January 2010 Vol. 16 No.

1
From the publishers of
The New England Journal of Medicine

CA RDI OLOGY
ARBITER 6-HALTS: ezetimibe group and by 10 mg/dL in the important outcomes
A Surprise Knockout niacin group. The mean HDL level de- of large trials of ezetimibe will not be
Niacin’s clear win over ezetimibe as an creased by 3 mg/dL in the ezetimibe group available for many years. In the meantime,
adjunct to statin therapy challenges and increased by 8 mg/dL in the niacin ezetimibe should be a drug of last resort,
assumptions about lipid management. group. if it is used at all.
To compare the effects of niacin versus Niacin, but not ezetimibe, was associ- — Harlan M. Krumholz, MD, SM
ezetimibe when added to statin treatment, ated with a significant reduction in CIMT. Taylor AJ et al. Extended-release niacin or ezetimibe
investigators conducted a randomized, In the ezetimibe group, paradoxically, and carotid intima–media thickness. N Engl J Med
open-label trial with blinded adjudication of greater decreases in LDL levels were asso- 2009 Nov 26; 361:2113.
endpoints. All patients were already taking ciated with greater increases in CIMT.
a statin and had LDL levels <100 mg/dL, The rate of major cardiovascular events ARBs in Heart Failure: What
HDL levels <55 mg/dL, and coronary heart was higher in the ezetimibe group than Difference Does a Dose Make?
disease or a risk equivalent (e.g., diabetes or in the niacin group (5% vs. 1%; P=0.04).
High-dose losartan yielded small but signifi-
a 10-year Framingham risk score of ≥20%). cant improvements in clinical outcomes,
COMMENT
The primary endpoint was change in carotid compared with a lower dose.
In this small trial, niacin was superior to
intima–media thickness (CIMT) after 14
ezetimibe in high-risk patients on statin A growing body of data suggests that
months. The industry-funded, investigator-
monotherapy. These findings do not deliver angiotensin-receptor blocker doses higher
initiated trial was terminated early on the
a final verdict on ezetimibe. (Nor do they than those currently given could achieve
basis of results of prespecified interim
prove that the niacin-statin combination clinical benefits in patients with heart fail-
analysis.
confers clinical benefit beyond statin ure. In the international, double-blind,
A total of 208 participants (mean age, monotherapy in this patient population.) manufacturer-sponsored and manufac-
65; 80% men) had 14-month endpoint However, they add to concerns about a turer-administered HEAAL study, 3846
data. At baseline, mean levels of LDL and medication that continues to be quite patients with NYHA class II–IV heart
HDL were 82 mg/dL and 42 mg/dL, re- popular, despite a lack of evidence that its failure symptoms, LV ejection fractions
spectively. At 14 months, the mean LDL ability to reduce LDL levels translates into ≤40%, and intolerance to ACE inhibitors
level had decreased by 18 mg/dL in the patient benefits. Unfortunately, patient- were randomly assigned to receive either
150 mg or 50 mg of losartan daily. Most
patients were taking standard therapies
CONTENTS for heart failure at enrollment, including
diuretics (76%), beta-blockers (72%),
SUMMARY & COMMENT In-Hospital Mortality After MI: and aldosterone blockers (38%).
ARBITER 6-HALTS: Vive la Différence? ..................................................... 4
A Surprise Knockout ...................................... 1 Self-Management for Hypertension ......................... 5
During a median follow-up of
ARBs in Heart Failure: Lipids, Apolipoproteins, and Vascular Disease:
4.7 years, high-dose losartan significantly
What Difference Does a Dose Make? .................... 1 What to Measure? ..................................................... 5 reduced the rate of the primary composite
Should Patients with Heart Failure Folic Acid and Cancer................................................... 6 outcome of death or hospital admission
“Pump” Iron?............................................................... 2
Revascularization Is Ineffective for heart failure, compared with low-dose
LV Assistance for End-Stage Heart Failure: for Atherosclerotic Renal Artery Stenosis ............ 6
Have We Reached Our Destination? ...................... 2 losartan (43% vs. 46%; P=0.027); both
Two Clopidogrel Loading Doses Compared components of the composite endpoint
Again I Say, Again: Avoid Pacing the in Patients with STEMI .............................................. 6
Right Ventricle! ........................................................... 3 contributed to the overall result. The
Cangrelor Is Not the New Champion......................... 7
Primary PCI for STEMI: How Important composite outcome of death or cardiovas-
Are Hospitals’ Procedure Volumes?....................... 3 CLINICAL PRACTICE GUIDELINE WATCH
USPSTF Doesn’t Recommend Using cular admission occurred in 54% of pa-
Reducing Door-to-ECG Time Without
Nontraditional Risk Factors for CHD Risk .............. 7 tients in the high-dose group and in 57%
Increasing ED Staffing............................................... 4
Investigation of Incidental Findings
in the low-dose group. The rate of study-
on Cardiac CT .............................................................. 4 drug discontinuation during follow-up

JOURNAL WATCH (AND ITS DESIGN) IS A REGISTERED TRADEMARK OF THE MASSACHUSETTS MEDICAL SOCIETY.
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
2 CARDIOLOGY
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
MASSACHUSETTS MEDICAL SOCIETY
Christopher R. Lynch, Vice President for
Publishing; Alberta L. Fitzpatrick, Publisher
Betty Barrer, Christine Sadlowski, Sharon S.
Salinger, Staff Editors; Kara O’Halloran, Copy
Editor; Misty Horten, Layout; Matthew O’Rourke,
Director, Editorial Operations and Development;
Art Wilschek, Christine Miller, Lew Wetzel,
Advertising Sales; William Paige, Publishing
Services; Bette Clancy, Customer Service
Published 12 times a year. Subscription rates per
year: $119 (U.S.), C$166.67 (Canada), US$165 (Intl);
Residents/Students/Nurses/PAs: $69 (U.S.), C$96.19
(Canada), US$80 (Intl); Institutions: $219 (U.S.),
C$256.19 (Canada), US$230 (Intl); individual print
only: $89 (U.S.). Prices do not include GST, HST,
or VAT. In Canada remit to: Massachusetts Medical
Society C/O #B9162, P.O. Box 9100, Postal Station F,
Toronto, Ontario, M4Y 3A5. All others remit to:
Journal Watch Cardiology, P.O. Box 9085, Waltham,
MA 02454-9085 or call 1-800-843-6356. E-mail
inquiries or comments via the Contact Us page at
JWatch.org. Information on our conflict-of-interest
policy can be found at JWatch.org/misc/conflict.dtl
was substantial (28% and 27% in the
high- and low-dose groups, respectively).
Adverse events, including hyperkalemia,
hypotension, and renal impairment,
were significantly more common in the
high-dose group than in the low-dose
group.
COMMENT
These findings suggest a favorable effect
of 150 mg of losartan, compared with
50 mg, in patients with systolic heart fail-
ure, although the benefit came at a cost
of adverse events. As an editorialist points
out, we cannot assume similar results in
patients who can tolerate ACE inhibitors,
and this trial does not compare a high-
dose ARB with a high-dose ACE inhibi-
tor. We are well reminded, however, to
uptitrate all medications to the highest
efficacious dose (according to the best
available trial evidence), as tolerated by
the patient. — Joel M. Gore, MD
Konstam MA et al. Effects of high-dose versus
low-dose losartan on clinical outcomes in patients
with heart failure (HEAAL study): A randomised,
double-blind trial. Lancet 2009 Nov 28; 374:1840.
Krum H. Optimising management of chronic heart
failure. Lancet 2009 Nov 28; 374:1808.
Should Patients with Heart
Failure “Pump” Iron?
In a randomized trial, intravenous iron
improved symptoms, even in patients
without anemia.
Anemia is common and associated with
adverse outcomes in patients with heart
failure. Iron deficiency is also common in
heart failure, sometimes in the absence of
frank anemia. Although results of small
trials suggest benefits of iron supplemen-
tation for iron deficiency in heart failure
patients, definitive evidence has been
lacking.
In the manufacturer-sponsored
FAIR-HF trial, 459 patients with systolic
heart failure, iron deficiency, and NYHA
class II–III symptoms were randomized in
a 2:1 ratio to receive intravenous ferric car-
boxymaltose or placebo. Notably, half of
the patients had normal baseline hemoglo-
bin levels, and patients with clinically sig-
nificant renal dysfunction were excluded.
Participants were treated for 24 weeks:
weekly until estimated iron repletion was
achieved and monthly thereafter.
Vol. 16 No. 1
Iron recipients were significantly
more likely than placebo recipients to im-
prove clinically, as measured by the pri-
mary endpoints — Patient Global Assess-
ment (odds ratio, 2.51) and NHYA
classification (OR, 2.40) — as well as by
health-related quality of life and 6-minute
walk distance. The benefits were apparent
by 4 weeks and were similar in patients
with and without anemia. Aside from a
higher rate of injection-site discomfort or
discoloration (6 iron recipients vs. zero
placebo recipients), adverse events did not
differ significantly between the two
groups.
COMMENT
In this trial, intravenous ferric carboxy-
maltose significantly improved symptoms
and sense of well-being in patients with
systolic heart failure, suggesting that iron
has benefits beyond anemia treatment per
se (e.g., improved muscle energetics). We
don’t know if (1) oral iron — considerably
less expensive and more convenient than
intravenous iron — confers the same ben-
efits, (2) all intravenous iron preparations
are equivalent in this context (ferric car-
boxymaltose is currently unavailable in
the U.S.), or (3) this therapy benefits pa-
tients with clinically important renal dys-
function, which also commonly causes
anemia. Nonetheless, these provocative
findings suggest possible benefits of
screening for and treating iron deficiency
in patients with heart failure — even those
without anemia.
— Frederick A. Masoudi, MD, MSPH
Anker SD et al. Ferric carboxymaltose in patients
with heart failure and iron deficiency. N Engl J
Med 2009 Nov 17; [e-pub ahead of print].
(http://dx.doi.org/10.1056/NEJMoa0908355)
Dec GW. Anemia and iron deficiency — New thera-
peutic targets in heart failure? N Engl J Med 2009
Nov 17; [e-pub ahead of print]. (http://dx.doi
.org/10.1056/NEJMe0910313)
LV Assistance for End-Stage
Heart Failure: Have We Reached
Our Destination?
A continuous-flow device achieves impressive
results in a randomized trial.
LV assistance has been proposed as per-
manent, or destination, therapy for pa-
tients with advanced heart failure who are
not candidates for cardiac transplantation.
Findings from the REMATCH trial
January 2010
(JW Cardiol Feb 2002, p. 20, and N Engl
J Med 2001; 345:1435) provided proof of
concept for this approach, demonstrating
improved survival in end-stage heart
failure patients randomized to receive a
pulsatile-flow LV assist device (LVAD)
versus ongoing medical treatment. However,
survival in the LVAD group was limited
by device complications, including stroke,
infection, and the need for reoperation. In
a manufacturer-sponsored, randomized
controlled trial, investigators compared
an FDA-approved pulsatile-flow LVAD
with a second-generation, investigational
continuous-flow LVAD.
Two hundred patients with advanced
heart failure who were not considered
candidates for cardiac transplantation
were randomized in a 2:1 ratio to receive
the continuous-flow or the pulsatile-flow
LVAD. The primary composite endpoint
was survival free from disabling stroke and
device repair or replacement at 2 years.
Secondary endpoints included survival,
frequency of adverse events, quality-of-life
changes, and functional capacity. Sixty-
two patients (46%) in the continuous-flow
group achieved the primary endpoint
compared with 7 patients (11%) in the
pulsatile-flow group (hazard ratio, 0.38;
95% confidence interval, 0.27–0.54;
P<0.001). Continuous-flow device recipi-
ents had a better actuarial survival rate at
2 years than pulsatile-flow device recipients
(58% vs. 24%; P=0.008), as well as fewer
adverse events and device replacements.
COMMENT
A new, continuous-flow LVAD is superior
to the currently available pulsatile-flow de-
vice at improving morbidity and mortality
in end-stage heart failure patients who are
not candidates for cardiac transplantation.
Good candidates for such destination thera-
py are patients with very low LV ejection
fractions, advanced heart failure symptoms,
and recurrent hospitalization or inotropic
support. — William T. Abraham, MD
Slaughter MS et al. for the HeartMate II Investigators.
Advanced heart failure treated with continuous-flow
left ventricular assist device. N Engl J Med 2009
Dec 3; 361:2241.
Fang JC. Rise of the machines — Left ventricular
assist devices as permanent therapy for advanced
heart failure. N Engl J Med 2009 Dec 3; 361:2282.
JWatch.org
Again I Say, Again:
Avoid Pacing the Right Ventricle!
Findings from yet another study show the
detriment of RV pacing.
Biventricular pacing, or cardiac resynchro-
nization therapy (CRT), has been shown to
benefit patients with reduced LV ejection
fractions and NYHA class III heart failure
symptoms and, more recently, those with
NYHA class I or II symptoms (JW Cardiol
Oct 2009, p. 77, and N Engl J Med 2009;
361:1329). By contrast, although RV-only
pacing has long been suspected of causing
LV dysfunction and is thought to have re-
sulted in worsened heart failure in the
DAVID trial (JW Cardiol Apr 2003, p. 31,
and JAMA 2002; 288:3115), evidence of its
detrimental effects is relatively scarce.
In a multicenter, manufacturer-
sponsored trial of RV pacing versus CRT
in patients with preserved LV function,
177 patients received a CRT device and
were randomized to programmed RV-only
or biventricular pacing. The indication for
pacing was advanced atrioventricular block
in 104 participants (59%) and sinus node
dysfunction in 73 (41%). The study proto-
col called for obligatory RV pacing in all
patients assigned to it, even those with
intact AV conduction systems.
At 12 months of follow-up, the aver-
age percentage of patients with ventricular
pacing was 98% in the CRT group and
97% in the RV-pacing group (P=0.95).
Mean LVEF was significantly lower in the
RV-pacing group than in the CRT group
(54.8% vs. 62.2%), although no between-
group differences were seen in 6-minute
walk distance, hospitalization for heart
failure, or quality-of-life measures.
COMMENT
These results add to those of a series of
studies demonstrating the potential detri-
ment of RV pacing. However, this study’s
findings are weakened by the protocol-
mandated RV pacing, which is not the
standard of care for patients with intact
AV conduction systems, and by the lack of
between-group differences in clinical out-
comes. These results should not change
current recommendations, in which pacing
the right ventricle is avoided if possible, but
CRT is not indicated in patients with pre-
served LV function. — Mark S. Link, MD
3
Yu C-M et al. Biventricular pacing in patients with
bradycardia and normal ejection fraction. N Engl J
Med 2009 Nov 26; 361:2123.
Primary PCI for STEMI:
How Important Are Hospitals’
Procedure Volumes?
Lower-than-recommended procedure
volume was common but not associated
with elevated mortality.
Guidelines recommend that at hospitals
offering primary percutaneous coronary
intervention for patients with ST-segment-
elevation MI, at least 36 such procedures
— and at least 200 angioplasties — should
be performed per year. To assess the asso-
ciation between volume of primary PCI
and patient outcomes, investigators identi-
fied 29,513 patients hospitalized for STEMI
who underwent primary PCI at 166 hospi-
tals participating in the American Heart
Association’s Get With The Guidelines
quality-improvement registry from 2001
through 2007.
The participating hospitals’ annual
primary PCI volumes ranged from 9 to
224 and were characterized as high (>70),
medium (36–70), or low (<36). Sixty-five
percent of hospitals met the guideline rec-
ommendation of 36 procedures per year.
High-volume hospitals had shorter door-
to-balloon times than medium- or low-
volume hospitals (median times, 88, 90,
and 98 minutes, respectively). Patients at
low-volume hospitals were less likely than
those at high-volume hospitals to receive
smoking-cessation counseling or prescrip-
tions for aspirin, beta-blockers, and ACE
inhibitors or angiotensin-receptor blockers
at discharge.
JOURNAL WATCH ONLINE
• Ring in the new year with our
exclusive in-depth analysis
of the most important topics
in General Medicine in 2009.
Available January 1.
• Coming January 5, only at
JWatch.org: Year in Review
discussions of the most
important developments in
Psychiatry and in HIV/AIDS
Clinical Care.
JWatch.org/online
4 CARDIOLOGY
In-hospital mortality was 3.2% overall,
with the lowest rate at the high-volume
hospitals (3.0%, vs. 3.2% and 3.9% in
medium- and low-volume hospitals, re-
spectively). In an adjusted analysis, mor-
tality did not differ significantly among
the three groups. Duration of stay was also
similar in all groups.
COMMENT
These findings indicate that many hospi-
tals do not meet the guideline recommen-
dations for primary PCI volume. However,
the researchers failed to detect an associa-
tion between volume and patient outcomes
in this sample of hospitals, which partici-
pate in a national quality-improvement
initiative and comprise about 10% of U.S.
hospitals that offer PCI. We do not know
whether these results can be generalized to
other hospitals.
— Harlan M. Krumholz, MD, SM
Kumbhani DJ et al. for the Get With the Guidelines
Steering Committee and Investigators. Association of
hospital primary angioplasty volume in ST-segment
elevation myocardial infarction with quality and
outcomes. JAMA 2009 Nov 25; 302:2207.
Reducing Door-to-ECG Time
Without Increasing ED Staffing
Training registration clerks to page dedicated
ECG technicians when patients present with
chest pain significantly reduced time to ECG.
Guidelines from the American College of
Cardiology and the American Heart Asso-
ciation state that an electrocardiogram
should be obtained within 10 minutes after
patients present with chest pain. These au-
thors evaluated the effect on time to ECG
of an intervention that involved training
registration clerks to page dedicated emer-
gency department ECG technicians when
patients present with chest pain or other
complaints associated with acute coronary
syndromes. The technician immediately de-
livered the ECG to an emergency physician
for interpretation. Before the intervention,
patients were registered by clerks and tri-
aged by nurses before an ECG was ordered.
The authors compared data for 313
consecutive adult patients who presented
with chest pain during the month before
the intervention and 405 such patients who
presented during the month after at a single
urban academic emergency department
(ED). The proportion of patients for whom
an ECG was obtained within 10 minutes
increased significantly from 16% before the
intervention to 64% after. Median time to
ECG decreased from 16 to 9 minutes. An
ECG was obtained within 10 minutes in
none of four patients with ST-segment-
elevation myocardial infarction before
the intervention and in all seven patients
with STEMI after the intervention. (Two
STEMI patients before the intervention
had dehydration or shortness of breath as
the chief complaint, whereas all seven
STEMI patients after the intervention had
chest pain as the chief complaint.)
COMMENT
As ED volume increases, adhering to the
10-minute presentation-to-ECG guideline
for patients with chest pain becomes more
challenging. This simple intervention of-
fers a starting point, but the goal must be
ECGs within the 10-minute window for
100% of patients. Meeting that goal re-
quires constant measurement and adjust-
ment, willingness to deploy or dedicate
additional staff, and detailed review of
every significant failure.
— Diane M. Birnbaumer, MD, FACEP,
Journal Watch Emergency Medicine
Takakuwa KM et al. A method for improving arrival-
to-electrocardiogram time in emergency department
chest pain patients and the effect on door-to-balloon
time for ST-segment elevation myocardial infarction.
Acad Emerg Med 2009 Oct; 16:921.
Investigation of Incidental
Findings on Cardiac CT
These findings are clinically relevant in only
a minority of cases and are associated with
risks and costs.
Cardiac computed tomography (CCT),
which is increasingly popular for evaluat-
ing patients with coronary calcification
and arterial disease, often produces non-
cardiac incidental findings. To evaluate
the incidence, clinical importance, and
costs of these incidental findings, re-
searchers studied 966 consecutive patients
who underwent CCT during 12 months at
a single Canadian institution.
Incidental findings were noted in 401
patients (41.5%); of these, 12 were deemed
to be clinically significant (e.g., 5 thrombi,
1 aortic dissection that was not clinically
suspected, 1 ruptured breast implant),
and 68 were deemed to be indeterminate
(e.g., 34 noncalcified pulmonary nodules
<1 cm, 11 larger lung nodules, 9 liver nod-
Vol. 16 No. 1
ules/cysts). After a mean 18-month
follow-up, no indeterminate finding be-
came clinically significant, although three
malignancies were diagnosed after sub-
sequent diagnostic tests. Noncardiac and
cancer death rates were not significantly
different between patients with and with-
out incidental findings. In all, 164 addi-
tional diagnostic tests and procedures
were performed in the 80 patients with in-
determinate or clinically significant inci-
dental findings, including 1 patient who
suffered empyema and abdominal ab-
scesses as a complication of transthoracic
biopsy.
COMMENT
This study highlights the dilemma posed
by incidental findings that are a common
byproduct of cardiac CT. These findings
are clinically relevant in only a few cases
but are associated with real risks and costs
as well as benefits. Editorialists suggest
one way of dealing with the issue: Ask
patients about their concerns and prefer-
ences and then reconstruct images of and
evaluate noncardiac structures only if
patients provide informed consent. In
the meantime, as CCT becomes more
widespread, individual clinicians will
continue to struggle with the best way
to address “incidentalomas.”
— Kirsten E. Fleischmann, MD, MPH,
Journal Watch General Medicine
MacHaalany J et al. Potential clinical and economic
consequences of noncardiac incidental findings on
cardiac computed tomography. J Am Coll Cardiol
2009 Oct 13; 54:1533.
Hlatky MA and Iribarren C. The dilemma of inci-
dental findings on cardiac computed tomography.
J Am Coll Cardiol 2009 Oct 13; 54:1542.
In-Hospital Mortality After MI:
Vive la Différence?
Sex differences in survival to discharge are
getting smaller.
Previous prospective, observational data
from the National Registry of Myocardial
Infarction (NRMI) have shown that the risk
for death after MI is higher in women than
in men, particularly in younger patients
(N Engl J Med 1999; 341:217). In a new
NRMI study, researchers examined whether
that sex difference persists.
The analysis included 916,380 patients
hospitalized with confirmed acute coro-
nary ischemia from 1994 through 2006.
January 2010
During this period, the prevalence of many
coexisting conditions increased across age
and sex subgroups, and the proportion of
patients with ST-segment-elevation MI
decreased. Diabetes, heart failure, and
stroke were more prevalent among younger
women than among younger men.
Over time, in-hospital mortality rates
declined across the age spectrum, generally
more in women than in men. The decline in
mortality was most pronounced in women
younger than 55 (from 5.1% in 1994–1995
to 2.4% in 2004–2006). Within the <55 age
group, the unadjusted female-to-male odds
ratio for death declined from 1.93 in 1994–
1995 to 1.34 in 2004–2006, although it re-
mained statistically significant. Notably,
multivariable analyses showed that the nar-
rowing of the risk between young women
and young men resulted from changes in
coexisting illnesses and clinical features at
admission rather than in processes of care.
COMMENT
Sex differences in in-hospital mortality after
MI have narrowed over time, particularly
among younger people. However, the analy-
sis suggests that this temporal trend stems
from concomitant changes in clinical pro-
files rather than from improvements in care.
Furthermore, changes in practice patterns
(e.g., shorter hospital stays and more fre-
quent use of skilled nursing facilities) might
result in lower in-hospital mortality rates
that do not reflect improved longer-term
outcomes. Gratifying as these data are, there
is still ample room for the medical commu-
nity to do better.
— Frederick A. Masoudi, MD, MSPH
Vaccarino V et al. Sex differences in mortality after
acute myocardial infarction: Changes from 1994 to
2006. Arch Intern Med 2009 Oct 26; 169:1767.
Self-Management
for Hypertension
Two interventions helped patients reach
blood pressure goals.
Because many hypertensive patients do
not achieve good control of blood pres-
sure, strategies are needed beyond physi-
cian adjustment of medication based on
office-visit blood pressure measurements.
In a study of two self-management strat-
egies, North Carolina investigators ran-
domized 636 patients with hypertension
to receive bimonthly nurse-delivered
JWatch.org
telephone calls, with tailored behavioral
counseling focused on medication adher-
ence; thrice-weekly home blood pressure
measurement, with values recorded in
logs (logs were mailed to primary care
providers every 2 months); both interven-
tions; or usual care. Blood pressure con-
trol was defined as systolic blood pressure
(SBP) <140 mm Hg and diastolic blood
pressure (DBP) <90 mm Hg for patients
without diabetes, and SBP <130 mm Hg and
DBP <80 mm Hg for patients with diabetes.
At 24 months, blood pressure control
was achieved by 11% more patients in the
combined-intervention group than in the
usual-care group. The drop in SBP from
baseline was also significant only for the
combined-intervention group (3.9 mm Hg
lower than usual care alone).
COMMENT
To achieve better outcomes for patients
with chronic conditions, we need to go be-
yond what we can do in the confines of of-
fice visits. Implementation of these two
strategies for management of hypertension
seems feasible, as long as resources are
available. Similar strategies likely would
work for other chronic conditions.
— Richard Saitz, MD, MPH, FACP, FASAM,
Journal Watch General Medicine
Bosworth HB et al. Two self-management interven-
tions to improve hypertension control: A random-
ized trial. Ann Intern Med 2009 Nov 17; 151:687.
Lipids, Apolipoproteins,
and Vascular Disease:
What to Measure?
Total and HDL cholesterol and apolipopro-
teins, fasting or not, are equally accurate.
To assess vascular disease risk conferred by
serum lipids, we typically measure fasting
levels of total cholesterol, HDL, and triglyc-
erides, and the laboratory calculates LDL
from the other results. However, an alter-
native is to measure only total cholesterol
and HDL (neither measurement requires
fasting); subtracting HDL from total cho-
lesterol yields the so-called non-HDL
cholesterol, which roughly parallels LDL.
Less commonly measured predictors are
apolipoproteins (apo) A1 and B.
To investigate the capacity of these
markers to predict vascular risk, researchers
collapsed 68 long-term studies of lipids
and vascular disease, mostly from Europe
5
and North America, with a total popula-
tion of 300,000 patients and mean follow-
up of about 6 years. Risk for coronary dis-
ease, adjusted for several demographic and
clinical risk factors, was associated with
higher values of non-HDL and LDL, higher
ratios of non-HDL/HDL and apo B/A1,
and lower values of HDL. Risks for coro-
nary disease and ischemic stroke were not
associated with triglyceride levels, and risk
for ischemic stroke was only weakly associ-
ated with HDL or non-HDL levels. No dif-
ference in risk prediction was observed be-
tween fasting and nonfasting measurements.
COMMENT
Because many physicians have relatively
easier access to standard cholesterol pro-
files than to apolipoprotein measurements,
because patients appreciate the convenience
of nonfasting tests, and because risk was
similar for all lipid parameters including
non-HDL or directly measured LDL, one
efficient approach supported by this study
is to use nonfasting cholesterol profiles
(without triglyceride or LDL levels) for
assessing risk for vascular disease. Although
some clinicians already use this approach,
considerable effort will be required to
change the current culture of lipid manage-
ment, with its heavy emphasis on LDL.
— Thomas L. Schwenk, MD,
Journal Watch General Medicine
Di Angelantonio E et al. for the Emerging Risk
Factors Collaboration. Major lipids, apolipoproteins,
and risk of vascular disease. JAMA 2009 Nov 11;
302:1993.
Save time and stay informed
with a FREE daily e-mail alert.
• Relevant information and practical
intelligence you can use
• Brief reviews of the medical news
that affects your practice
• Gleaned from government
agencies, journals, and other
key sources
• Delivered to your e-mail box each
weekday by 7:30 a.m. ET
Visit JWatch.org
to sign up FREE
6 CARDIOLOGY
Folic Acid and Cancer
Cancer incidence and mortality rose with
vitamin use.
Since 1998, when the U.S. mandated folic
acid (FA) fortification of flour and other
grain foods to lower risk for neural tube
defects, FA intake has risen dramatically.
Supplementation with FA and other B vita-
mins also has been proposed to prevent
cardiovascular disease (by lowering homo-
cysteine levels), although no studies yet
have shown such benefit. To examine a
possible association between FA treatment
and cancer risk, researchers combined the
results of two Norwegian trials of vitamin
B supplementation in nearly 7000 patients
with ischemic heart disease. More than
70% of patients were current or former
smokers. Norway does not mandate FA
fortification of foods.
Patients were randomized to one of four
daily regimens: FA (0.8 mg) plus vitamin
B12 (0.4 mg) plus vitamin B6 (40 mg); FA
plus vitamin B12; vitamin B6 alone; or pla-
cebo. After a median of 78 months of treat-
ment and follow-up, risk for developing
cancer in groups that were taking FA com-
pared with those that were not taking FA
was 21% higher (number needed to harm
[NNH], about 63). Risk for dying from can-
cer was 38% higher in the FA groups (NNH,
91), and, for all-cause mortality, risk was
18% higher (NNH, 43). Lung cancer inci-
dence accounted for much of the risk for
developing or dying from cancer.
COMMENT
Because folic acid impairs immune surveil-
lance of cancer cells and might stimulate the
growth of established cancers, these find-
ings have a biological basis; indeed, in an-
other 2009 trial, folic acid supplementation
was associated with excess risk for prostate
cancer (J Natl Cancer Inst 2009; 101:432).
Differences in baseline FA intake and smok-
ing history might account for the results of
earlier studies that did not show elevated
risk for cancer. In any case, these results
provide further reason not to recommend
FA supplements for most middle-aged or
older adults. The issue of what to do about
FA fortification of foods is much more com-
plicated, but editorialists believe that U.S.
fortification places the population well with-
in safe limits.
— Thomas L. Schwenk, MD,
Journal Watch General Medicine
Ebbing M et al. Cancer incidence and mortality
after treatment with folic acid and vitamin B12.
JAMA 2009 Nov 18; 302:2119.
Drake BF and Colditz GA. Assessing cancer preven-
tion studies — A matter of time. JAMA 2009 Nov
18; 302:2152.
Revascularization Is Ineffective
for Atherosclerotic Renal Artery
Stenosis
This procedure conferred substantial risk
without clinical benefit.
Revascularization for atherosclerotic renal
artery stenosis can improve artery patency,
but is it associated with clinical benefit? In
a 5-year U.K. study, investigators random-
ized 806 patients with renal artery stenosis
and related clinical findings (such as
difficult-to-control hypertension or un-
explained renal dysfunction) to medical
management alone or to medical manage-
ment plus angioplasty (with stenting at the
discretion of treating physicians). In all
cases, treating physicians were uncertain
whether revascularization would confer
benefit. Median follow-up was 34 months.
Among participants who were assigned
to revascularization, 17% did not undergo
the procedure, mainly because angiogra-
phy revealed that their stenoses were less
severe than expected. Compared with
medical management–only patients,
those assigned to revascularization had a
borderline significant mean lower rate of
disease progression (as measured by the
reciprocal of the mean serum creatinine
level; P=0.06). However, no significant
differences were noted between groups in
serum creatinine level, systolic blood pres-
sure, adverse renal events, adverse cardio-
vascular events, or death. Mean diastolic
blood pressure was significantly lower in
the medical management–only group.
Researchers found no effects of revascu-
larization in subgroups as defined by
stenosis or renal dysfunction severity.
Twenty-three patients suffered serious
complications related to revascularization.
COMMENT
A small recently published study sug-
gested that revascularization produced no
benefit (Ann Intern Med 2009; 150:840);
now, a much larger study yielded similar
findings. The authors note that the main
limitation of their study is that they excluded
Vol. 16 No. 1
people who required revascularization,
in their doctors’ opinions: Examples are
patients with flash pulmonary edema or
acute renal injury (or rapidly progressing
disease) that was thought to be caused by
renal artery stenosis. Whether such pa-
tients benefit from revascularization is
unknown. But, for most people, revascu-
larization for renal artery stenosis does
not appear to be associated with clinical
benefit.
— Richard Saitz, MD, MPH, FACP, FASAM,
Journal Watch General Medicine
The ASTRAL Investigators. Revascularization
versus medical therapy for renal-artery stenosis.
N Engl J Med 2009 Nov 12; 361:1953.
Two Clopidogrel Loading
Doses Compared in Patients
with STEMI
STEMI patients who underwent primary
PCI had better clinical outcomes with a
600-mg loading dose than with 300 mg.
Given that platelet inhibition during per-
cutaneous coronary intervention is more
rapid and complete when a 600-mg load-
ing dose of clopidogrel is used, it is often
preferred over a 300-mg dose, both for
PCI with stenting and in acute coronary
syndrome patients who undergo PCI.
Now, using data from the HORIZONS-
AMI trial (JW Cardiol Aug 2008, p. 67,
and N Engl J Med 2008; 358:2218), investi-
gators have compared outcomes in pa-
tients with ST-segment-elevation MI who
received a 300-mg (1153 patients) or a
600-mg (2158 patients) loading dose
of clopidogrel before being randomized
either to bivalirudin alone or to unfrac-
tionated heparin plus a glycoprotein (GP)
IIb/IIIa inhibitor.
For each of the 30-day endpoints —
death, reinfarction, major adverse cardio-
vascular events, and major bleeding un-
related to bypass surgery — recipients of
the 600-mg clopidogrel loading dose fared
significantly better than recipients of the
300-mg dose, without any greater risk for
stroke or thrombocytopenia and regard-
less of antithrombotic-therapy assign-
ment. Among stent recipients, the inci-
dence of definite or probable stent
thrombosis was significantly lower with
600-mg than with 300-mg of clopidogrel
(1.7% vs. 2.8%).
January 2010
COMMENT
STEMI patients who underwent PCI had
significantly better ischemic outcomes with
a 600-mg loading dose of clopidogrel com-
pared with 300 mg without any greater risk
for bleeding, regardless of which anti-
thrombotic therapy was used and whether
a GP IIb/IIIa inhibitor was included. The
findings are consistent with data from the
TRITON-TIMI 38 trial, in which prasugrel
(which achieves greater platelet inhibition
than clopidogrel) outperformed clopid-
ogrel in terms of patient outcomes (J Am
Coll Cardiol 2009; 54:678). Based in part on
these results, the newly revised American
College of Cardiology/American Heart
Association STEMI guidelines support the
use of 300–600 mg of clopidogrel before
primary PCI.
— Howard C. Herrmann, MD
Dangas G et al. for the HORIZONS-AMI Trial
Investigators. Role of clopidogrel loading dose in
patients with ST-segment elevation myocardial
infarction undergoing primary angioplasty: Results
from the HORIZONS-AMI (Harmonizing Out-
comes With Revascularization and Stents in Acute
Myocardial Infarction) Trial. J Am Coll Cardiol
2009 Oct 6; 54:1438.
Simon DI and Parikh SA. Hunting for the “sweet
spot” in P2Y12 receptor blockade. J Am Coll
Cardiol 2009 Oct 6; 54:1447.
Cangrelor Is Not the
New Champion
Unexpected setbacks for a promising new
antiplatelet agent illustrate the gap between
laboratory results and clinical efficacy.
Cangrelor, an investigational intravenous
agent that reversibly inhibits the platelet
P2Y12 adenosine diphosphate receptor, has
two potential advantages over clopidogrel:
a rapid onset of action and a short half-life
that allows normalization of platelet func-
tion within 60 minutes of discontinuation.
In two manufacturer-sponsored studies,
investigators assessed cangrelor’s efficacy
in patients undergoing percutaneous coro-
nary intervention. Both trials were termi-
nated early based on findings from interim
analyses.
In the CHAMPION PLATFORM
trial, 5301 patients undergoing PCI for
acute coronary syndromes were random-
ized to receive cangrelor or placebo for
2 to 4 hours during the procedure and
clopidogrel (600 mg) at the end of the
procedure. Glycoprotein (GP) IIb/IIIa
JWatch.org
CLINICAL PRACTICE GUIDELINE WATCH
USPSTF Doesn’t Recommend Using
Nontraditional Risk Factors for CHD Risk
The task force finds the evidence to be insufficient to make a recommendation.
The U.S. Preventive Services Task Force
(USPSTF) has issued a new guideline
about the use of nontraditional markers
for coronary heart disease risk to screen
patients, particularly those at intermedi-
ate risk according to traditional risk
factors (Framingham score). The task
force evaluated nine nontraditional
markers: high-sensitivity C-reactive
protein (hs-CRP), ankle-brachial index
(ABI), leukocyte count, fasting blood
glucose level, periodontal disease, carotid
intima–media thickness, coronary artery
calcification score as determined by
electron-beam computed tomography,
homocysteine level, and lipoprotein(a)
level.
The USPSTF concluded that evi-
dence is insufficient to assess the balance
of benefits and harms of using nontradi-
tional risk factors to screen asymptomatic
men and women with no histories of
CHD to prevent subsequent CHD events.
I statement (insufficient evidence; the
grading system can be accessed on the
USPSTF website.)
In the evidence review, researchers
found that 11% of men with intermediate
CHD risk would be reclassified as having
high risk and 12% would have low risk by
hs-CRP; 10% of women would be reclas-
sified as having high risk by ABI. Data
are insufficient for all other tests. The
evidence is also insufficient to determine
whether CHD events (and deaths) would
be lessened following nontraditional risk
factor screening. The USPSTF also cites
possible harms of screening, such as ad-
verse psychological consequences of
inhibitors were used in 9.2% of patients.
The primary composite endpoint of death,
MI, or ischemia-driven revascularization
within 48 hours occurred in 7% of can-
grelor recipients and in 8% of placebo
recipients, a nonsignificant difference.
However, cangrelor was associated with
significant reductions in the stent throm-
7
overestimating CHD risk, expense of
testing, and side effects of any preventive
interventions (such as statins) that gener-
ally are safe but have known side effects
that would be acceptable only if the inter-
ventions provide benefits.
COMMENT
The temptation exists to collect as much
information as possible to prevent a
common cause of death. However, based
on current data, the best outcome of
screening with nontraditional risk fac-
tors would be to reclassify a small pro-
portion of patients; such screening
would not necessarily be associated with
preventing CHD. Some experts still
might advocate testing because they
hope that the evidence will catch up to
clinical practice. Although this ap-
proach perhaps is not entirely unreason-
able, it is problematic, because it could
distract us from focusing on preventive
health interventions of proven benefit.
— Richard Saitz, MD, MPH, FACP,
FASAM, Journal Watch General
Medicine
U.S. Preventive Services Task Force. Using non-
traditional risk factors in coronary heart disease
risk assessment: U.S. Preventive Services Task
Force recommendation statement. Ann Intern
Med 2009 Oct 6; 151:474.
Buckley DI et al. C-reactive protein as a risk
factor for coronary heart disease: A systematic
review and meta-analyses for the U.S. Preventive
Services Task Force. Ann Intern Med 2009 Oct
6; 151:483.
Helfand M et al. Emerging risk factors for coro-
nary heart disease: A summary of systematic
reviews conducted for the U.S. Preventive Services
Task Force. Ann Intern Med 2009 Oct 6;
151:496.
bosis rate (0.2%, vs. 0.6% with placebo)
and mortality (0.2% vs. 0.7%). Major and
minor bleeding rates were similar in the
two groups, although groin hematomas
occurred more frequently in cangrelor
recipients. Dyspnea was more common in
cangrelor recipients (1.4%) than in placebo
recipients (0.5%).
 No part of this newsletter may be reproduced or otherwise incorporated into any information retrieval system without the written
JW ONLINE CME permission of the Massachusetts Medical Society. Printed in the USA. ISSN 1521-5822.

JOURNAL WATCH SUBSCRIBERS

HAVE 10 FREE CREDITS!
Massachusetts Medical Society
This is one of four questions in a recent Journal
860 Winter Street
Watch Online CME exam.
Waltham, MA 02451-1413
from “ARBITER 6-HALTS: A Surprise
Knockout” (p. 1)
JWatch.org
Which of the following statements
describes a finding from a randomized
trial of statin therapy plus ezetimibe or
extended-release niacin in patients at
high risk for cardiovascular events?
A. The mean low-density lipoprotein (LDL)
level increased significantly in the
ezetimibe group.
B. The mean high-density lipoprotein
(HDL) level decreased significantly in
the niacin group.
C. Carotid intima–media thickness de-
creased significantly in the niacin group.
D. The major cardiovascular event rate was
significantly lower in the ezetimibe
group than in the niacin group.
Category: Cardiovascular Diseases
Exam Title: HDL Cholesterol
Posted Date: Dec 15 2009
View this exam and others at http://cme.jwatch.org
User name and password are required.
CME FACULTY
Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

8 CARDIOLOGY Vol. 16 No. 1

In the CHAMPION PCI trial, 8877
patients undergoing PCI were randomized
to receive either 600 mg of clopidogrel
or cangrelor at the beginning of the pro-
cedure. GPIIb/IIIa inhibitors were used
in 26.5% of patients. Cangrelor recipients
received clopidogrel at the end of the infu-
sion. The rate of the composite endpoint
of death, MI, or ischemia-driven revascu-
larization did not differ significantly be-
tween the two groups at either 48 hours
or 30 days or among subgroups with
stable angina, unstable angina, and ST-
segment-elevation MI. Bleeding rates
were similar in the two treatment groups,
but dyspnea occurred in slightly more
cangrelor recipients (1.0%) than clopid-
ogrel recipients (0.4%).
COMMENT
Given the importance of platelet inhibition
in ACS treatment and PCI, the fact that
cangrelor did not improve outcomes —
despite presumably achieving earlier and
greater platelet inhibition than clopidogrel
alone — is surprising. Study design issues, The Journal Watch Series
including the definition of periprocedural Journal Watch AIDS Clinical Care
MI and the abrupt transition to an oral Journal Watch Cardiology
antiplatelet after cangrelor infusion, could Journal Watch Dermatology
have contributed to these negative results. Journal Watch Emergency Medicine
However, newer oral agents with a faster Journal Watch Gastroenterology
onset of action and more-consistent plate-
Journal Watch General Medicine
let inhibition than clopidogrel are now
Journal Watch Hospital Medicine
available and will pose a further challenge
Journal Watch Infectious Diseases
to cangrelor’s development.
Journal Watch Neurology
— Howard C. Herrmann, MD
Journal Watch Oncology
Dr. Herrmann was a site investigator for the CHAMPION
and Hematology
PCI study but was not involved in data analysis or manu-
script preparation. Journal Watch Pediatrics and
Adolescent Medicine
Bhatt DL et al for the CHAMPION PLATFORM
Investigators. Intravenous platelet blockade with Journal Watch Psychiatry
cangrelor during PCI. N Engl J Med 2009 Dec 10; Journal Watch Women’s Health
361:2330.
FOR MORE INFORMATION
Harrington RA et al. Platelet inhibition with cangre-
From the United States and Canada: call (800) 843-
lor in patients undergoing PCI. N Engl J Med 2009
Dec 10; 361:2318. 6356, fax (781) 893-0413, or see JWatch.org
From all other locations: call (49) 30 312 3883,
Kastrati A and Ndrepepa G. Cangrelor — A cham-
fax (49) 30 313 2032 (Germany) call +1 781 893 3800
pion lost in translation? N Engl J Med 2009 Dec 10;
x5515, fax +1 781 893 0413 (U.S.)
361:2382.