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From the publi shers ofThe New England Journal of Medicine July 2008 Vol. 14 No. 7

The ACCORD and ADVANCETrials: Implicationsfor Patients with

Type 2 Diabetes

I n patients with diabetes, high glycatedhemoglobin (HbA1c) levels are associ-

ated with elevated risks for cardiovas-

cular events and death. Some, but not

all, studies have shown that loweringHbA

1clevels reduces cardiovascular risk,

and these data have been used to support

current guidelines that recommend a

target HbA1c

level of7.0%. To furtherinvestigate the effect of tight glucose

control on cardiovascular outcomes in

high-r isk patients with type 2 diabetes,

two studies were conducted: the Action

to Control Cardiovascular Risk in Diabetes

(ACCORD) trial and the Action in Diabe-

tes and Vascular Disease: Preterax and

Diamicron Modified Release Controlled

Evaluation (ADVANCE) trial.

In the ACCORD trial, 10,251 type 2

diabetic patients (mean age, 62; 38%

women) were randomized to receive

intensive glucose-lowering therapy

(target HbA1c

,

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pothesis that tight glucose control in

patients with type 2 diabetes will

reduce their risk for macrovascular

complications. Moreover, the strategies

were associated with an increased risk

for hypoglycemia in both studies and

with higher mortality in ACCORD. The

lower risk for microvascular complica-tions in ADVANCE (this outcome was

not reported in ACCORD) was the only

favorable finding. The bottom line is

that these studies will cause a reexami-

nation of guidelines and performance

measures and are further evidence that

knowing the effect of a strategy on a

surrogate outcome, such as a risk factor,

does not always tell you the effect on

patients.

Harlan M. Krumholz, MD, SM

Dr. Krumholz is the author of RedefiningQuality Implications of Recent Clinical

Trials in the same issue of theNewEngland Journal of Medicine as the citedarticles.

Patel A et al . for the ADVANCE Collabora-

tive Group. Intensive blood glucose control

and vascular outcomes in patients with

type 2 diabetes. N Engl J Med2008 Jun 12;

358:2560.

Gerstein HC et al. for the Action to Control

Cardiovascular Risk in Diabetes Study

Group. Effects of intensive glucose lower-

ing in type 2 diabetes. N Engl J Med2008

Jun 12; 358:2545.

Beyond Blood PressureControl: TargetingProteinuria with Renin-

Angiotensin-AldosteroneInhibitors

Aliskiren is an oral renin inhibitorrecently approved for marketingin the U.S. In the Aliskiren in the Evalu-

ation of Proteinuria in Diabetes (AVOID)

trial, a double-blind, randomized,

placebo-controlled study sponsored

by the manufacturer of al iskiren, inves-

tigators explored whether combining

aliskiren with losartan, an angiotensin-receptor blocker, would be renoprotec-

tive in patients with type 2 diabetes. Af-

ter a 3-month, open-label run- in period,

patients with type 2 diabetes, hyperten-

sion, and proteinuria who were receiv-

ing losartan (with or without other anti-

hypertensive agents that do not block

the renin-angiotensin-aldosterone sys-

tem) were assigned to receive additional

aliskiren (150 mg/day for 3 months,

300 mg/day thereafter) or placebo for

6 months. The primary outcome of

interest was reduction of albuminuria.

Baseline characteristics and the pro-

portions of patients receiving glucose-

lowering or lipid-lowering drugs and

aspirin were similar in the two groups.

At 6 months, the mean urinary albumin-

to-creatinine ratio was about 20% lowerin the aliskiren group than in the placebo

group (P

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ized 302 patients with symptomatic heartfailure and essential hypertension (78%

male, 79% with LV systolic dysfunction)

to receive aliskiren (150 mg/day) or

placebo in addition to their usual stable

doses of a beta-blocker plus an ACE in-

hibitor or ARB. Among the exclusion

criteria were hyperkalemia (potassium

5.1 mEq/dL ), renal dysfunction (creati-nine >2.0 mg/dL), hypotension (systolic

blood pressure

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with heart failure. Larger trials with hard

clinical endpoints will better elucidate

what role, if any, this new drug class has

in treating heart failure.

Frederick A. Masoudi, MD, MSPH

McMurray JJV et al. for the Aliskiren

Observation of Heart Failure Treatment

(ALOFT) Investigators. Effects of the oraldirect renin inhibitor aliskiren in patients

with symptomatic heart failure. Circ

Heart Fail2008 May; 1:17.

Nesiritide InfusionComes Up Short Again

P atients with advanced symptomaticheart failure are at considerable riskfor premature death, hospitalization, and

functional l imitation, even when receiv-

ing the most current evidence-based

therapy. Nesiritide, a recombinant B-type

natriuretic peptide, holds theoreticalappeal as an adjunct to standard therapy

because of its vasodilatory and natriuret-

ic effects. It is approved for acute treat-

ment of decompensated heart failure;

however, it has also been commonly

administered via intermittent outpatient

infusion, despite a lack of data to sup-

port this practice. The Follow-Up Serial

Infusions of Nesiritide (FUSION I) tr ial

(Am J. Cardiol2004; 94:545) found no

benefit from intermittent nesiritide infu-

sions in outpatients with heart failure,

but the findings suggested the possibility

of benefit in higher-risk subgroups, in-cluding patients with reduced renal

function. FUSION II, a manufacturer-

sponsored trial, was designed to study

intermittent outpatient nesiritide infu-

sions in these high-risk patients.

Investigators randomized 920 patients

with severely symptomatic systolic heart

failure (mean age, 65; NYHA class IV,

53%; mean LV ejection fraction, 25%)

and renal dysfunction (mean estimated

glomerular filtration rate, 52 mL/min

1.72 m2) to receive outpatient infusions

of placebo or nesiritide, either once or

twice weekly, for 12 weeks. Twelve

weeks after the last infusion, no differ-

ence was found in the rate of combined

death and hospitalization for heart

failure or renal dysfunction between

patients assigned to placebo (36.8%)and those assigned to either nesiritide

regimen (36.7% in both groups com-

bined). More patients in the nesiritide

group than in the placebo group experi-

enced hypotension (32.4% vs. 18.0%;

P2.0 mg/dL because

renal dysfunction may influence tro-

ponin concentration.

Of the 105,388 heart failure hospital-

izations in the registry, 84,872 included

a troponin measurement at initial evalu-

ation, and 67,924 met the study enroll-

ment criteria. The 4240 hospitalizations

in which troponin levels were elevated

were more likely to culminate in death

than the 63,684 hospitalizations in

which no elevation was found (8.0% vs.

2.7%,P

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ment based on established cardiovascu-

lar risk factors.

During median follow-up of 10 years,

136 of 315 deaths were caused by cardio-

vascular disease. In models adjusted for

established risk factors, each biomarker

individually predicted cardiovascular

death. Compared with a model that used

established risk factors alone, the incor-

poration all four biomarkers significantly

increased the C statistic for prediction

of cardiovascular death (from 0.664 to

0.766,P5 seconds in atrial fibrillation [AF]).

Key Points (CRT):

1. CRT now carries a Class I recommendation for the treatment

of NYHA class III or ambulatory class IV heart failure in pa-

tients with LV ejection fractions 120

ms on optimal medical treatment.

2. Class IIa indications for CRT now include patients with AF

and patients dependent on ventricular pacing (provided that

heart failure class and QRS duration conditions are met).

3. CRT now carries a Class IIb recommendation in patients

who have NYHA class I or II heart failure, are undergoing PPM

and ICD implantation, and are expected to require frequent

ventricular pacing. This condition is the only indication for

CRT in patients with NYHA class II or lower heart failure.

Key Points (ICDs):

1. Little has changed in the recommendations for ICDs for

secondary prevention of ventricular arrhythmias, except that

pharmacologic management of arrhythmias induced during

electrophysiologic studies for syncope is no longer recom-

mended as an option.

2. The recommendations for ICDs for primary prophylaxis of

sudden cardiac death have changed considerably. Most of the

following new Class I recommendations are based on results

of the MUSTT (JW CardiolFeb 2000, p. 13), MADIT II (JW

CardiolJun 2002, p. 45), SCD-HeFT (JW CardiolApr 2005,

p. 29), and DEFINITE (JW CardiolJul 2004, p. 53) studies:

Ischemic cardiomyopathy patients now qualify for an ICD

if their ejection fractions are 30% but 35%, and they

have NYHA class II or III heart failure. The recommendeddelay

of >40 days post-MI and >3 months post-revascularization

remains.

Ischemic cardiomyopathy patients with ejection fractions

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Comment:

These results suggest that a combination

of selected biomarkers of cardiac and

renal disease may improve assessment

of risk for cardiovascular death among

older men. As noted in an accompanying

editorial, several reasons might account

for the differences in these findingscompared with those of previous studies:

better choice of biomarkers; the restric-

tion of the cohort to lean white men;

and, most importantly, the inclusion of

patients with prevalent cardiovascular

disease. Even if these results are con-

firmed in more-diverse cohorts, however,

before we change our practices we must

undertake the formidable task of deter-

mining the costs and implications for

current prevention strategies of measuring

ever-increasing numbers of biomarkers.

Beat J. Meyer, MD

Zethelius B et al. Use of multiple

biomarkers to improve the prediction of

death from cardiovascular causes. N Engl

J Med2008 May 15; 358:2107.

de Lemos JA and Lloyd-Jones DM. Multiple

biomarker panels for cardiovascular risk

assessment. N Engl J Med2008 May 15;

358:2172.

How Often Do We Need toCheck Cholesterol Levels?

T

o examine variations in cholesterol

concentrations, investigators used

data from the Long-term Intervention

with Pravastatin in Ischaemic Disease

(LIPID) study of 9014 patients (mean age,

62 years; 83% men) with coronary heart

disease who were randomized to receive

pravastatin (40 mg) or placebo. Lipid

concentrations were measured by a

single laboratory at randomization, at 6

and 12 months, and then annually until

5 years. The average pretreatment cho-

lesterol level was 5.65 mmol/L.

Standard deviations for within-person

short-term variability of a single mea-

surement (based on measures taken 4

weeks before randomization ) were 0.38

and 0.42 mmol/L for the placebo and

pravastatin groups, respectively (average

variation, 7%). Both the placebo and

pravastatin groups had small increases

in within-person variability over time.

The mean cholesterol increase in the

pravastatin group from 6 months to 5

years was 0.14 mmol/L (average varia-

tion, 0.7% per year). Mean LDL levels

had similar variances over time (vari-

ances of difference from baseline to

years 1, 3, and 5 were 0.32, 0.42, and 0.45

mmol/L, respectively, in the placebo

group and 0.49, 0.53, and 0.56 mmol/L

in the pravastatin group).

Comment:

This study reaff irms that adherent pa-

tients with well-controlled cholesterollevels can be monitored every 3 to 5

years. A clinical point frequently forgot-

ten is that cholesterol levels can and will

vary by 7%. Therefore, treatment deci-

sions should not be made based on a

single measure. These findings do not

apply to triglyceride levels, which are

more variable.

Joel M. Gore, MD

Glasziou PP et al. for the Lipid Study

Investigators. Monitoring cholesterol levels :

Measurement error or true change?Ann

Intern Med2008 May 6; 148:656.

AHA Statementon Stimulants andCardiovascular Screening

T he American Heart Association hasreleased a statement suggestingthat clinicians can reasonably request

electrocardiograms, in addition to

complete histories and physical exami-

nations, for children who receive stimu-

lants for attention-deficit/hyperactivity

disorder (ADHD) . It recommends that

ECGs should be read by physicians with

expertise in reading pediatric ECGs.About 2.5 mill ion U.S. children take

stimulants for ADHD. From 1999 through

2003, 19 sudden deaths and 26 adverse

cardiovascular events were reported in

children who received ADHD medica-

tions. Causes of sudden cardiac death in

children included cardiomyopathies,

long QT syndrome, and coronary anom-

alies; ECG might be superior to history

and physical examination for detecting

some of these disorders. The premise of

the AHA statement is that adverse cardio-

vascular effects of prescribed st imulants

can provoke sudden death in childrenwith predisposing conditions and that

early detection of those conditions

(through clinical examination and ECG)

could prevent some of those deaths.

COMMENT:

The AHA recently revised recommenda-

tions regarding preparticipation cardio-

vascular screening in athletes in

these, the AHAdoes notsupport ECG

for children and adolescents before they

engage in competitive sports (JW Pedi-

atr Adolesc MedFeb 2008, p. 10, and

Circulation 2007; 115:1643) . However,

based on nearly the same data, the AHA

now states that ECG might be warranted

in children and adolescents who cur-

rently are taking or are about to start

taking st imulants. This recommendation

contrasts with the position of the Ameri-can Academy of Pediatrics, whose

guideline does not contain specific rec-

ommendations about performing

screening ECGs before treatment with

stimulants. The AHA recommendation

is puzzling, given its acknowledgement

of the lack of relevant clinical trials and

given the uncertainty of whether children

who take stimulants have higher risk for

sudden cardiac death. Indeed, a recent

study failed to show an association be-

tween stimulant use and cardiac death

in children (JWJan 15 2008, p 18, and

Pediatrics 2007; 120:e1494).Howard Bauchner, MD

Dr. Bauchner is Professor of Pediatrics at theBoston University School of Medicine andPublic Health and Director of the Division ofGeneral Pediatrics at Boston Medical Center.

TheJournal WatchCardiology Perspective

Vetter and colleagues, under the aus-

pices of the AHA, have made screening

ECGs a Class 1 indication for all chil-

dren for whom a stimulant drug is pre-

scribed. This classification assumes gen-

eral agreement on ECG screening,

which is not the case. The level of evi-

dence assigned to this recommendation

is C, denoting only consensus opinion

of experts, case studies, or standard of

care; arguably, even this designation is

a stretch. In fact, physicians do disagree

about the value of ECG screening of

stimulant drug recipients, a population

for which scarcely any data exist. By

contrast, many studies of the potential

benefits of ECG screening have been

conducted in athletes. Of these, only

one supports ECG screening: a retro-

spective, nonrandomized study from Ita-

ly that has never been replicated and

has several important limitations that re-

strict its general applicability in the U.S.

In my opinion, a Class 1 recommenda-

tion for ECG screening of children who

are taking or about to take stimulants is

premature.

Mark S. Link, MD

Vetter VL et al . Cardiovascular monitoring

of children and adolescents with heart dis-

ease receiving stimulant drugs: A scientific

statement from the American Heart Associ-

Page 58 JOURNAL WATCH CARDIOLOGY Volume 14 Number 7

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ation Council on Cardiovascular Disease

in the Young Congenital Cardiac Defects

Committee and the Council on Cardiovas-

cular Nursing. Circulation2008 May 6;

117:2407.

Early Repolarization in

Survivors of IdiopathicVentricular Fibrillation

E arly repolarization is a commonelectrocardiographic finding that isthought to be benign. However, experi-

mental evidence suggests that early re-

polarization is potentially associated

with sudden cardiac arrest. In an inter-

national retrospective study of data from

22 tertiary-care arrhythmia centers, in-

vestigators compared 206 survivors of

idiopathic ventricular fibrillation (VF)

with 412 age-, sex -, and race-matched

controls. Idiopathic VF was definedas sudden cardiac arrest occurring in the

absence of present or inducible struc-

tural or electrical abnormalities, in-

cluding (among others) long QT syn-

drome, short QT interval, and Brugada

syndrome.

Early repolarization was present in 64

case subjects (31%) versus 21 control

subjects (5%,P

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Fergusson DA et al. A comparison of

aprotinin and lysine analogues in high-risk

cardiac surgery. N Engl J Med2008 May

29; 358:2319.Ray WA and Stein CM. The aprotinin

story Is BART the final chapter?N Engl J

Med2008 May 29; 358:2398.

Beta-Blockers forNoncardiac Surgery:

A Shift in Balance?

S tudies of the benefits of using pre-operative beta-blockers to reducethe risk for cardiovascular events in

patients undergoing noncardiac surgery

have yielded inconsistent results. To

investigate this issue further, the Peri-

operative Ischemic Evaluation (POISE)

investigators randomized 8351 patients

with cardiovascular disease or at high

risk for cardiovascular events (mean

age, 69; 37% women) to oral extended-

release metoprolol (100 mg) or match-

ing placebo, administered 2 to 4 hours

before noncardiac surgery and continued

(metoprolol dose, 200 mg/day) for 30

days. The prespecified primary outcome

at 30 days after randomization was a

composite of cardiovascular death, non-

fatal MI, and nonfatal cardiac arrest.

The primary outcome occurred in

5.8% of patients in the metoprolol group

and in 6.9% of those in the placebo group

(hazard ratio, 0.84;P=0.04). By contrast,

more deaths and more strokes occurred

in the metoprolol group than in the pla-

cebo group (all -cause mortality, 3.1% vs.

2.3%,P=0.032; stroke rate, 1.0% vs. 0.5%,

P=0.005). The between-group mortality

difference appears to have resulted from

higher rates of hypotension, bradycardia,

and stroke in the metoprolol group than

in the placebo group.

Comment:

These findings will dampen the currententhusiasm for preoperative use of beta-

blockers to reduce cardiovascular risk in

patients undergoing noncardiac surgery.

In their discussion, the authors estimat-

ed that for every 1000 patients with

similar risk profiles, extended-release

metoprolol prevents 15 MIs but produces

eight additional deaths and five additional

strokes. The dose of the study medication

was relatively high, and the authors of

an accompanying editorial speculate

that this may have accounted for some

of the adverse affects, but we do not

know whether a lower dose would have

resulted in a more favorable risk-benefit

profile. Until results of further research

show otherwise, the balance of risks

and benefits does not favor this strategy

in this patient population.

Harlan M. Krumholz, MD, SM

POISE Study Group. Effects of extended-

release metoprolol succinate in patients

undergoing non-cardiac surgery (POISE

trial): A randomised controlled trial.

Lancet2008 May 31; 371:1839.

Fleisher LA and Poldermans D. Per iopera-

tive blockade: Where do we go from here?Lancet2008 May 31; 371:1813.

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No part of th is newsletter may be reproduced or otherwise incorporated into any informa-tion retrieval system without the wr itten permission of the Massachusetts Medical Society.Printed in the USA. ISSN 1521-5822.

Massachusetts Medical Society860 Winter Street

Waltham, MA 02451-1413

Journal Watch

Online CME ProgramSubscribers have 10 FREE exam credits

Can you answer the followingquestion about the summaryBeta-Blockers for Noncardiac Surgery:A Shift in Balance? below?

Which of the following statements describes a

30-day finding of a study evaluating the use of

metoprolol to reduce cardiovascular risk in

patients undergoing noncardiac surgery?

A. Almost twice as many strokes occurred in themetoprolol as in the placebo group.

B. There was no between-group difference inthe combined rate of cardiovascular death,nonfatal MI, and cardiac arrest.

C. There were no between-group differences inthe rates of hypotension and bradycardia.

D. All-cause mortality was signi ficantly lower inthe metoprolol than in the placebo group.

* Category: Cardiovascular DiseasesExam Title: Cardiovascular Risks ofNoncardiac SurgeryPosted Date: Jun 3 2008

CME Faculty: Kelly Anne Spratt, DO, FACC

Section Editor, Cardiology

This is one of four questions in a recent JournalWatch Online CME exam.* Click on the CME link

from theJournal Watchsummary online athttp://www.jwatch.org

or go to http://cme.jwatch.organd view the exam listings.

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