
(≈1000 IU/day) yielded a nonsignificant
reduction in CVD risk (relative risk com-
pared with placebo, 0.90; 95% confidence
interval, 0.77–1.05).
COMMENT
The bottom line: No randomized trials
have focused primarily on the effect of vi-
tamin D and calcium supplementation on
CVD endpoints. The best evidence comes
from trials that were designed to explore
other issues. The secondary and observa-
tional evidence we do have suggests a pos-
sible CVD-prevention benefit of vitamin D
and no benefit of calcium supplementation.
As the editorialists note, we still have in-
sufficient evidence to justify widespread
use of vitamin D supplementation in gen-
eral populations. — Joel M. Gore, MD
Wang L et al. Systematic review: Vitamin D and cal-
cium supplementation in prevention of cardiovascular
events. Ann Intern Med 2010 Mar 2; 152:315.
Guallar E et al. Vitamin D supplementation in the
age of lost innocence. Ann Intern Med 2010 Mar 2;
152:327.
Chromosome 9p21 SNPs
and Heart Disease Risk
A meta-analysis clarifies the risk associated
with genotype.
Findings from multiple studies have dem-
onstrated associations between single nu-
cleotide polymorphisms (SNPs) on chro-
mosome 9p21 and cardiovascular disease
(e.g., JW Cardiol Mar 2009, p. 25, and Ann
Intern Med 2009; 150:65; and JW Cardiol
Sep 2007, p. 75, and N Engl J Med 2007;
357:443). To assess the strength and magni-
tude of these associations, investigators
performed a systematic review of 47 dis-
tinct datasets from 22 studies of 9p21 SNPs
and heart disease.
The analysis included 35,872 case
patients and 95,837 controls. Compared
with individuals with one 9p21 risk allele,
individuals with two risk alleles had an
odds ratio (OR) for heart disease of 1.25
(95% confidence interval, 1.21–1.29), and
those with no risk alleles had an OR of 0.80
(CI, 0.77–0.82). Interestingly, the ORs dif-
fered according to age at disease onset.
42
Individuals with two versus one 9p21 risk
allele had an OR of 1.35 for heart disease at
age 55 or younger but an OR of 1.21 for
heart disease at age 75 or younger. Heart
disease risk did not differ between Asians
and whites.
COMMENT
In this meta-analysis, possession of two
risk alleles on chromosome 9p21 was asso-
ciated with a significant 25% overall in-
crease in risk for heart disease that ap-
peared to vary by age at disease onset.
Genetic testing might enable clinicians to
stratify patients at intermediate cardiac risk
for appropriate preventive interventions.
However, the impact of such testing on clini-
cal outcomes remains to be determined.
— JoAnne M. Foody, MD
Palomaki GE et al. Association between 9p21 ge-
nomic markers and heart disease: A meta-analysis.
JAMA 2010 Feb 17; 303:648.
Does Absence of CAC Exclude
Obstructive CAD?
In symptomatic patients, overall sensitivity
of a CAC score of 0 for predicting absence of
obstructive CAD was only 45%.
Evaluation of coronary artery calcium
(CAC) by computed tomography (CT) has
been proposed as a filter before invasive di-
agnostic procedures or hospital admission
in symptomatic patients. This proposal is
based on data suggesting that low CAC
scores are associated with low risk for ob-
structive coronary artery disease (CAD).
In a substudy of an international trial of
angiographic methodologies, investigators
analyzed the prevalence of obstructive
CAD (≥50% stenosis) in 291 symptomatic
patients for whom CAC scores were avail-
able (obtained ≤30 days before angiogra-
phy). Patients with CAC scores >600 were
excluded.
Overall prevalence of obstructive CAD,
as identified by angiography, was 56%, and
14 of the 72 patients (19%) with CAC scores
of 0 had CAD. The overall sensitivity of a
CAC score of 0 for predicting absence of
CAD was 45%. In a vessel-based analysis,
47 of 383 vessels (12%) without calcification
had CAD, whereas 13 of 64 occluded vessels
(20%) had no calcification. Revasculariza-
tion was performed within 30 days of CAC
scoring in 9 patients with scores of 0. The
authors conclude that the absence of CAC
CARDIOLOGY
does not exclude CAD in patients for whom
clinical suspicion is high enough to prompt
referral for angiography.
COMMENT
This study suggests that the absence of coro-
nary artery calcification cannot exclude
obstructive CAD in symptomatic people
who are referred for angiography. This
finding contrasts with those of prior stud-
ies and meta-analyses, in which absence of
calcification was associated with low risk
for CAD and for adverse cardiovascular
events. Clearly, pretest probability plays a
role here, as 95% of this symptomatic popu-
lation was at intermediate or high risk for
CAD by clinical scoring. Nonetheless,
these data call into question one proposed
use for CAC evaluation — as a gatekeeper
to determine who, in a symptomatic popu-
lation with significant clinical suspicion for
CAD, undergoes angiography.
— Kirsten E. Fleischmann, MD, MPH,
Journal Watch General Medicine
Gottlieb I et al. The absence of coronary calcification
does not exclude obstructive coronary artery disease
or the need for revascularization in patients referred
for conventional coronary angiography. J Am Coll
Cardiol 2010 Feb 16; 55:627.
Sharing Cardiovascular Risk
Information with Patients
Patients benefit from getting their risk
scores, but only if it’s done repeatedly or
reinforced with counseling.
Current cardiovascular prevention guide-
lines strongly recommend that clinicians
inform patients of their global risk (i.e.,
give a quantified estimate based on known
risk factors) for coronary heart disease
(CHD). However, evidence to support this
recommendation is lacking. In a systematic
review, investigators identified 20 reports
from 18 studies — mostly randomized or
cluster-randomized trials — of the effect of
informing patients about their global CHD
risk on several outcomes, including the ac-
curacy of patients’ perception of risk, their
intent to start risk-modifying therapy
when appropriate, and their changes in
global risk over time.
The studies varied in size, design, in-
tervention studied, and outcomes of inter-
est. In four studies focused on risk percep-
tion, the findings suggested that providing
global risk information increased patients’
Vol. 16 No. 5
ability to accurately categorize their risk by
approximately 10%. In four studies that ex-
amined intent to start therapy, informing
patients of their risk increased intent by
about 15% to 20%, with greater effects
when counseling was added. In nine stud-
ies focusing on changes in CHD risk over
time, the researchers found that presenting
risk information repeatedly or adding risk
counseling resulted in small reductions in
10-year risk (approximately 0.2%–2.0%),
whereas less-intensive approaches ap-
peared ineffective. The only study that
focused on adherence produced equivocal
results.
COMMENT
Despite the heterogeneity of the studies in
this systematic review, these findings sug-
gest that information and counseling can
motivate patients, which supports the rec-
ommendation that patients be informed of
their global risk for cardiovascular disease.
However, one-time provision of risk infor-
mation might not be effective at all; more-
intensive approaches, including repeat
feedback and concomitant counseling, are
probably necessary. The next challenge is
figuring out how to incorporate such inter-
ventions effectively in busy outpatient
practices.
— Frederick A. Masoudi, MD, MSPH
Sheridan SL et al. The effect of giving global coro-
nary risk information to adults: A systematic review.
Arch Intern Med 2010 Feb 8; 170:230.
Ahmad T and Mora S. Providing patients with global
cardiovascular risk information: Is knowledge power?
Arch Intern Med 2010 Feb 8; 170:227.
A New Agent for Lowering
Lipid Levels?
Eprotirome yielded promising results when
added to statins.
Although statins have dramatically re-
duced the incidence of cardiovascular
events in some populations, many patients
remain at high risk. Thyroid hormone has
favorable effects on lipid levels, but adverse
effects have thwarted previous efforts to
develop effective thyromimetic drugs.
In this 12-week, manufacturer-
sponsored, multicenter, double-blind,
randomized trial, investigators assessed
the safety and efficacy of the thyroid hor-
mone analogue eprotirome in 184 patients
who had serum LDL levels of ≥116 mg/dL
May 2010
despite taking simvastatin (≤40 mg/day) or
atorvastatin (≤20 mg/day) at stable doses.
Patients were assigned to receive placebo
or one of three doses of eprotirome (25, 50,
or 100 μg/day) in addition to their statins.
The primary outcome was change in LDL
level; secondary outcomes included changes
in levels of apolipoprotein B, triglycerides,
and Lp(a) lipoprotein, and adverse heart,
bone, and thyroid effects.
Compared with placebo, all three doses
of eprotirome substantially reduced LDL
levels (mean reduction: 7%, 22%, 28%, and
32% for placebo and low-, medium-, and
high-dose eprotirome, respectively). Simi-
lar reductions occurred in levels of the other
lipoproteins. Triiodothyronine and thyro-
tropin levels did not change, nor were any
heart or bone abnormalities noted. Small,
reversible increases were detected in alanine
aminotransferase levels.
COMMENT
In this small study, eprotirome added to
statin treatment was associated with im-
provements in levels of LDL, apolipopro-
tein B, triglycerides and Lp(a) lipoprotein
in a dose-dependent fashion. No adverse
cardiac effects were seen; however, hepatic
enzyme levels were mildly elevated. These
results are promising, but whether they will
translate into improvements in clinical out-
comes remains to be determined.
— JoAnne M. Foody, MD
Ladenson PW et al. Use of the thyroid hormone a
nalogue eprotirome in statin-treated dyslipidemia.
N Engl J Med 2010 Mar 11; 362:906.
Women from JUPITER . . .
. . . benefited from rosuvastatin as much as
men did.
The role of lipid lowering in primary pre-
vention of cardiovascular events in women
is unestablished because few studies have
included enough women to achieve ade-
quate statistical power. The results of the
JUPITER trial (JW Cardiol Dec 2008, p. 93,
and N Engl J Med 2008; 359:2195), which
included 17,802 men and women, suggest
that rosuvastatin (20 mg daily) benefits pa-
tients whose only cardiovascular risk fac-
tors are age and elevated levels of high-
sensitivity C-reactive protein (hsCRP).
Now, we have findings of a planned sub-
study involving the 6801 JUPITER partici-
pants who were women (aged ≥60).
JWatch.org
Compared with placebo, rosuvastatin
lowered women’s relative risk for major
cardiovascular events by 46%, slightly
more than the 42% reduction seen in men.
The benefit in women was driven predomi-
nantly by a 76% reduction in relative risk
for revascularization or hospitalization for
unstable angina in the rosuvastatin group
compared with the placebo group
(P<0.001). Because overall cardiovascular
risk (and thus absolute risk reduction) was
lower in women than in men, the estimated
number needed to treat with rosuvastatin
for 5 years to prevent one myocardial in-
farction, hospitalization, cardiovascular
death, stroke, or revascularization was
slightly higher for women than for the total
JUPITER population (36 vs. 25). Rosuva-
statin was not associated with significant
increases in rates of myopathy and can-
cer in men or women. The incidence of
physician-reported diabetes, however, was
significantly higher with rosuvastatin than
with placebo in women (1.53 vs. 1.03 per
100 person-years) but not in men (1.36
vs. 1.20 per 100 person-years).
COMMENT
This landmark trial provides important
evidence that women with elevated hsCRP
levels who are otherwise at low cardiovas-
cular risk can benefit from rosuvastatin
treatment. Although the measurement of
hsCRP in cardiac risk assessment remains
controversial, the JUPITER data have al-
ready informed Canadian practice guide-
lines for lipid management as well.
— JoAnne M. Foody, MD
Mora S et al. Statins for the primary prevention of
cardiovascular events in women with elevated high-
sensitivity C-reactive protein or dyslipidemia. Re-
sults from the Justification for the Use of Statins in
Prevention: An Intervention Trial Evaluating Rosu-
vastatin (JUPITER) and meta-analysis of women
from primary prevention trials. Circulation 2010
Mar 9; 121:1069.
Neurohormone-Driven
Treatment for Heart Failure
Findings favor a BNP-guided approach,
particularly in younger patients.
Advocates of the use of patients’ natriuretic
peptide levels to guide heart failure therapy
have been disappointed by the results of a
string of studies that failed to demonstrate
meaningful benefits of this approach
(JW Cardiol Jun 2007, p. 48, and J Am Coll
43
Cardiol 2007; 49:1733; JW Cardiol Mar
2009, p. 21, and JAMA 2009; 301:383; and
JW Cardiol Mar 2010, p. 21, and J Am Coll
Cardiol 2010; 55:53). However, possible
benefits were found with regard to some
secondary outcomes, and findings from
two studies suggested benefits in younger
patient subgroups. Now, investigators have
performed a meta-analysis of eight ran-
domized controlled studies that compared
usual clinical care with therapy guided
by B-type natriuretic peptide (BNP) or
N-terminal pro-BNP level in a total of
1726 outpatients with heart failure.
The studies varied substantially in size,
treatment targets, duration, and primary
endpoints, but all included symptomatic
patients with systolic dysfunction. In the
meta-analysis, the risk for death from any
cause was significantly lower in the BNP-
guided therapy group than in the usual-
care group (relative risk, 0.76). In an analy-
sis of the two studies that yielded separate
results for younger and older patients,
BNP-guided therapy was associated with
significantly reduced all-cause mortality
in patients younger than 75 (RR, 0.52;
P=0.005) but not in older patients (RR,
0.94; P=0.70). The risks for all-cause hos-
pitalization and survival free of hospitali-
zation did not differ significantly between
the two groups in the studies that reported
these endpoints.
COMMENT
These findings are likely to be hailed by
BNP advocates as long-awaited confirma-
tion, while detractors will probably con-
sider the study an attempt to turn lead
into gold. Given the marked variability
among the component studies, this meta-
analysis is inadequate to win my endorse-
ment of the widespread use of BNP levels
to calibrate heart failure therapy. It might
provide some justification for a clinical
trial involving only younger patients with
systolic dysfunction, if anyone is intrepid
enough to undertake such a trial at this
point.
— Frederick A. Masoudi, MD, MSPH
Porapakkham P et al. B-type natriuretic peptide–
guided heart failure therapy: A meta-analysis.
Arch Intern Med 2010 Mar 22; 170:507.
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Which of the following accurately
describes a finding from a recent study
of surgery for native valve endocarditis?
A. The rate of in-hospital death was lower
in medical-therapy recipients than in
surgical-therapy recipients.
B. Patients with Staphylococcus aureus de-
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surgery than from medical therapy.
C. Patients with paravalvular complica-
tions derived no greater benefit from
surgery than from medical therapy.
D. In-hospital mortality was significantly
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than in those without heart failure.
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CME FACULTY
Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

44 CARDIOLOGY Vol. 16 No. 5

Awareness and Treatment
of Atrial Fibrillation
Blacks with AF are less likely than whites
both to know about their condition and to
receive warfarin for it.
In the U.S., blacks are at higher risk for
stroke than whites (Stroke 2004; 35:1557).
To assess racial disparities in the aware-
ness and treatment of atrial fibrillation
(AF), a major risk factor for stroke, inves-
tigators studied data from the REGARDS
study, a U.S. population-based, longitudi-
nal study of 30,239 adults aged ≥45 with
an oversampling of blacks and residents of
the southern “stroke belt.” Participants
were enrolled between January 2003 and
October 2007.
AF was identified on baseline electro-
cardiograms of 432 individuals (20%
black; median age, 74). Of these individ-
uals, more than 80% had at least one addi-
tional CHADS2 (congestive heart failure,
hypertension, age, diabetes, prior stroke
or transient ischemic attack) stroke risk
factor, and 60% were aware they had AF. cians should be particularly vigilant in the
In a univariate analysis, white race, higher diagnosis and treatment of AF in blacks
education levels, and higher incomes were and residents of the southern “stroke belt.”
associated with awareness of AF; in par- — Joel M. Gore, MD
ticular, blacks were less than one third as
Meschia JF et al. Racial disparities in awareness
likely as whites to know of their condition. and treatment of atrial fibrillation: The Reasons
In individuals who were aware that they for Geographic and Racial Differences in Stroke
had AF, race was the only independent (REGARDS) study. Stroke 2010 Apr 1; 41:581.
predictor of warfarin use in both univari-
ate and multivariate analyses. For blacks,
the odds of being treated with warfarin Interested in global health?
were only one quarter those of whites. Want to help solve
international health problems?
COMMENT
In this large cohort, blacks were less likely Join the Global Medicine
than whites to be aware that they had AF Network today!
and less likely than whites to be treated A free and open service
with warfarin. Furthermore, the CHADS2 established by the Massachusetts
score, widely used to guide prescription of Medical Society to create personal
oral anticoagulants, was not an indepen- and professional contacts among
individuals and organizations
dent predictor of warfarin use, possibly
working in international health
reflecting deficiencies in evidence-based
and global medicine.
care. These results suggest that under-
treatment of AF contributes to the in- www.globalmedicine.org
creased risk for stroke in blacks. Clini-