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ABSTRACT

Medical management in patients with acute coro-nary syndrome (ACS) should relieve ischemiaand reduce the risk of adverse outcomes. TheAmerican College of Cardiology/AmericanHeart Association (ACC/AHA) PracticeGuidelines recommend a variety of pharmaco-logic interventions to precede invasive treatmentfor patients with non–ST-elevation myocardialinfarction or unstable angina (NSTEMI/UA).Clinical presentation will determine the appropri-ate use of medical therapy prior to invasive inter-ventions. For those patients who are goodcandidates for pharmacologic intervention, theACC/AHA recommends anti-ischemic agents,antiplatelet agents, and anticoagulants. Some ofthese agents—especially aspirin, angiotensin-converting enzyme inhibitors, and beta block-ers—may be continued indefinitely in patientswho present with ACS. However, other pharma-cologic agents, such as the various formulationsof heparin and platelet glycoprotein IIb/IIIainhibitors, are more appropriate for acute admin-istration. When patients do not respond toappropriate pharmacologic intervention, thechoice of an invasive intervention will depend on

the extent of coronary disease because the mostinvasive techniques are reserved for the patientsat the most risk. This article reviews theACC/AHA Practice Guidelines for the treatmentof patients who present with NSTEMI/UA, includ-ing recommendations for pharmacologic andinvasive interventions. The treatment implicationsof recent clinical trials of pharmacologic inter-ventions are also discussed.(Adv Stud Pharm. 2006;3(3):112-120)

For patients who present with non–ST-eleva-tion myocardial infarction or unstable angi-na (NSTEMI/UA), the goals of medicalmanagement include relieving ischemia and

preventing poor outcomes. Figure 1 shows theAmerican College of Cardiology/American HeartAssociation (ACC/AHA) Practice Guidelines recom-mended treatment strategy for patients with acuteischemia.1 Following diagnosis of NSTEMI/UA, thetreatment strategy recommends anti-ischemia,antiplatelet, and antithrombotic therapies prior to aninvasive treatment or further monitoring. High-riskpatients or those who do not respond to pharmaco-logic therapies are candidates for an early invasiveintervention. For patients who are not considered highrisk, further testing to evaluate left ventricular func-tion and cardiac structure will determine the need forangiography and possible revascularization. Forpatients who stabilize after initial pharmacologic ther-apy, patient preference for a definitive therapeuticapproach should be considered.1

This article reviews the current ACC/AHA PracticeGuidelines for the pharmacologic and invasive treat-ment of patients who present with NSTEMI/UA.

REVIEW

CURRENT AND EMERGING TREATMENT STRATEGIES FOR ACUTE CORONARY SYNDROME

—

M. Dominique Ashen, PhD, CRNP*

*Program Coordinator, Department of Medicine—Cardiovascular, Johns Hopkins University School ofMedicine; Nurse Practitioner, Johns Hopkins CiccaronePreventive Cardiology Center, The Johns Hopkins Hospital,Baltimore, Maryland.

Address correspondence to: M. Dominique Ashen, PhD,CRNP, Program Coordinator, Department of Medicine—Cardiovascular, Johns Hopkins University School ofMedicine; Nurse Practitioner, Johns Hopkins CiccaronePreventive Cardiology Center, The Johns Hopkins Hospital,East Baltimore Campus, Blalock 524C Division ofCardiology, 600 North Wolfe Street, Baltimore, MD21287. E-mail: mashen1@jhmi.edu.

Also, the treatment implications of recent clinical tri-als in patients with acute coronary syndrome (ACS)will be discussed.

PHARMACOLOGIC THERAPY

ANTI-ISCHEMIC AGENTS

Nitroglycerin (NTG) is a vasodilator that affectsmyocardial oxygen demand and supply. Oxygendemand is reduced through dilation of the venouscapacitance vessels, thus reducing venous return to theheart (preload). Myocardial oxygen supply is increasedby NTG through coronary vasodilation. NTG therapypromotes dilation of large coronary arteries, collateralflow, and redistribution of blood flow to ischemicmuscle. In the absence of a beta blocker, increasedheart rate and contractility partially offset the benefitsof NTG therapy; therefore, these agents are usuallyadministered concurrently. Patients whose ischemia isnot relieved by sublingual NTG and the addition of anintravenous (IV) beta blocker, in addition to high-riskpatients who are not hypotensive, may benefit from IVNTG if no contraindications exist.1,2 IV NTG is usu-ally started at a low dose of 10 mg per minute and thedose is titrated upward every 3 to 5 minutes based onchest pain, blood pressure, and heart rate.

IV morphine sulfate may benefit patients whoseischemia is not relieved by serial sublingual NTGdoses. Morphine sulfate may be administered concur-rently with IV NTG to maintain patient comfort.Morphine reduces myocardial oxygen demand byreducing systolic blood pressure, reducing heart rate,and causing venodilation.1

Beta blockers reduce myocardial contractility, sinusnode rate, and atrioventricular node conduction veloc-ity by inhibiting the action of catecholamines on beta-adrenergic receptors in the myocardium. These agentsreduce systolic blood pressure, myocardial contractili-ty, heart rate, and chest pain, thereby decreasingmyocardial oxygen demand. In addition, beta blockersimprove coronary flow and collateral flow by increas-ing the duration of diastole and diastolic pressure time.

Beta blockers without sympathomimetic activityare the preferred agents. The choice among theseagents is determined by pharmacokinetics and/or sideeffect profiles. In high-risk patients and in those withongoing chest pain at rest, beta blockers should be ini-tially administered intravenously followed by oral dos-ing. Following administration of the IV loading dose,patients who do not experience side effects can be con-

verted to oral administration, with a resting heart rategoal of 50 to 60 beats per minute.1,3 Intermediate- andlow-risk patients can be started on oral therapy.1,3

Calcium antagonists cause vasodilation by reduc-ing the cellular uptake of calcium necessary formyocardial and vascular contraction. Some agents alsoslow atrioventricular node conduction and sinus nodeimpulse formation. The degree of a given effect variesamong agents. However, the beneficial effects inpatients with ACS are attributed to decreased myocar-dial oxygen demand and improved myocardial bloodflow.4 Calcium antagonists are recommended forpatients who experience ongoing or recurrent ischemiadespite appropriate treatment with nitrates and betablockers, or those patients unable to tolerate effectivedoses of either of these agents.1,4

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Figure 1. Treatment Algorithm for Acute Ischemia

LV = left ventricular; EF = ejection fraction.Adapted with permission from Braunwald et al. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed March 25, 2006.1

Early INVASIVE strategy Early CONSERVATIVE strategy

Immediateangiography

12–24 hourangiography

Recurrentsymptoms/ischemia

Heart FailureSerious arrhythmia

Patientstabilizes

Evaluate LV function

Low risk

Stress test

Follow onmedical Rx

Not low risk

EF < 40%

Recurrent ischemia and/orST segment shift, or

Deep T-wave inversion, Positive cardiac markers

Aspirin, beta blockers, NitratesAntithrombin regimen

GP iib/iia inhibitorMonitoring (rhythm and ischemia)

EF ≥ 40%

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Angiotensin-converting enzyme inhibitors havebeen shown to reduce death rates in patients withacute myocardial infarction and in patients with leftventricular dysfunction who are diabetic or who havehad a myocardial infarction (MI).5-9 These agents arerecommended in all post-ACS patients.1

ANTIPLATELET AGENTS

Aspirin reduces platelet aggregation by a singlemechanism. It prevents the formation of thromboxaneA2 by inhibiting cyclooxygenase-1 within platelets.The clinical benefits of aspirin therapy are present atlow doses (75–325 mg) and are rapidly established.10,11

In patients with ACS, the first dose of aspirin shouldbe chewed to quicken absorption, and subsequentdoses may be swallowed. Aspirin therapy is recom-mended immediately following the diagnosis or suspi-cion of ACS, and should be continued indefinitely inpatients with NSTEMI/UA or any significant coro-nary disease.1,3,10,12

The adenosine diphosphate receptor antagonists,ticlopidine and clopidogrel, are approved forantiplatelet therapy. Because their mechanism ofaction differs from that of aspirin, combination thera-py may provide additional benefit. Clopidogrel treat-ment is recommended over ticlopidine treatmentbecause ticlopidine has a slow onset and less favorablesafety profile than clopidogrel.13-15 Clopidogrel in com-bination with aspirin is the recommended pretreat-ment in patients undergoing percutaneous coronaryintervention (PCI), especially coronary artery stent-ing.1 Clopidogrel is initially administered in a loadingdose and should be continued for up to 12 monthsafter coronary stenting.16

The glycoprotein (GP) IIb/IIIa inhibitors occupythe GP IIb/IIIa receptors that are abundant on theplatelet surface. These inhibitors prevent platelet aggre-gation by preventing interplatelet fibrinogen bind-ing.17,18 It is recommended that GP IIb/IIIa inhibitorsbe administered in addition to aspirin and heparin inpatients who are scheduled for PCI. The GP IIb/IIIainhibitor may be administered prior to PCI.1

ANTICOAGULANTS

Unfractionated heparin prevents clotting byenhancing the effect of the proteolytic enzymeantithrombin that inactivates thrombin, factor IXa,and factor Xa.19 Unfractionated heparin is a mixture ofmolecules of widely varying molecular weights

(5000–30 000 g) and variable anticoagulant effects,resulting from its nonspecific binding to plasma pro-teins, blood cells, and endothelial cells.20 This nonspe-cific binding translates into a variable anticoagulantresponse among patients that necessitates monitoringof the activated partial thromboplastin time to deter-mine the extent of anticoagulant effect. The variableanticoagulant response is exacerbated by differences inpatient body weight, age, smoking history, and thepresence of diabetes.21

Low–molecular-weight heparins are a mixture ofmolecules that vary in molecular weight from 4200 gto 6000 g. The low–molecular-weight heparins haveless binding affinity for plasma proteins and endothe-lial cells, a longer half-life, and dose-dependent clear-ance. Therefore, these preparations have predictableand long-acting effects that can be sustained withonce- or twice-daily subcutaneous injection.20

However, the level of anticoagulant effect cannot easi-ly be measured for low–molecular-weight heparins. Itis recommended that patients be switched fromlow–molecular-weight heparins to unfractionatedheparin prior to coronary artery bypass graft (CABG)surgery so the level of anticoagulation activity can beaccurately measured during surgery.1

Lepirudin is a direct thrombin inhibitor that is cur-rently indicated only for patients with heparin-induced thrombocytopenia.1,22 Similarly, warfarinshould only be used in patients with NSTEMI/UAwho have other indications for warfarin, such as atrialfibrillation or mechanical heart valves.1

INVASIVE THERAPY

Coronary angiography can define the coronaryartery anatomy in patients with NSTEMI/UA andidentify those patients who would benefit from earlyrevascularization. Angiography provides detailed coro-nary structural information that is helpful in deter-mining prognosis. Left ventricular angiography alsoallows the assessment of left ventricular function.23 Anearly invasive approach that incorporates coronaryangiography within 24 hours is indicated for patientswith NSTEMI/UA who have symptoms of ischemiadespite appropriate pharmacologic treatment or thosewho have high-risk clinical symptoms (Table 1).Figure 2 shows the ACC/AHA recommended strategyfor proceeding from coronary angiography to revascu-larization. The decision to move to revascularization isinfluenced by coronary anatomy and other factors,

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such as age, ventricular function,comorbid conditions, physical function,symptom severity, and amount ofmyocardium at risk.3,24

The choice of revascularization pro-cedure primarily depends on the extentof coronary disease (Table 2).1 PCI refersto a group of revascularization tech-niques, including balloon angioplasty,placement of an intracoronary stent, andatheroablation. Balloon angioplasty fol-lowed by stent placement, usually withdrug-eluting stents, constitutes the bulkof PCIs today. The efficacy and safety ofPCI techniques have been increased bythe addition of GP IIb/IIIa inhibitors tostandard antithrombotic regimens.1

CABG surgery is the recommendedrevascularization procedure for high-riskpatients, especially those with multives-sel disease and left ventricular dysfunction. CABGsurgery provides modest long-term benefit to low-riskpatients compared with the benefit to high-risk patients.However, low-risk patients whose symptoms are severeor impair their physical function may elect to undergorevascularization to improve their quality of life.1

Because the ACC/AHA guidelines were developedapproximately 4 years ago, it is important to note thatour understanding of the benefits and risks of PCI ver-sus CABG in specific patient groups is constantly evolv-ing. As such, in today’s clinical practice, the number ofpatients undergoing PCI is rapidly increasing comparedwith those undergoing CABG surgery.

SEX DIFFERENCES AND NSTEMI/UA TREATMENT

Although women are more likely than men to havechest pain that is not caused by coronary artery disease(eg, noncardiac pain, coronary vasospasm), womenstill represent a significant percentage of patients withNSTEMI/UA.25,26 Because women develop coronaryartery disease later in life than men, they tend to beolder and have more comorbid conditions when theypresent with ACS.27-29 Despite the considerable inci-dence of ACS in both sexes, differences in treatmentpatterns have been observed. For example, aspirin andother antithrombotics are consistently prescribed forfewer women with ACS compared with men.30 In thecase of invasive procedures, successful PCI and out-comes are similar in both sexes, although women may

Figure 2. Revascularization Strategy After Angiography

CABG = coronary artery bypass graft; LAD= left anterior descending; PCI= percutaneus coronary intervention.Adapted with permission from Braunwald et al. Available at http:www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed March 25, 2006.1

Cardiac catheterization

3-vessel disease or 2-vessel disease with proximal

LAD involvement

Coronary artery disease

1- or 2- vessel disease

Left main disease

NO

Medical therapy

PCI or CABG

CABG

PCI or CABG

Left ventricular dysfunction or

treated diabetes

Discharge from protocol

CABG

YES

NO

YES

NO

Table 1. Indicators for an Early Invasive Strategy in Patients withNSTEMI/UA

• Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy

• Elevated troponin T or troponin I• New or presumably new ST-segment depression• Recurrent angina/ischemia with congestive heart failure symptoms, an S3 gallop,

pulmonary edema, worsening rales, or new or worsening mitral regurgitation murmur• High-risk findings on noninvasive stress testing• Depressed left ventricular systolic function (eg, ejection fraction <0.40 on noninvasive

study)• Hemodynamic instability• Sustained ventricular tachycardia• Percutaneous coronary intervention within 6 months• Prior coronary artery bypass graft

NSTEMI/UA = non–ST-elevation myocardial infarction/unstable angina.Adapted with permission from Braunwald et al. Available at: http:www.acc.org/clinical/guidelines/unsta-ble/unstable.pdf. Accessed March 25, 2006.1

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have early complications more frequent-ly and generally undergo angiographyless frequently.1 In older studies ofwomen undergoing CABG surgery,women had higher death rates, fewercomplete revascularizations, and a lowerlikelihood of receiving an internal mam-mary artery.1 Fortunately, more recentstudies show a normalization of thesetrends.28,30

RECENT STUDIES IN PATIENTS

WITH ACSPRIMARY PREVENTION OF

CARDIOVASCULAR EVENTS

Investigators in the CHARISMAtrial randomized more than 15 000patients with symptomatic cardiovascu-lar disease to receive low-dose aspirinand either clopidogrel or placebo.Follow-up lasted for 28 months.31

Patients received clopidogrel and low-dose aspirin orplacebo and low-dose aspirin. The primary endpointwas a composite of cardiovascular death, MI, or stroke.Overall, dual therapy provided no significant benefitover aspirin alone. Among patients with multiple riskfactors but no history of a prior vascular event, dualtherapy was associated with increased death rates.However, fewer patients with symptomatic cardiovas-cular disease who received clopidogrel reached theendpoint compared with patients receiving placebo(6.9% vs 7.9%, P = .046). The risk of moderate bleed-ing was increased in the clopidogrel group (2.1% vs1.3%, P <.001). These findings indicate that clopido-grel therapy offers no additional benefit to aspirin inpatients at high risk for cardiovascular events.

SECONDARY PREVENTION OF CARDIOVASCULAR EVENTS

The CREDO trial enrolled 2116 patients withACS who were scheduled for PCI or deemed goodcandidates for PCI.32 Patients were randomized toreceive a 300-mg loading dose of clopidogrel or place-bo 3 to 24 hours prior to PCI. All patients receivedclopidogrel 75 mg per day for 28 days after PCI. Onday 29, the group given the loading dose continued toreceive clopidogrel 75 mg per day for 12 months,whereas the group given placebo continued to receiveplacebo. All patients received aspirin throughout thetrial. The primary outcome measures were 1-year rates

of death, MI, or stroke, and 28-day rates of death, MI,or urgent revascularization.

Long-term clopidogrel therapy was associated with a27% risk reduction in the primary endpoint (P = .02).Clopidogrel pretreatment did not provide benefit overplacebo except in the subpopulation of patients whoreceived clopidogrel treatment at least 6 hours prior toPCI, in which there was a trend toward risk reduction(39%, P = .051). Risk of bleeding was the same betweentreatment groups.

The CURE trial randomized 12 562 patients withNSTEMI to receive clopidogrel (300 mg, followed by75 mg once daily) or placebo for 3 to 12 months.33 Allpatients received aspirin. The primary endpoint ofdeath, MI, or stroke occurred in 9.3% of patients inthe clopidogrel group compared with 11.4% ofpatients receiving placebo (P <.001). Refractoryischemia or the primary endpoint occurred in 16.5%of patients receiving clopidogrel and 18.8% of patientsreceiving placebo (P <.001). Clopidogrel therapy wasalso associated with lower rates of in-hospital refracto-ry or severe ischemia, heart failure, and revasculariza-tion, but higher rates of major bleeding.

The CLARITY-TIMI 28 investigators randomized3491 patients with STEMI to receive clopidogrel(300-mg loading dose, then 75 mg daily) or placebo.34

Patients received a fibrinolytic agent, aspirin, andheparin as appropriate. All patients were scheduled for

Table 2. Mode of Coronary Revascularization Is Dictated by Extent ofDisease

Extent of Disease Treatment

Left main disease No contraindication CABG

Contraindication PCI

3-vessel disease EF <50% CABG

Multivessel disease Proximal LAD, EF <50%, CABG or PCIand treated diabetes

Multivessel disease EF >50% and no diabetes PCI

1- or 2-vessel disease No proximal LAD, with CABG or PCIextensive myocardial ischemia or high-risk criteria

CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention; LAD = left anterior descending; EF = ejection fraction.Adapted with permission from Braunwald et al. Available at http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed March 25, 2006.1

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angiography 48 to 192 hours after starting the studymedication. The primary endpoint was a composite ofdeath, recurrent MI before angiography, or occludedartery on angiography. Significantly fewer clopidogrel-treated patients reached the endpoint compared withthe placebo group (15.0% vs 21.7%, P <.001). By 30days, combined rates of cardiovascular death, recurrentMI, or urgent revascularization were reduced in theclopidogrel group compared with the placebo group(11.6% vs 14.1%, P = .03). The incidence of majorbleeding or intracranial hemorrhages was the samebetween groups.

The PCI-CLARITY study was a subanalysis ofCLARITY-TIMI 28, in which 1863 patients withSTEMI underwent PCI following angiography.35 Theprimary endpoint was the composite of death, recur-rent MI, or stroke within 30 days of PCI. For theclopidogrel group, significantly fewer deaths, MI, orstrokes occurred through 30 days compared with theplacebo group (7.5% vs 12.0%, P = .001). No differ-ence in the rates of bleeding was observed betweentreatment groups.

In the COMMITT/CCS-2 study conducted inChina, 45 852 patients with acute myocardial infarc-tion (93% of patients had an STEMI) were enrolled toassess the effects of adding clopidogrel (vs placebo) andearly IV followed by oral metoprolol (vs placebo) toaspirin therapy.36,37 Clopidogrel was administered at 75mg daily, and metoprolol was administered intra-venously in three 5-mg doses over 15 minutes followedby daily oral doses of up to 200 mg. The primary end-point was the composite of death, reinfarction, orstroke. In the clopidogrel arm, significantly fewerpatients reached the endpoint compared with the con-trol group (9.3% vs 10.1%, P = .002). No differencein the occurrence of major bleeding was observedbetween treatment groups. In the metoprolol arm,there was no significant reduction in the incidence ofthe composite endpoint of death, reinfarction, or ven-tricular fibrillation/cardiac arrest associated with meto-prolol treatment, although there were significantreductions in the risk of reinfarction (P = .001) andventricular fibrillation (P <.001). Metoprolol treat-ment was associated with an increased risk of cardio-genic shock (P <.00001), especially during the first dayof hospitalization.

In the ISAR-REACT 2 trial, 2022 patients withNSTEMI who were scheduled for PCI were random-ized to receive bolus and 12-hour infusion abciximab

and heparin (70 U/kg) or placebo and heparin (140U/kg).38 All patients were pretreated with clopidogrel600 mg and aspirin 500 mg. The primary endpointwas death, MI, or urgent revascularization. Overall,abciximab treatment reduced the risk of reaching theendpoint by 25% compared with placebo (8.9% vs11.9%, P = .03). In patients with elevated troponinlevels, abciximab reduced the risk of a poor outcome(13.1% vs 18.3%, P = .002). No benefit was shown forpatients without elevated troponin levels who receivedabciximab. No significant difference in the risk ofbleeding was observed between the group given abcix-imab and the group given placebo.

In OASIS-5, 20 078 patients with NSTEMI/UAwere randomized within 24 hours of symptom onsetto receive fondaparinux, a selective factor Xainhibitor, 2.5 mg daily or enoxaparin 1 mg/kg twicedaily for 6 days.39 The primary endpoint was theoccurrence of major bleeding, death, MI, refractoryischemia by 9 days, or a combination of these events.There was a trend toward fewer combined events inthe fondaparinux group (P = .13 at 30 days and P =.06 at study end). The rate of major bleeding was48% lower in the fondaparinux group (2.2% vs 4.1%,P <.001), and the incidence of major bleeding incombination with the other endpoints was signifi-cantly lower in the fondaparinux group at 9 days(7.3% vs 9.0%, P <.001). Fondaparinux treatmentwas associated with lower mortality than enoxaparinat 30 days (2.9% vs 3.5%, P = .02) and 180 days(5.8% vs 6.5%, P = .05).

In OASIS-6, 12 092 patients with STEMI wererandomized to receive an 8-day course of fondaparin-ux 2.5 mg, unfractionated heparin for 48 hours fol-lowed by placebo for up to 8 days, or an 8-day courseof placebo in patients with contraindication to unfrac-tionated heparin.40 The primary endpoint was death orreinfarction at 30 days. Significantly fewer patients inthe fondaparinux group reached the endpoint com-pared with the control group (9.7% vs 11.2%, P =.008). There was no benefit from fondaparinux treat-ment in patients undergoing PCI. Fondaparinux treat-ment was associated with fewer deaths andreinfarctions at 30 days (P = .08) and the study end (P= .008) compared with unfractionated heparin.Significant benefits were observed for patients under-going thrombolytic therapy (P = .003) and those notreceiving reperfusion therapy (P = .03). Fondaparinuxtreatment was associated with fewer incidences of car-

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diac tamponade (P = .02) and a trend toward fewersevere bleeds.

The ExTRACT-TIMI 25 investigators randomized20 506 patients with STEMI who were scheduled forfibrinolysis to receive enoxaparin throughout hospital-ization or unfractionated heparin for at least 48hours.41 The primary endpoint was death or reinfarc-tion within 30 days. Fewer patients in the enoxaparingroup reached the primary endpoint compared withthe unfractionated heparin group (9.9% vs 12.0%, P<.001). This difference was mainly due to varied ratesof reinfarction between groups.

Fewer patients in the enoxaparin group reached thecomposite endpoint of death, reinfarction, or urgentrevascularization (11.7% vs 14.5%, P <.001). Also,fewer patients in the enoxaparin group reached thecomposite endpoint of death, reinfarction, or nonfatalintracranial hemorrhage (10.1% vs 12.2%, P <.001).Major bleeding was more frequent in the enoxaparingroup compared with the unfractionated heparingroup (2.1% vs 1.4%, P <.001).

Collectively, these clinical trials provide importantnew information about the efficacy and safety ofantiplatelet and antithrombotic agents in ACS.However, it is important to remember that bleeding isa significant adverse effect associated with these agents.An analysis of the results of the CRUSADE studypointed out that excessive doses of unfractionatedheparin, low–molecular-weight heparin, and glycopro-tein IIb/IIIa inhibitors are frequently administered topatients with ACS.42 Importantly, these excessive dosesare associated with increased risk of bleeding.

TREATMENT IMPLICATIONS OF RECENT

CLINICAL TRIALS

As a primary preventive treatment in patients withmultiple risk factors but no history of prior vascularevents, dual aspirin and clopidogrel therapy provided nobenefit compared with aspirin alone. However, inpatients with symptomatic cardiovascular disease, dualaspirin and clopidogrel therapy reduced the incidence ofcardiovascular events while increasing the risk of bleed-ing. Therefore, in this high-risk patient population, theaddition of clopidogrel to aspirin therapy is not recom-mended. As secondary preventive treatment, pharmaco-logic therapy with clopidogrel and aspirin significantlyreduced the rates of cardiovascular events but increasedthe risk of bleeding. Clopidogrel pretreatment followedby daily clopidogrel therapy significantly reduced the

risk of cardiovascular events in the 30-day period fol-lowing angiography and subsequent PCI without anincreased risk of bleeding. Similarly, long-term clopido-grel therapy following PCI significantly reduced the riskof cardiovascular events without increasing the risk ofbleeding. These outcomes suggest that clopidogrel ther-apy provides significant benefits to patients receivingpharmacologic or invasive intervention. Clopidogreltherapy seems to increase the risk of bleeding only inpatients who do not receive invasive intervention.Additional monitoring will be required in these patients.

Significant short-term reductions in the rates ofmajor bleeding and cardiovascular events wereobserved in patients receiving fondaparinux treatmentcompared with those receiving enoxaparin treatment.Thirty-day mortality was also reduced in the fonda-parinux group. Similarly, fondaparinux treatment sig-nificantly reduced mortality and cardiovascular eventrates compared with patients receiving unfractionatedheparin. However, there was no observed treatmentdifference between fondaparinux and unfractionatedheparin for those patients who required PCI. Theseoutcomes suggest that fondaparinux therapy wassuperior to enoxaparin therapy and unfractionatedheparin therapy in patients who underwent pharma-cologic intervention but not those who required inva-sive intervention. Fondaparinux therapy does notseem to require additional monitoring for bleeding.

Enoxaparin treatment reduced the rates of mortal-ity and cardiovascular events in patients undergoingfibrinolysis therapy compared with patients receivingunfractionated heparin. Benefits from enoxaparintherapy were also seen in the rates of intracranial hem-orrhage. However, the risk of major bleeding wasincreased in the enoxaparin group. Enoxaparin thera-py seems to provide greater benefit than unfractionat-ed heparin as ancillary treatment to fibrinolysis.However, enoxaparin therapy will require additionalmonitoring for bleeding in this scenario.

Abciximab treatment reduced the risk of mortalityand cardiovascular events in patients with elevated tro-ponin levels who underwent PCI compared with thosepatients who received placebo. Treatment benefitswere not observed in patients without elevated tro-ponin levels, and there was no difference in the inci-dence of bleeding between groups. This study suggeststhat patients who are at risk for significant myocardialdamage, as indicated by elevated troponins, may ben-efit most from abciximab therapy.

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CONCLUSIONS

The ACC/AHA Practice Guidelines for patientswith NSTEMI/UA recommend pharmacologic thera-pies, including anti-ischemic agents, antiplateletagents, and anticoagulants. Depending on the clinicalpresentation and the patient’s level of risk, these agentsare recommended prior to an invasive intervention orprior to further observation. Patients who require inva-sive revascularization will benefit from PCI or CABG,depending on the extent of coronary artery disease andpresence of contraindications.

Recent clinical trials of pharmacologic agents haveconfirmed their therapeutic benefits. Clopidogrel wasshown to be an effective agent in pharmacologic ther-apy and as pretreatment for an invasive intervention.Fondaparinux was superior to enoxaparin and unfrac-tionated heparin for patients receiving pharmacologictreatment alone, and enoxaparin was superior tounfractionated heparin as ancillary treatment to fibri-nolysis. Finally, abciximab was shown to benefitpatients who have elevated troponins. Although somepharmacologic therapies are associated with anincreased risk of bleeding, their appropriate use mayhelp to lower the high mortality attributable to ACS.

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