CLINICAL REVIEW CLINICIAN’S CORNER

A Simplified Approach to the Management

of Non–ST-Segment Elevation
Acute Coronary Syndromes
Ty J. Gluckman, MD Context While current practice guidelines provide an evidence-based approach to
Molly Sachdev, MD, MPH management of acute coronary syndromes (ACS), application of the evidence by in-
Steven P. Schulman, MD dividual physicians has been suboptimal.

Roger S. Blumenthal, MD Objective To assess and synthesize the evidence regarding optimal management
of non–ST-segment elevation ACS (NSTE-ACS).

W
HILE ONGOING EFFORTS Data Sources Systematic searches of peer-reviewed publications were performed
by the American Col- in MEDLINE and the Cochrane Database from January 1990 through November 2004,
lege of Cardiology with consultation by content experts. Search terms included antiplatelet therapy, an-
(ACC) and the Ameri- tithrombotic therapy, angiotensin-converting enzyme inhibition, angiotensin recep-
can Heart Association (AHA) have led tor blockade, ␤-blockade, hypertension, hyperlipidemia, cigarette smoking, diet, dia-
to guidelines for the management of pa- betes mellitus, exercise, myocardial ischemia, and coronary artery disease.
tients with non–ST-segment elevation Study Selection and Data Extraction Criteria for selection of studies included
acute coronary syndromes (NSTE- controlled study design, English language, and clinical pertinence. Data quality was
ACS),1 implementation of these rec- based on the publishing journal and relevance to clinical management of NSTE-ACS.
ommended acute and long-term treat- Data Synthesis While outcomes of controlled studies support a comprehensive ap-
ment strategies remains suboptimal.2,3 proach in the management of patients with NSTE-ACS, many physicians perceive ex-
In order to simplify the guidelines, we isting guidelines as lengthy and complex. After risk stratification to identify those pa-
propose a modification of the “ABC” ap- tients most likely to benefit from an early invasive vs early conservative strategy, a
comprehensive management plan can be assembled through an “ABCDE” approach.
proach initially developed by the ACC/
The elements of this include “A” for antiplatelet therapy, anticoagulation, angiotensin-
AHA4 that incorporates risk factor re- converting enzyme inhibition, and angiotensin receptor blockade; “B” for ␤-blockade
duction, lifestyle changes, and medical and blood pressure control; “C” for cholesterol treatment and cigarette smoking ces-
therapies that can be easily used by cli- sation; “D” for diabetes management and diet; and “E” for exercise.
nicians. Conclusion An “ABCDE” approach for the management of NSTE-ACS provides a prac-
tical and systematic means to implement evidence-based medicine into clinical practice.
METHODS
JAMA. 2005;293:349-357 www.jama.com
We performed a systematic review of
peer-reviewed publications that were
identified through searches of Author Affiliations: Division of Cardiology, the Johns
MEDLINE and the Cochrane Data- emia, cigarette smoking, diet, diabetes Hopkins Hospital (Drs Gluckman, Sachdev, and Schul-
base from January 1990 through No- mellitus, exercise, myocardial ischemia, man) and Ciccarone Preventive Cardiology Center (Dr
and coronary artery disease. Bibliogra- Blumenthal), Johns Hopkins University, Baltimore, Md.
vember 2004. Search terms included an- Financial Disclosures: Dr Gluckman has received hono-
tiplatelet therapy, antithrombotic therapy, phies from these references were also raria from Pfizer Inc and Aventis Pharmaceuticals. Dr Sch-
reviewed, as were additional articles ulman and Dr Blumenthal have received honoraria from
angiotensin-converting enzyme inhibi- Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer.
tion, angiotensin receptor blockade, identified by content experts. Criteria Corresponding Author: Roger S. Blumenthal, MD, Cic-

β-blockade, hypertension, hyperlipid- used for study selection were con- carone Preventive Cardiology Center, Johns Hopkins
University, 600 N Wolfe St, Blalock 524 C, Baltimore,
trolled study design, English lan- MD 21287 ([email protected]).
guage, relevance to clinicians, and va- Clinical Review Section Editor: Michael S. Lauer, MD.
CME available online at lidity based on venue of publication and We encourage authors to submit papers for consid-
www.jama.com eration as a “Clinical Review.” Please contact Mi-
power analysis. chael S. Lauer, MD, at [email protected].

©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, January 19, 2005—Vol 293, No. 3 349
MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

published in 2002.1 In this update, sev- tic coronary angiography and angio-
Box 1. TIMI Risk Score eral areas were highlighted, including graphically directed revascularization
Predictor Variables* (1) early risk stratification; (2) new in- within 48 hours of symptom onset. In
Age >65 years dications for pursuing an early inva- contrast, the conservative strategy re-
sive strategy; (3) the early use of aspi- lies on noninvasive evaluation of ische-
Three or more risk factors for coro-
rin and clopidogrel; (4) the use of mia after a period of observation, with
nary artery disease
glycoprotein (Gp) IIb/IIIa inhibitors, es- catheterization and revascularization
Known coronary artery stenosis of pecially in patients undergoing percu- recommended only if ischemia recurs
⬎50%
taneous coronary intervention (PCI) or or is unresolved. Anti-ischemic and an-
ST-segment deviation on present- those with high-risk features; (5) the tithrombotic therapy is recommended
ing electrocardiogram preferential use of low-molecular- for all patients regardless of treatment
Two or more episodes of angina weight heparin (LMWH); and (6) the strategy.
within the preceding 24 hours early use of lipid-lowering therapy. Based on several trials,9,10,16,17 the
Use of aspirin within the preceding While these areas still remain impor- strongest evidence supporting an early
7 days tant in the treatment of patients with invasive strategy has come from its use
Elevated serum cardiac biomarker NSTE-ACS, much has been learned in individuals with ST-segment depres-
levels over the last 2 years that has helped to sion, elevated troponin levels, and/or
Abbreviation: TIMI, Thrombolysis in better define their roles. intermediate to high (⬎3) TIMI risk
Myocardial Infarction. scores.9,10 Accordingly, the ACC/AHA
*As presented in Antman et al.5 Risk Stratification recommends that an early invasive ap-
Estimation of risk is an integral compo- proach be used for patients with high-
nent in the evaluation of patients with risk features (BOX 2), reserving the early
DATA SYNTHESIS NSTE-ACS. While several risk stratifi- conservative approach for patients at
Definition and Diagnosis cation tools are available, one that is fre- lower risk.1 This strategy is not only
NSTE-ACS represents one part in the quently used is the Thrombolysis in cost-effective18 but is of particular ben-
continuum of disease processes result- Myocardial Infarction (TIMI) risk score.5 efit in elderly patients, despite an in-
ing from reduced coronary blood flow This tool combines 7 variables in an creased risk of bleeding.19
due to plaque disruption and subse- evenly weighted scale (BOX 1) and can
quent thrombus formation. Also known predict short- and long-term risk based ABCDE Approach to NSTE-ACS
as unstable angina and non–ST- on the calculated score.6,7 It also helps Several years ago, our center ad-
segment elevation myocardial infarc- to identify patients that benefit most dressed the implementation of previ-
tion (MI), NSTE-ACS is a more compre- from Gp IIb/IIIa inhibitors8 and an early ous ACC/AHA guidelines by adapting
hensive term that combines these 2 invasive strategy.9,10 Even without cal- a previously proposed “ABC” ap-
entities. culating the TIMI risk score, elevated proach to risk management.20 Through
NSTE-ACS should be differentiated troponin levels and ST-segment depres- a modification of this approach, this re-
from ST-segment elevation MI, as the sion help to distinguish individuals at view intends to provide an overview of
treatment differs substantially. ST- increased cardiovascular (CV) risk.11 medical therapies and lifestyle changes
segment elevation MI is typically char- The identification of these and other im- that are useful in NSTE-ACS (TABLE).
acterized by complete thrombotic occlu- portant predictors of risk (eg, hemo-
sion of a coronary artery and is generally dynamic instability, signs and symp- Antiplatelet Therapy
treated with immediate reperfusion toms of heart failure, renal insufficiency, Aspirin. By inhibiting platelet activa-
therapy. In contrast, NSTE-ACS usu- and elevated levels of C-reactive pro- tion and aggregation, aspirin is able to
ally results from a transiently or nearly tein and natriuretic peptides)12-15 can be reduce the incidence of death and non-
completely occluded coronary artery and particularly helpful in stratifying the fatal MI in patients with unstable an-
may or may not require revasculariza- early delivery of beneficial treatments gina21,22 or acute MI,23 with only a small
tion. NSTE-ACS should be suspected in for patients with NSTE-ACS. increased risk of major bleeding (0.2%).
patients with clinical evidence of myo- Higher doses of aspirin (⬎100 mg) do
cardial ischemia but without electrocar- Early Invasive vs Early not provide greater benefit and in fact
diographic evidence of ST-segment el- Conservative Approach may be less desirable due to increased
evation, a true posterior MI, or a new left One of the greatest impacts of risk strati- bleeding, especially when combined
bundle-branch block. fication in NSTE-ACS has been whether with clopidogrel. 24 Current guide-
to pursue an early routine invasive vs lines, therefore, recommend that all pa-
Update to the Guidelines early conservative (selective invasive) tients with NSTE-ACS receive 162 to
The most recent update to the ACC/ strategy. The early routine invasive 325 mg of aspirin initially, followed by
AHA guidelines for NSTE-ACS was strategy generally consists of diagnos- 75 to 160 mg daily thereafter.1
350 JAMA, January 19, 2005—Vol 293, No. 3 (Reprinted) ©2005 American Medical Association. All rights reserved.
 MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

Adenosine Diphosphate Receptor end point that included all-cause mor-

Antagonists. For patients unable to take tality, CV death, MI, and/or stroke Box 2. High-Risk Features
aspirin because of intolerance or hy- (P = .002 to P=.02). No significant dif- Favoring an Early Invasive
persensitivity, the thienopyridene clo- ferences in major bleeding were noted, Strategy*
pidogrel (75 mg daily) should be sub- even among patients who received con- Recurrent angina/ischemia at rest or
stituted.1 This is based largely on the current Gp IIb/IIIa inhibitors. with low-level activities despite in-
results of the Clopidogrel vs Aspirin in For patients undergoing surgical re- tensive anti-ischemic therapy
Patients at Risk of Ischemic Events vascularization, clopidogrel offers both Elevated troponin level
(CAPRIE) study,25 a trial of 19 185 pa- benefit and harm. While its early use
New or presumably new ST-
tients with known atherosclerotic vas- is associated with significantly im-
segment depression
cular disease randomized to receive proved outcomes,30 it increases the risk
either clopidogrel (75 mg daily) or as- of bleeding if administered within 5 Recurrent angina/ischemia with
symptoms of heart failure, an S3 gal-
pirin (325 mg daily). Because patients days of surgery.31,32 This is of little con-
lop, pulmonary edema, worsening
receiving clopidogrel experienced a 9% sequence in surgeries performed elec- rales, or new or worsening mitral re-
relative risk reduction in adverse CV tively but may have major implica- gurgitation
events (5.3% vs 5.8%, P=.04), clopido- tions if urgent revascularization is
High-risk findings on noninvasive
grel may be used in lieu of aspirin, al- required. Accordingly, clopidogrel stress testing
beit at much higher cost. should be withheld in high-risk pa-
Left ventricular systolic dysfunc-
Most patients with NSTE-ACS who tients managed with an early invasive
tion (ejection fraction ⬍40% on a
are at low bleeding risk should have clo- strategy if surgery is likely or if coro- noninvasive study)
pidogrel added to aspirin at hospital ad- nary angiography is to be performed
Hemodynamic instability
mission, with continuation for up to 12 early (ie, within 12 hours of presenta-
months.26 Support for this recommen- tion). For all others, clopidogrel should Sustained ventricular tachycardia
dation comes from the Clopidogrel in be started early,30 with continuation up Percutaneous coronary interven-
Unstable Angina to Prevent Recurrent until 5 days of surgery.1 tion within 6 months
Ischemic Events (CURE) trial.27 In this Gp IIb/IIIa Inhibitors. Based on their Prior coronary artery bypass graft
study, 12562 patients with NSTE-ACS ability to prevent ischemic complica- surgery
were randomized to receive clopido- tions following PCI, Gp IIb/IIIa inhibi- *Adapted from American College of Car-
g re l ( l o a d i n g d o s e o f 3 0 0 m g tors should be administered to pa- diology/American Heart Association
guidelines.1
followed by 75 mg daily) plus aspirin tients with NSTE-ACS managed with
(75-325 mg daily) vs aspirin alone (75- an early invasive strategy.1 In a pooled
325 mg daily) for a mean of 9 months. analysis of 14644 patients undergoing
Patients receiving dual antiplatelet PCI, treatment with a Gp IIb/IIIa in-
therapy experienced a 20% relative risk hibitor was associated with a 42% rela- inhibitor was associated with a 9%
reduction in the primary combined end tive risk reduction in MI and urgent re- relative risk reduction in the incidence
point of CV death, nonfatal MI, or vascularization at 30 days (95% of death or MI at 30 days (P=.02).39
stroke (9.3% vs 11.4%, P⬍.001). confidence interval [CI], 0.47-0.74).33 This benefit was limited, however, to
Clopidogrel is also efficacious among Although similar effects have been patients with a positive troponin level
patients with NSTE-ACS undergoing noted with each of the Gp IIb/IIIa in- or in need of early revascularization.
PCI. Both PCI-CURE,28 a subset of the hibitors (abciximab, eptifibatide, and ti- Thus, eptifibatide or tirofiban should
CURE study that included patients un- rofiban), the timing of PCI should be be used as a continuous infusion for
dergoing PCI, and the Clopidogrel for determined before an agent is se- only conservatively managed patients
the Reduction of Events During Obser- lected.34 Available data favor the use of only if there is continuing ischemia,
vation (CREDO) study29 support the abciximab35 or accelerated-dose eptifi- positive cardiac biomarker levels, or
long-term use of clopidogrel in pa- batide36 if PCI is anticipated soon after other high-risk features (ie, TIMI risk
tients treated with PCI. Between both presentation (⬍4 hours), reserving ti- score >4).1,40
studies, 4774 patients were random- rofiban9,37 and eptifibatide38 for pa- The benefits of Gp IIb/IIIa inhibi-
ized to receive aspirin (75-325 mg daily) tients treated medically during the first tors in conservatively managed pa-
or aspirin plus clopidogrel (300 mg 48 hours. tients do not extend to abciximab. The
loading dose followed by 75 mg daily), For patients undergoing an early Global Utilization of Strategies to Open
with treatment initiated prior to PCI and conservative strategy, the benefit of Gp Occluded Coronary Arteries IV-Acute
continued for a mean of 8 to 12 months. IIb/IIIa inhibitors is less pronounced. Coronary Syndromes (GUSTO IV-
Among patients receiving dual anti- In a meta-analysis of 31402 conserva- ACS) trial41 randomized 7800 patients
platelet therapy, there was a 27% to 31% tively managed patients with NSTE- to receive abciximab (bolus with infu-
relative risk reduction in a combined ACS, treatment with a Gp IIb/IIIa sion over 24 or 48 hours) vs placebo
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, January 19, 2005—Vol 293, No. 3 351
MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

and found no significant difference in matory effects of subthreshold Gp IIb/ to treatment with just 2 antiplatelet
the primary end point of death or MI IIIa receptor blockade.42 agents (ie, aspirin plus clopidogrel or
at 30 days. In fact, a trend toward worse Unfortunately, the optimal antiplate- aspirin plus a Gp IIb/IIIa inhibitor).
outcomes with longer infusions of ab- let regimen for patients with NSTE- While there is in vitro evidence to sup-
ciximab was noted, limiting its use in ACS remains to be defined. Much of this port triple antiplatelet therapy in pa-
the treatment of patients for whom PCI is based on the absence of clinical trial tients with NSTE-ACS,43 event-driven
is not planned. While the exact etiol- data comparing the combined use of as- studies are needed to clarify the incre-
ogy for this paradoxical effect is not pirin, clopidogrel, and a Gp IIb/IIIa in- mental value vs increased bleeding risk
known, it may be related to proinflam- hibitor (ie, triple antiplatelet therapy) associated with this strategy.

Table. ABCDEs of Cardiovascular Disease Management in NSTE-ACS*

Intervention Agent(s)/Treatment Modalities Comments
A
Antiplatelet therapy Aspirin All patients indefinitely
Initially with 162-325 mg followed by 75-160 mg daily thereafter
ADP Receptor antagonist All patients, unless anticipated need for urgent CABG surgery or within
(clopidogrel) 5 days of electively scheduled CABG surgery
Duration of up to 1 year
Gp IIb/IIIa Inhibitor (abciximab, All patients with continuing ischemia, an elevated troponin level, a TIMI
eptifibatide, tirofiban) risk score ⬎4, or anticipated PCI
Avoid abciximab if PCI is not planned
Anticoagulation Unfractionated heparin Alternative to LMWH for patients managed with an early invasive
strategy
LMWH (specifically enoxaparin) Preferred anticoagulant if managed conservatively
Alternative to unfractionated heparin for patients managed with an
early invasive strategy
Avoid if creatinine clearance is ⬍60 mL /min (unless anti-Xa levels are
to be followed) or CABG surgery within 24 hours
ACE Inhibition No clear preferred agent All patients with LVSD (ejection fraction ⬍40%), heart failure,
hypertension, or other high-risk features
Angiotensin receptor blockade No clear preferred agent All patients intolerant of ACE inhibitors
Avoid combination therapy with ACE inhibitors acutely, but consider in
patients with chronic LVSD (ejection fraction ⬍40%) and heart
failure
B
␤-Blockade No clear preferred agent All patients
Blood pressure control ACE Inhibitors and ␤-blockers Goal BP at least ⬍130/85 mm Hg (⬍130/80 mm Hg if diabetes or
first line chronic kidney disease present)
Optimal BP may be as low as 125/75 mm Hg
C
Cholesterol treatment Potent, high-dose statin All patients
Goal LDL-C level ⬍70 mg/dL
Ezetimibe or bile acid All patients unable to achieve an LDL-C level ⬍70 mg/dL while taking
sequestrant (resin) a potent, high-dose statin
Fibrates or nicotinic acid (niacin) Consider in patients with an HDL-C level ⬍40 mg/dL or a triglyceride
level ⬎150 mg/dL while taking a potent, high-dose statin
Cigarette smoking cessation Long-term behavioral support All patients using tobacco
Bupropion plus nicotine
replacement
D
Diabetes management Glycemic control (HbA1C ⬍7% All patients with diabetes
[minimum])
Diet Weight reduction to achieve All patients
optimal body mass index
Dietary modification
E
Exercise Aerobic and weight-bearing All patients, preferably within a cardiac rehabilitation program
exercise 4-5 times per week
for ⬎30 min
Abbreviations: ACE, angiotensin-converting enzyme; ADP, adenosine diphosphate; BP, blood pressure; CABG, coronary artery bypass graft; Gp, glycoprotein; HbA1C, glycosylated
hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LMWH, low-molecular-weight heparin; LVSD, left ventricular systolic dys-
function; MI, myocardial infarction; NSTE-ACS, non–ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial
Infarction.
SI conversion factors: To convert creatinine clearance values from mL/min to mL/s, multiply by 0.0167; to convert LDL-C and HDL-C values from mg/dL to mmol/L, multiply by
0.0259; to convert triglyceride values from mg/dL to mmol/L, multiply by 0.0113.
*Modified and adapted from American College of Cardiology/American Heart Association guidelines.4

352 JAMA, January 19, 2005—Vol 293, No. 3 (Reprinted) ©2005 American Medical Association. All rights reserved.
 MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

Anticoagulation also demonstrated a significantly in- evaluated in placebo-controlled trials of

Through its potentiation of circulat- creased risk of bleeding and adverse patients with NSTE-ACS. Nonethe-
ing antithrombins and ability to in- events in patients who had their antico- less, support for their long-term out-
hibit clot propagation, heparin re- agulant changed (either from unfrac- patient use has come from the Heart
duces ischemia in NSTE-ACS.44 When tionated heparin to LMWH or from Outcomes Prevention Evaluation
used in its unfractionated form, how- LMWH to unfractionated heparin) early (HOPE) trial53 and the European Trial
ever, heparin requires frequent moni- in the hospital course. On Reduction of Cardiac Events With
toring of the partial thromboplastin The results from the SYNERGY and Perindopril in Stable Coronary Artery
time and can be associated with de- A to Z trials, along with 4 other acute Disease (EUROPA).54 These trials ran-
lays in achieving therapeutic antico- coronary syndrome trials, were re- domized 22952 high-risk patients with
agulation.45 By fractionating heparin cently pooled in a study of 21946 pa- established vascular disease or diabe-
into molecules of lower molecular tients randomized to receive LMWH or tes to receive ramipril (10 mg daily) or
weight, an LMWH is produced with unfractionated heparin.48 In this analy- perindopril (8 mg daily) vs placebo for
better bioavailability, more predict- sis, patients receiving LMWH experi- a mean of 4 to 5 years. Treatment with
able pharmacokinetics, and a longer enced a lower 30-day incidence of death ACE inhibitors in these trials resulted
half-life. In addition, LMWH is associ- or nonfatal MI (10.1% vs 11.0%; 95% CI, in a 20% to 22% relative risk reduc-
ated with less platelet activation and 0.83-0.99), with no significant differ- tion in the combined end point of CV
heparin-induced thrombocytopenia. ence in major bleeding. In spite of sub- death, MI, and stroke or cardiac arrest
Regardless, many practitioners have stantial differences between these trials (P⬍.001 for all).
been hesitant to use LMWH (espe- with regard to study design, one group When used in low-risk patients, how-
cially if cardiac catheterization with PCI in which LMWH consistently pro- ever, ACE inhibitors do not provide the
is planned) because of concerns of re- vided benefit was in those managed with same benefit. In the Prevention of Events
duced efficacy, increased bleeding, and an early conservative strategy. Similar With Angiotensin-Converting Enzyme
an inability to easily monitor antico- findings were recently demonstrated in Inhibition (PEACE) trial,55 8290 pa-
agulation in the catheterization a post hoc analysis of the A to Z study, tients with coronary artery disease
laboratory. in which conservatively managed pa- (CAD) and either normal or mildly de-
Two large trials recently compared the tients treated with LMWH had im- pressed left ventricular function (ejec-
safety and efficacy of LMWH with that proved outcomes, with no overall in- tion fraction ⬎40%) were randomized
of unfractionated heparin in patients with creased bleeding risk.49 Based on this, to receive trandolopril (up to 4 mg daily)
NSTE-ACS. In the A to Z study,46 3987 LMWH (specifically enoxaparin) should or placebo for a median of 4.8 years. Pa-
patients were randomized to receive be the preferred anticoagulant in pa- tients were required to be at least 2
either unfractionated heparin or LMWH tients managed with an early conserva- months out from an acute coronary
(enoxaparin) concurrently with tirofi- tive strategy.49,50 When used in patients event and in general were well treated—
ban and aspirin. While the incidence of with renal insufficiency (creatinine clear- there was excellent control of blood pres-
the primary outcome, a 7-day compos- ance ⬍60 mL/min [1.0 mL/s]), how- sure (BP) (mean, 133/78 mm Hg), a high
ite of death, MI, or refractory ischemia, ever, it is important that anti–factor Xa rate of revascularization, and frequent
was similar in both groups (9.4% for un- levels be monitored to ensure appropri- use of other risk-reducing medications
fractionated heparin vs 8.4% for LMWH; ate dosing.51,52 Given that either antico- (eg, antiplatelet therapy, ␤-blocker, lipid-
95% CI, 0.71-1.08), major bleeding epi- agulant may be used in patients man- lowering agent). Unlike the HOPE and
sodes were more common with LMWH aged with an early invasive strategy, it EUROPA trials, however, treatment with
(0.9% vs 0.4%, P=.05). In the Superior is more important that open dialogue be trandolopril produced no significant im-
Yield of the New Strategy of Enoxapa- maintained between emergency depart- provement in the primary combined end
rin Revascularization and Glycoprotein ments, coronary care units, and car- point of CV death, MI, or need for re-
IIb/IIIa Inhibitors (SYNERGY) trial,47 diac catheterization laboratories so as to vascularization (P=.43). While this sug-
10027 high-risk patients undergoing an avoid in-hospital changes in the type of gests a limited value for the long-term
early invasive strategy were random- anticoagulant administered. use of ACE inhibitors in individuals
ized to receive unfractionated heparin or similar to those in the PEACE trial,56
LMWH (enoxaparin). Although this Angiotensin-Converting ACE inhibitors should remain an im-
study found no significant difference in Enzyme Inhibition portant therapy in those at higher risk.
the 30-day end point of death or MI While angiotensin-converting en-
(14.5% for unfractionated heparin vs zyme (ACE) inhibitors have emerged Angiotensin Receptor Blockade
14.0% for LMWH; 95% CI, 0.86-1.06), as standard care for most patients with The role of angiotensin receptor block-
patients treated with LMWH were more atherosclerosis, diabetes mellitus, left ers in NSTE-ACS is not addressed by
likely to experience major bleeding (9.1% ventricular systolic dysfunction (LVSD), current guidelines; however, recent data
vs 7.6%, P=.008). Importantly, this study or heart failure, they have not been from the Valsartan in Acute Myocar-
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, January 19, 2005—Vol 293, No. 3 353
MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

dial Infarction Trial (VALIANT)57 sug- disease66), recent evidence from the quiring rehospitalization, revascular-
gest that they may be used as an alter- Comparison of Amlodipine vs Enala- ization, and stroke (P⬍.005), along
native to, but not in combination with, pril to Limit Occurrences of Thrombo- with a substantially lower posttreat-
ACE inhibitors in patients with MI and sis (CAMELOT) study suggests that the ment mean LDL-C level (62 mg/dL vs
underlying LVSD (ejection fraction optimal level may be even lower (ie, 95 mg/dL [1.6 mmol/L vs 2.5 mmol/
⬍40%) or heart failure. Among the 125/75 mm Hg) in patients with stable L]). These benefits were seen as early
14703 patients enrolled, there were no CAD.67,68 This study randomized 1991 as 30 days after treatment, similar to the
significant differences in mortality be- normotensive patients (mean BP, effects noted with atorvastatin (80 mg
tween those taking valsartan (up to 160 129/78 mm Hg) with angiographi- daily) in the Myocardial Ischemia Re-
mg twice daily) compared with capto- cally proven CAD to receive amlo- duction With Aggressive Cholesterol
pril (up to 50 mg 3 times daily) (haz- dipine (10 mg daily), enalapril (20 mg Lowering (MIRACL) study.71
ard ratio [HR], 1.00; 97.5% CI, 0.90- daily), or placebo for 2 years. While pa- More modest differences were noted
1.11) or those taking valsartan (up to 80 tients in both active treatment groups in the recent A to Z study,72 which ran-
mg twice daily) plus captopril (up to 50 achieved modest BP reduction (mean, domized 4497 patients to receive early
mg 3 times daily) compared with cap- 5/3 mm Hg), those taking amlodipine intensive therapy (simvastatin 40 mg
topril alone (HR, 0.98; 97.5% CI, 0.89- experienced a more significant rela- daily for 1 month followed by 80 mg
1.09). While these findings contrast with tive risk reduction in adverse CV events daily) vs delayed less-intensive therapy
the benefits derived from the addition (31%, P=.003). Therefore, although (placebo for 4 months followed by sim-
of angiotensin receptor blockers to ACE ACE inhibitors and ␤-blockers should vastatin 20 mg daily) after experienc-
inhibitors in patients with chronic LVSD be used preferentially in NSTE-ACS,1 ing an acute coronary syndrome. While
(ejection fraction ⬍40%) and heart fail- amlodipine represents an important intensive therapy only produced a trend
ure,58 their combined use in the acute agent for additional BP reduction in toward reduced CV events at 24 months
setting should still be avoided. those with stable CAD. (11% relative risk reduction, P=.14),
smaller relative differences in the post-
␤-Blockade Cholesterol Treatment treatment LDL-C levels of the 2 groups
Through their sympatholytic effects, By inhibiting the rate-limiting step in (when compared with PROVE IT-
␤-blockers reduce cardiac workload and cholesterol synthesis, the 3-hydroxy- TIMI 22) may have accounted for this.
thus myocardial oxygen demand. Data 3-methylglutaryl coenzyme-A reduc- For those unable to achieve an LDL-C
supporting their use in the acute set- tase inhibitors (statins) have become level less than 70 mg/dL, another lipid-
ting comes from a 13% relative risk re- standard care for most patients with lowering agent (eg, ezetimibe or a bile
duction in the rate of progression to an NSTE-ACS. Their sustained use re- acid sequestrant) should be added.73
acute MI59 and a 29% relative risk re- sults in a significant reduction in the Similarly, if high-density lipoprotein
duction in death among high-risk indi- level of low-density lipoprotein cho- cholesterol levels are less than 40 mg/dL
viduals with a threatened or evolving lesterol (LDL-C), along with more mod- (1.0 mmol/L) or triglyceride levels are
MI.60 When used in patients with hyper- est but favorable effects on levels of greater than 150 mg/dL (1.7 mmol/L),
tension,61 LVSD,62 or following an MI,63-65 other serum lipids. Based on a recom- addition of niacin or a fibrate should be
␤-blockers also produce significant re- mended LDL-C goal of less than 70 considered.1 All patients treated with a
ductions in adverse CV events. These mg/dL (1.8 mmol/L),69 nearly all pa- high-dose, potent statin should have cre-
studies form the basis for current rec- tients with NSTE-ACS should begin atine kinase and transaminase levels
ommendations to use intravenous treatment with a high-dose, potent closely monitored, with dose adjust-
␤-blockers in the setting of chest pain, statin during their hospitalization. ment or discontinuation of medication
followed by long-term use of oral Support for intensive and early should muscle or liver toxicity occur.
␤-blockers for low- to intermediate- LDL-C reduction in patients with
risk patients with angina and for all high- NSTE-ACS has come predominantly Cigarette Smoking Cessation
risk patients unless contraindicated.1 from the Pravastatin or Atorvastatin Smoking has been shown to promote
Evaluation and Infection (PROVE IT)- the development and progression of CV
BP Control TIMI 22 study.70 This trial random- disease74 and is an important predic-
Because high BP increases myocardial ized 4162 patients hospitalized with tor of future CV events.75 Because ab-
oxygen demand, its treatment re- NSTE-ACS to receive high-dose ator- stinence from smoking has been found
mains an important goal in the man- vastatin (80 mg daily) or moderate- to greatly lower the risk of future coro-
agement of patients with NSTE-ACS. dose pravastatin (40 mg daily) for a nary events,76,77 all smokers with NSTE-
Although current guidelines recom- mean of 24 months. Patients receiving ACS should be encouraged to quit
mend a BP of less than 130/85 mm Hg1 atorvastatin experienced a 16% rela- smoking immediately. Behavioral sup-
(reserving ⬍130/80 mm Hg for pa- tive risk reduction in the composite end port,78,79 as well as bupropion with or
tients with diabetes or chronic kidney point of death, MI, unstable angina re- without nicotine replacement,80 have
354 JAMA, January 19, 2005—Vol 293, No. 3 (Reprinted) ©2005 American Medical Association. All rights reserved.
 MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES

been shown to have the greatest effi- tients with NSTE-ACS, implementa- 5. Antman EM, Cohen M, Bernink PJ, et al. The TIMI
risk score for unstable angina/non-ST elevation MI: a
cacy in helping patients quit and thus tion of these recommended acute and method for prognostication and therapeutic decision
should be offered to all patients to im- long-term treatment strategies remains making. JAMA. 2000;284:835-842.
6. Sabatine MS, Antman EM. The thrombolysis in myo-
prove long-term smoking cessation. suboptimal. While in part this may be re- cardial infarction risk score in unstable angina/non-
lated to a lack of awareness, familiarity, ST-segment elevation myocardial infarction. J Am Coll
Diabetes Management, Diet, or agreement with guideline recommen- Cardiol. 2003;41(suppl S):89S-95S.
7. Samaha FF, Kimmel SE, Kizer JR, Goyal A, Wade
and Exercise dations,97 their length and perceived M, Boden WE. Usefulness of the TIMI risk score in pre-
Long-term CV risk reduction is a ten- complexity may play a role as well. We dicting both short- and long-term outcomes in the Vet-
erans Affairs Non-Q-Wave Myocardial Infarction Strat-
able and necessary step in the treat- have accordingly proposed a modified egies In-Hospital (VANQWISH) trial. Am J Cardiol.
ment of all patients with NSTE-ACS. In and simple “ABCDE” approach to NSTE- 2002;90:922-926.
8. Sabatine MS, Morrow DA, Giugliano RP, et al. Im-
addition to the aforementioned thera- ACS that allows physicians and hospi- plications of upstream glycoprotein IIb/IIIa inhibition
pies, all patients with diabetes should tals to more effectively create disease and coronary artery stenting in the invasive manage-
maintain strict glycemic control with management protocols, define roles and ment of unstable angina/non-ST-elevation myocar-
dial infarction: a comparison of the Thrombolysis In
a glycosylated hemoglobin level of less responsibilities for different medical per- Myocardial Infarction (TIMI) IIIB trial and the Treat an-
than 7.0%.81 All patients should be sonnel, and ensure implementation of gina with Aggrastat and determine Cost of Therapy
with Invasive or Conservative Strategy (TACTICS)-
strongly encouraged to adhere to a diet short- and long-term medical and risk- TIMI 18 trial. Circulation. 2004;109:874-880.
enriched with protein, complex carbo- reducing strategies. 9. Cannon CP, Weintraub WS, Demopoulos LA, et al.
hydrates, fruits, vegetables, nuts, and Comparison of early invasive and conservative strat-
Author Contributions: Dr Blumenthal had full access egies in patients with unstable coronary syndromes
whole grains and restricted in satu- to all of the data in the study and takes responsibility treated with the glycoprotein IIb/IIIa inhibitor tirofiban.
rated fat, cholesterol, and salt.82 Fi- for the integrity of the data and the accuracy of the N Engl J Med. 2001;344:1879-1887.
data analyses. 10. Fragmin and Fast Revascularisation during Insta-
nally, all patients should be encour- Study concept and design: Gluckman, Blumenthal. bility in Coronary Artery Disease Investigators. Inva-
aged to participate in moderate levels Acquisition of data; administrative, technical, or ma- sive compared with non-invasive treatment in un-
terial support: Gluckman, Sachdev, Blumenthal. stable coronary-artery disease: FRISC II prospective
of aerobic and weight-bearing exer- Analysis and interpretation of data: Gluckman, randomised multicentre study. Lancet. 1999;354:708-
cise for at least 30 minutes on most days Schulman, Blumenthal. 715.
of the week,83,84 preferably within a car- Drafting of the manuscript; critical revision of the 11. Kaul P, Newby LK, Fu Y, et al. Troponin T and
manuscript for important intellectual content: quantitative ST-segment depression offer comple-
diac rehabilitation program.85 Gluckman, Sachdev, Schulman, Blumenthal. mentary prognostic information in the risk stratifica-
Obtained funding: Blumenthal. tion of acute coronary syndrome patients. J Am Coll
Follow-up Study supervision: Schulman, Blumenthal. Cardiol. 2003;41:371-380.
Funding/Support: This study was supported by an un- 12. Jacobs DR Jr, Kroenke C, Crow R, et al. PREDICT:
Although substantial advances have restricted educational grant from the Maryland Ath- A simple risk score for clinical severity and long-term
letic Club Charitable Foundation, Lutherville (Dr prognosis after hospitalization for acute myocardial in-
taken place in the management of pa- Blumenthal). farction or unstable angina: the Minnesota heart survey.
tients with NSTE-ACS, many individu- Role of the Sponsor: The Maryland Athletic Club Chari- Circulation. 1999;100:599-607.
als remain at high risk. Advanced age, table Foundation had no role in the design and con- 13. Eagle KA, Lim MJ, Dabbous OH, et al. A vali-
duct of the study; the collection, management, analy- dated prediction model for all forms of acute coro-
heart failure, persistent ST-segment de- sis, and interpretation of the study; or the preparation, nary syndrome: estimating the risk of 6-month post-
pression and renal insufficiency, as well review, or approval of the manuscript. discharge death in an international registry. JAMA.
2004;291:2727-2733.
as elevated levels of troponin, C- 14. Morrow DA, Braunwald E. Future of biomarkers
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©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, January 19, 2005—Vol 293, No. 3 357
LETTERS

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2003;289:450-453.
nificant for men (P = .02) but not women (P = .17). 3. Diliberti N, Bordi PL, Conklin MT, Roe LS, Rolls BJ. Increased portion size leads
In the sensitivity analysis to estimate the potential im- to increased energy intake in a restaurant meal. Obes Res. 2004;12:562-568.
4. Wansink B. Can package size accelerate usage volume? J Marketing. 1996;60:
pact of the 5 nonparticipants, the effect of bowl size re- 1-14.
mained significant (P = .02). 5. Wansink B. Environmental factors that unknowingly influence the consump-
tion and intake of consumers. Annu Rev Nutr. 2004;24:455-479.
Comment. Small environmental factors can have a large
influence on food consumption.4 At this party, large serv-
ing bowls led to a 56% greater intake (a mean of 142 more
calories/person). The size of a serving bowl (or of a por- CORRECTIONS
tion) may provide a consumption cue that implicitly sug- Incorrect Data: In the Clinical Review entitled “A Simplified Approach to the Man-
gests an appropriate amount to eat.5 Larger bowls, like larger agement of Non–ST-Segment Elevation Acute Coronary Syndromes” published
packages or portions, may suggest that a proportionately in the January 19, 2005, issue of JAMA (2005;293:349-357), incorrect data were
reported. In the “Anticoagulation” rows of the Table on Page 352, “creatinine
larger amount is appropriate to consume. Although this study clearance ⬍60 mL/min” should have been reported as “⬍30 mL/min.” Also, in
was not conducted in a medical setting, it is possible that if the center column on page 353, “creatinine clearance ⬍60 mL/min [1.0 mL/s]”
should have been reported as “⬍30 mL/min [0.5 mL/s].”
a physician giving diet-related advice recommends using
smaller serving bowls, patients may serve themselves smaller Incorrect Information: In the Medical News & Perspectives article “Michael E. De-
Bakey, MD: Father of Modern Cardiovascular Surgery” published in the February
portions. 23, 2005, issue of JAMA (2005;293:913-918), President John F. Kennedy was er-
Portion distortion has generally focused on how con- roneously described as one of the world leaders who were treated by DeBakey.
sumption cues lead people to overeat less healthy, energy- DeBakey worked with Kennedy on medical legislation for Medicare.

dense foods. An appropriate area for further research is Reference Error: In the Review entitled “Bariatric Surgery: A Systematic Review
whether these same cues, ie, larger serving bowls, can be and Meta-analysis” published in the October 13, 2004, issue of JAMA (2004;
292:1724-1737), there was a reference error. The Swedish Obese Subjects Inter-
used to encourage people to eat greater amounts of healthier vention Study has not published any of its mortality data. On page 1736, column
foods such as fruits and vegetables. 1, first full paragraph, sentences 4 and 5 should be deleted. Sentence 6 should be
“MacDonald et al57 reported that diabetic patients treated with an oral hypogly-
Brian Wansink, PhD cemic had a 4.5% annual mortality rate for 9 years of follow-up compared with a
[email protected] 1% mortality rate in diabetic patients who underwent gastric bypass.”
Applied Economics and Management
Error in Table: In the Preliminary Contribution entitled “Detection of Paternally In-
Cornell University herited Fetal Point Mutations for ␤-Thalassemia Using Size-Fractionated Cell-Free
Ithaca, NY DNA in Maternal Plasma” published in the February 16, 2005, issue of JAMA (2005;
Matthew M. Cheney, MS 293:843-849), there was an error in Table 2. On pages 847 and 848, Table 2 should
have read as follows. For each case (2 rows), the genotype and results (circulating
Graduate School of Library and Information Science fetal DNA and chorionic villus sampling) information (3 columns) was switched for
University of Illinois mother and father. For example, in case 1 for paternal IVSI-1 mutation, “Codon 39/N”
Champaign and “IVSI-1” and “IVSI-1/N” should be in the row with “Mother,” and “IVSI-1/N”
should be in the row with “Father” in that order. The subsequent rows of genotype
1. Rolls BJ, Roe LS, Kral TVE, et al. Increasing the portion size of a packaged snack and results information should be switched for each case for the rest of the Table.
increases energy intake in men and women. Appetite. 2004;42:63-69. Also, on page 848, the column heading “Patient Sex” should read “Parent.”

1728 JAMA, April 13, 2005—Vol 293, No. 14 (Reprinted) ©2005 American Medical Association. All rights reserved.