11
CLINICAL REVIEW Diagnosis and Management of Acute Coronary Syndrome: An Evidence-Based Update Jennifer N. Smith, PharmD, BCPS, Jenna M. Negrelli, PharmD, BCPS, Megha B. Manek, MD, Emily M. Hawes, PharmD, BCPS, and Anthony J. Viera, MD Acute coronary syndrome (ACS) describes the range of myocardial ischemic states that includes unstable angina, non-ST elevated myocardial infarction (MI), or ST-elevated MI. ACS is associated with substan- tial morbidity and mortality and places a large financial burden on the health care system. The diagno- sis of ACS begins with a thorough clinical assessment of a patient’s presenting symptoms, electrocardio- gram, and cardiac troponin levels as well as a review of past medical history. Early risk stratification can assist clinicians in determining whether an early invasive management strategy or an initial conser- vative strategy should be pursued and can help determine appropriate pharmacologic therapies. Key components in the management of ACS include coronary revascularization when indicated; prompt initi- ation of dual antiplatelet therapy and anticoagulation; and consideration of adjuvant agents including blockers, inhibitors of the renin angiotensin system, and HmG– coenzyme A reductase inhibitors. It is essential for clinicians to take an individualized approach to treatment and consider long-term safety and efficacy when managing patients with a history of ACS after hospital discharge. ( J Am Board Fam Med 2015;28:283–293.) Keywords: Acute Coronary Syndrome, Cardiology, Myocardial Infarction Acute coronary syndrome (ACS) describes the range of myocardial ischemic states that includes unstable angina (UA), non-ST elevated myocar- dial infarction (NSTEMI), or ST-elevated myo- cardial infarction (STEMI). The diagnosis and classification of ACS is based on a thorough re- view of clinical features, including electrocardio- gram (ECG) findings and biochemical markers of myocardial necrosis. 1 UA is defined by the pres- ence of ischemic symptoms without elevations in biomarkers and transient, if any, ECG changes. 2 The term myocardial infarction (MI) is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia. STEMI is differentiated from NSTEMI by the presence of persistent ECG findings of ST segment elevation. 3 In recent years, progress has been made in the management of ACS, particularly related to opti- mizing pharmacotherapy. 2,3 Family physicians care for patients presenting with ACS in office as well as emergency settings and play an important role in both acute and long-term management of such patients. In this article, we review the topic of ACS with particular emphasis on initial management and use of the newer medications. Specific coro- nary interventions performed by the cardiologist (eg, stents or balloon angioplasty) are beyond the scope of this review. Scope of the Problem Coronary heart disease (CHD) is responsible for more than half of all cardiovascular events in indi- viduals less than 75 years of age. The prevalence of This article was externally peer reviewed. Submitted 26 June 2014; revised 12 October 2014; ac- cepted 20 October 2014. From the Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC (JNS, JMN, EMH); Department of Family Medicine, Guthrie/Robert Packer Hospital, Sayre, PA (MBM); Department of Family Medicine, University of North Carolina School of Medi- cine, Chapel Hill, NC (EMH, AJV) Current affiliation: Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA (JNS); Inter- mountain Medical Center in Murray, UT (JMN). Funding: none. Conflict of interest: none declared. Corresponding author: Jennifer N. Smith, PharmD, BCPS, Philadelphia College of Pharmacy at University of the Sci- ences, 600 S 43rd Street, Philadelphia, PA 19104 (E-mail: [email protected]). doi: 10.3122/jabfm.2015.02.140189 Diagnosis and Management of Acute Coronary Syndrome 283

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  • CLINICAL REVIEW

    Diagnosis and Management of Acute CoronarySyndrome: An Evidence-Based UpdateJennifer N. Smith, PharmD, BCPS, Jenna M. Negrelli, PharmD, BCPS,Megha B. Manek, MD, Emily M. Hawes, PharmD, BCPS, and Anthony J. Viera, MD

    Acute coronary syndrome (ACS) describes the range of myocardial ischemic states that includes unstableangina, non-ST elevated myocardial infarction (MI), or ST-elevated MI. ACS is associated with substan-tial morbidity and mortality and places a large financial burden on the health care system. The diagno-sis of ACS begins with a thorough clinical assessment of a patients presenting symptoms, electrocardio-gram, and cardiac troponin levels as well as a review of past medical history. Early risk stratificationcan assist clinicians in determining whether an early invasive management strategy or an initial conser-vative strategy should be pursued and can help determine appropriate pharmacologic therapies. Keycomponents in the management of ACS include coronary revascularization when indicated; prompt initi-ation of dual antiplatelet therapy and anticoagulation; and consideration of adjuvant agents including blockers, inhibitors of the renin angiotensin system, and HmGcoenzyme A reductase inhibitors. It isessential for clinicians to take an individualized approach to treatment and consider long-term safetyand efficacy when managing patients with a history of ACS after hospital discharge. (J Am Board FamMed 2015;28:283293.)

    Keywords: Acute Coronary Syndrome, Cardiology, Myocardial Infarction

    Acute coronary syndrome (ACS) describes therange of myocardial ischemic states that includesunstable angina (UA), non-ST elevated myocar-dial infarction (NSTEMI), or ST-elevated myo-cardial infarction (STEMI). The diagnosis andclassication of ACS is based on a thorough re-view of clinical features, including electrocardio-gram (ECG) ndings and biochemical markers ofmyocardial necrosis.1 UA is dened by the pres-

    ence of ischemic symptoms without elevations inbiomarkers and transient, if any, ECG changes.2

    The term myocardial infarction (MI) is usedwhen there is evidence of myocardial necrosis inthe setting of acute myocardial ischemia. STEMIis differentiated from NSTEMI by the presence ofpersistent ECG ndings of ST segment elevation.3

    In recent years, progress has been made in themanagement of ACS, particularly related to opti-mizing pharmacotherapy.2,3 Family physicians carefor patients presenting with ACS in ofce as well asemergency settings and play an important role inboth acute and long-term management of suchpatients. In this article, we review the topic of ACSwith particular emphasis on initial managementand use of the newer medications. Specic coro-nary interventions performed by the cardiologist(eg, stents or balloon angioplasty) are beyond thescope of this review.

    Scope of the ProblemCoronary heart disease (CHD) is responsible formore than half of all cardiovascular events in indi-viduals less than 75 years of age. The prevalence of

    This article was externally peer reviewed.Submitted 26 June 2014; revised 12 October 2014; ac-

    cepted 20 October 2014.From the Department of Pharmacy, University of North

    Carolina Medical Center, Chapel Hill, NC (JNS, JMN,EMH); Department of Family Medicine, Guthrie/RobertPacker Hospital, Sayre, PA (MBM); Department of FamilyMedicine, University of North Carolina School of Medi-cine, Chapel Hill, NC (EMH, AJV)

    Current afliation: Philadelphia College of Pharmacy,University of the Sciences in Philadelphia, PA (JNS); Inter-mountain Medical Center in Murray, UT (JMN).

    Funding: none.Conict of interest: none declared.Corresponding author: Jennifer N. Smith, PharmD, BCPS,

    Philadelphia College of Pharmacy at University of the Sci-ences, 600 S 43rd Street, Philadelphia, PA 19104 (E-mail:[email protected]).

    doi: 10.3122/jabfm.2015.02.140189 Diagnosis and Management of Acute Coronary Syndrome 283

  • CHD is estimated to be 6.4% in United States (US)adults greater than or equal to 20 years of age,which represents approximately 15.4 million Amer-icans. During the past several years, the rates ofhospitalization for MI and mortality associatedwith CHD have decreased. The decline in CHDmortality is partially reective of the change in thepattern of clinical presentations of ACS.4 There hasbeen a substantial reduction in the incidence ofSTEMI and a subsequent increase in the incidenceof NSTEMI.3 An analysis of 46,086 hospitaliza-tions for ACS in a study conducted by Kaiser Per-manente demonstrated that the percentage ofSTEMI cases decreased from 48.5% to 24% be-tween 1999 and 2008.4 Despite the improvement insurvival associated with ACS, this medical condi-tion continues to have an association with fataloutcomes and places a burden on the entire healthcare system. A diagnosis of MI was responsible forapproximately 125,000 deaths in the US in 2009,and ACS was associated with an estimated 625,000hospital discharges in 2010.4 It is evident that thereis room for improvement in the prevention andmanagement of ACS.

    DiagnosisClinical PresentationA diagnosis of ACS should be considered in allpatients presenting with ischemic symptoms. Clin-ical signs and symptoms of ischemia include variouscombinations of chest pain, upper extremity, man-dibular or epigastric discomfort, dyspnea, diapho-resis, nausea, fatigue, or syncope. The pain anddiscomfort associated with an ACS event may occurwith exertion or at rest and is often diffuse ratherthan localized.1 Pain radiating to the left arm, rightshoulder, or both arms is more likely to be associ-ated with MI, as is pain associated with diaphore-sis.5 These symptoms are not specic for MI and donot occur in all patients experiencing an ACS event.Atypical symptoms of ACS may occur in certainpatient populations such as women, the elderly,diabetics, or postoperatively. In these situations,ACS may be associated with palpitations, cardiacarrest, or with an asymptomatic clinical presenta-tion.1

    Past Medical HistoryObtaining a thorough past medical history in pa-tients with suspected ACS is essential in assuring

    appropriate diagnosis and management. Factorsthat should be evaluated include the nature of apatients angina symptoms, prior history of coro-nary artery disease (CAD), sex, age, and presence ofrisk factors for ACS. For patients who do not havethese factors, consideration should be given to analternative disease process.2

    Differential DiagnosisIt is important to remember that MI representsmyocardial necrosis due to myocardial ischemia.Other clinical conditions, such as pericarditis,dissecting aortic aneurysm, and mitral valve pro-lapse represent nonischemic, cardiac causes ofmyocardial injury and thus do not fall within thedenition of ACS. In addition, there are severalnoncardiac conditions that may manifest withsimilar symptoms of ACS, including musculosk-eletal pain, esophageal discomfort, pulmonaryembolism, or anxiety. It is essential to determinethe correct etiology of a patients signs and symp-toms to determine an appropriate managementplan.1,2

    Cardiac BiomarkersCardiac troponins are biochemical markers of myo-cardial damage.6 Increases in cardiac biomarkers,notably cardiac troponin (I or T), or the MB frac-tion of creatine kinase (CKMB), signify myocardialinjury leading to necrosis of myocardial cells. Ele-vated cardiac biomarkers in and of themselves donot indicate the underlying mechanism of injuryand do not differentiate between ischemic or non-ischemic causes.1 There are several clinical condi-tions that have the potential to result in myocardialinjury and cause elevations in cardiac biomarkers,including acute pulmonary embolism, heart failure(HF), end-stage renal disease, and myocarditis.7 Asa result, cardiac biomarker elevations cannot beutilized in isolation to make a diagnosis of MI.1

    The preferred cardiac biomarker is troponin, whichhas high clinical sensitivity and myocardial tissuespecicity. An elevation in troponin concentrationis based on specic assays and is dened as a valueexceeding the 99th percentile of a normal referencepopulation. At this level, sensitive cardiac troponinI assays have a positive likelihood ratio (LR) of1114 and a negative LR of 0.060.15.6 It is es-sential to detect a rise and/or fall in cardiac bio-markers to distinguish acute from chronic eleva-tions in troponin concentrations, which may be

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  • associated with structural heart disease. Troponinlevels should be measured on rst assessment,within 6 hours of the onset of pain, and in the 612hour time frame after onset of pain, due to thedelayed increase in circulating levels of cardiac bio-markers (strength of recommendation A). In addi-tion, it is important to understand that elevations introponin may be seen for up to 2 weeks after theonset of myocardial necrosis. If troponin concen-trations are unavailable, then CKMB should bemeasured.1 Ideally, both troponin and CKMBshould be obtained during evaluation for ACS dueto the different concentrations of these biomarkersover time and the added diagnostic value of serialtesting (strength of recommendation A).2,3 For ex-ample, serial measurement of CKMB has a positiveLR of 20 and negative LR of 0.22.8

    ECG ChangesECG abnormalities that are potentially reectiveof myocardial ischemia include changes in the PRsegment, the QRS complex, and the ST-seg-ment. A meticulous evaluation of ECG changescan assist in estimating time of the event, amountof myocardium at risk, patient prognosis, andappropriate therapeutic strategies. ST-segmentelevation found on an ECG is the hallmark signof a STEMI.1 Similar to cardiac biomarkers, theECG alone is often insufcient to make the di-agnosis of an acute MI, and the sensitivity andspecicity of ECG are increased by serial assess-ments.9 ECG changes such as ST deviation maybe present in other conditions, such as left ven-

    tricular hypertrophy, left bundle branch block, oracute pericarditis.1

    Initial ACS ManagementEarly ManagementIt is essential to evaluate patients with suspectedACS immediately to prevent potentially fatal clin-ical consequences and relieve ongoing ischemia.Early risk stratication should be performed that isinclusive of a patients demographics and medicalhistory, physical examination, ECG, and cardiacbiomarker measurements (strength of recommen-dation A). A number of risk assessment tools havebeen developed to predict ones risk of recurrentischemia or death following an ACS event. TheThrombosis in Myocardial Infarction (TIMI) riskscore, a scoring system for UA and NSTEMI thatincorporates seven variables on hospital admission,has been validated as a reliable predictor of subse-quent ischemic events (Table 1). In addition, mea-surement of B-type natriuretic peptide may be con-sidered to assist in predicting risk of morbidity andmortality in patients with suspected ACS. Early riskstratication can assist in determining whether apatient should be managed with either an earlyinvasive strategy or an initial conservative strategyand can help determine the pharmacologic thera-pies that are recommended (Figure 1).2

    Coronary RevascularizationIn patients presenting with a STEMI, reperfusiontherapy should be administered to all eligible patientswith symptom onset within the prior 12 hours.3 Per-

    Table 1. The Thrombosis in Myocardial Infarction (TIMI) Risk Score for Unstable Angina (UA)/Non-ST ElevatedMyocardial Infarction (NSTEMI)2

    Baseline Characteristics (1 point for each ofthe following): TIMI Risk Score (points) Rate of Composite Endpoint (%)

    Age 65 years; At least 3 risk factors forCAD*; Prior coronary stenosis 50%;ST segment deviation; At least 2 anginalevents in last 24 hours; Use of aspirin inlast 7 days; Elevated serum cardiacbiomarkers

    01 4.72 8.33 13.24 19.95 26.2

    67 40.9

    *Risk factors include family history of CAD, hypertension, hypercholesterolemia, diabetes, or being a current smoker.CKMB fraction and/or cardiac-specic troponin level.All-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization through 14 days afterrandomization.CAD, coronary artery disease; MI, myocardial infarction; CKMB, MB fraction of creatine kinase.

    doi: 10.3122/jabfm.2015.02.140189 Diagnosis and Management of Acute Coronary Syndrome 285

  • cutaneous coronary intervention (PCI) is the recom-mended method of reperfusion when it can be per-formed in a timely fashion, with the goal of time fromrst medical contact to device time of less than orequal to 90 minutes (strength of recommendationA).3 If patients are unable to get to a PCI-capablehospital within 120 minutes of a STEMI, then -brinolytic therapy should be administered within 30minutes of hospital arrival, provided there are nocontraindications to its use (Figure 2) (strength ofrecommendation A).3 The benet of an early invasivestrategy of evaluation with coronary angiography forthe treatment of patients initially presenting withNSTEMI or UA is less certain. A recent meta-anal-ysis showed that current randomized controlled stud-ies are inconclusive with regard to survival benetassociated with early (typically 24 hours) versus de-layed invasive strategy in patients presenting withNSTEMI (OR, 0.83; 95% CI, 0.641.09; P .180).10 Early invasive coronary angiography is rec-ommended in NSTEMI/UA patients with refractory

    angina or hemodynamic or electric instability(strength of recommendation A). Early invasivestrategy is reasonable for higher-risk patients withNSTEMI/UA previously stabilized who do not haveserious comorbidities (i.e., liver or pulmonary failure,cancer) or contraindications to the procedure(strength of recommendation B).11 Specic strategiesutilized during revascularization are outside the scopeof this review.

    Antithrombotic AgentsAntiplatelet therapy, which reduces the risk ofthrombosis by interfering with platelet release andaggregation, is a cornerstone in the management ofACS.11 Well-established antiplatelet therapies inthe management of ACS include aspirin, adenosinediphosphate P2Y12 receptor antagonists, and gly-coprotein IIb/IIIa inhibitors.12 Aspirin should bestarted as soon as possible after an ACS event withan initial loading dose of 162325 mg, and shouldbe continued indenitely, unless contraindicated

    Figure 1. Pharmacologic management of patients with Unstable Angina (UA)/Non-ST Elevated MyocardialInfarction (NSTEMI).2,11 ECG, electrocardiogram.

    286 JABFM MarchApril 2015 Vol. 28 No. 2 http://www.jabfm.org

  • (strength of recommendation A). Aspirin 81 mgdaily is a reasonable maintenance dosing regimengiven that higher doses have not shown any benetover low-dose aspirin (level of evidence 1).13 Inaddition to aspirin, a P2Y12 antagonist should beadded for patients with ACS who are medicallymanaged as well as those undergoing PCI (strengthof recommendation A).3,11 P2Y12 receptor antago-nists frequently used in the management of ACSinclude clopidogrel (Plavix), prasugrel (Efent),and ticagrelor (Brilinta) (Table 2).1416 Glycopro-tein (GP) IIb/IIIa inhibitors have been shown to beefcacious when used during PCI in reducing isch-emic complications; however, the use of GP IIb/IIIa inhibitor therapy as part of triple antiplatelettherapy has also been associated with an increasedbleeding risk. Recent research supports the strategyof selective use rather than routine upstream use ofGP IIb/IIIa inhibitors as part of triple antiplatelet

    therapy with consideration of a patients risk-ben-et ratio (strength of recommendation A).11

    ClopidogrelBefore the approval of new therapeutic agents, clopi-dogrel was a standard therapy for patients presentingwith ACS. The benet of adding clopidogrel to aspi-rin was rst demonstrated in a 2001 trial in whichpatients presenting with UA or NSTEMI were ran-domly assigned to clopidogrel or placebo, in additionto aspirin, for a period of 312 months. The groupassigned to dual antiplatelet therapy (DAPT) wasshown to have a reduction in the primary outcome ofcardiovascular death, nonfatal MI, or stroke as com-pared with placebo (9.3 vs 11.4%; RR, 0.80; 95% CI,0.720.90; P .001), with a number needed to treat(NNT) of 48 to prevent one such event. There was asignicant increase in the rate of major bleeding as-sociated with the group randomized to DAPT as

    Figure 2. Pharmacologic management of patients with ST-elevated myocardial infarction (STEMI).3 ECG,electrocardiogram.

    doi: 10.3122/jabfm.2015.02.140189 Diagnosis and Management of Acute Coronary Syndrome 287

  • opposed to those randomized to placebo (3.7 vs 2.7%;RR, 1.38; 95% CI, 1.131.67; P .001 with a num-ber needed to harm (NNH) of 100 patients (level ofevidence 1).17

    PrasugrelThe 2007 landmark trial comparing clopidogrel toprasugrel showed that prasugrel was associatedwith a signicant 2.2% absolute reduction in acomposite endpoint of cardiovascular death, non-fatal MI, or nonfatal stroke as compared with clopi-dogrel, with a NNT of 46 patients over 615months to prevent one cardiovascular disease out-come (9.9 vs 12.1%; HR, 0.81; 95% CI, 0.730.90;P .001). Randomization to prasugrel was alsoassociated with a signicant increase in the rate ofbleeding, with a NNH of 166 patients for onebleeding event (2.4 vs 1.8%; HR, 1.32; 95% CI,1.031.68; P .03) (level of evidence 1). Patientswith body weight60 kg and patients75 years ofage lacked a net clinical benet. Patients with ahistory of stroke or transient ischemic attack hadnet harm with the use of prasugrel, and therefore itsuse in these patients is contraindicated.18 This trialwas conducted in patients with moderate-to-highrisk UA, NSTEMI, or STEMI who were referred

    for PCI, and prasugrel is U.S. Food & Drug Ad-ministration (FDA) approved for the reduction ofthrombotic cardiovascular events solely in patientswith ACS who are to be managed with PCI.15 Therole of prasugrel in patients with ACS who are notmanaged with PCI is yet to be dened.

    TicagrelorThe pivotal trial comparing ticagrelor to clopi-dogrel was conducted in patients with ACS, with orwithout ST-segment elevation, who had invasive ormedical management planned. Ticagrelor was as-sociated with a 1.9% absolute reduction in thecomposite outcome of vascular death, MI, or strokeas compared with clopidogrel, representing a NNTof 53 patients over the course of 12 months toprevent one outcome (9.8 vs 11.7%; HR, 0.84; 95%CI, 0.770.92; P .001). Ticagrelor was also as-sociated with a 1.4% absolute reduction in all-causemortality (4.5 vs 5.9%; HR, 0.78; 95% CI, 0.690.89; NNT, 72 patients). There was no signicantdifference in the risk of major bleeding betweentreatment groups; however, the ticagrelor grouphad a higher rate of major bleeding not related tocoronary artery bypass graft (CABG) surgery ascompared with the clopidogrel group, representing

    Table 2. Antiplatelet AgentsOral P2Y12 Inhibitors

    Clopidogrel (Plavix)14 Prasugrel (Efent)15 Ticagrelor (Brilinta)16

    DosingLoading dose for PCI 600 mg 60 mg 180 mgLoading dose for medical management 300 mg 180 mgMaintenance dose 75 mg once daily 10 mg once daily (Consider

    5 mg once daily ifpatient is 60 kg)

    90 mg twice daily

    Onset of action 6 hours with 300 mg dose 30 minutes 60 minutes2 hours with 600 mg dose

    Perioperative considerations Hold for 5 days prior tosurgery

    Hold for 7 days prior tosurgery

    Hold for 5 days prior tosurgery

    Clinical pearlsGenetic polymorphisms of the

    CYP 2C19 enzyme lead tovariable antiplatelet effects

    Not FDA approved formedical management,only for patientsundergoing PCI

    Should not be used withdaily aspirinmaintenance doses of100 mg

    Currently, the only genericprescription option

    Contraindicated in patientswith prior stroke or TIA

    May cause dyspnea,bradyarrythmias, andventricular pauses

    No net benet for patients60 kg and patients 75years of age

    Undergoes CYP 3A4metabolism (concernfor drug interactions)

    Only agent shown tohave mortality benet

    PCI, percutaneous coronary intervention; FDA, U.S. Food and Drug Administration; TIA, transient ischemic attack.

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  • an NNH of 142 patients to cause one event (4.5 vs3.8%; HR, 1.19; 95% CI, 1.021.38; P .03) (levelof evidence 1).19

    VorapaxarThe most recent addition to the arsenal of anti-platelet agents was the approval of vorapaxar, ahigh-afnity oral antagonist that selectively inhibitsthrombin from activating platelets through theprotease-activated receptor 1. Vorapaxar is indi-cated for the reduction of thrombotic cardiovascu-lar events in patients with a history of MI or withperipheral arterial disease (PAD).20 This novelagent was approved by the FDA in 2014 based onthe results of a large, phase III randomized con-trolled trial. This trial included 26,449 patientswith a history of MI, ischemic stroke, or PAD whowere randomly assigned to receive vorapaxar (2.5mg daily) or placebo in addition to standard anti-platelet therapy for a median time of 30 months.Vorapaxar was associated with a 1.2% absolute riskreduction in the primary composite endpoint ofdeath from cardiovascular causes, MI, or stroke ascompared with placebo (HR, 0.87; 95% CI, 0.800.94; P .001, NNT 84 patients). Moderate-to-severe bleeding was more common in the vorapaxargroup as opposed to the placebo group (4.2 vs2.5%; HR, 1.66; 95% CI, 1.431.93; P .001,NNH 58 patients) (level of evidence 1). The role ofvorapaxar in the management of ACS has not beenfully elucidated and will likely evolve in the comingyears.21

    AnticoagulantsThe decision to use anticoagulation in additionto standard post-ACS treatment is challengingdue to the intricate balance between safety andefcacy. During the initial management of ACS,parenteral anticoagulants are used in combina-tion with antiplatelet agents (strength of recom-mendation A). Parenteral anticoagulants thatmay be used during this time include unfraction-ated heparin (UFH), low-molecular-weight hep-arin, fondaparinux, or bivalirudin. The choice ofanticoagulant agent is dependent on the initialmanagement strategy and the recommended du-ration of therapy varies based on the chosenagent (Figure 1).2,3 Although current guidelinesdo not recommend anticoagulants for post-ACSmanagement following hospital discharge (unlessindicated for a concomitant disease state), several

    studies have been conducted to investigate theuse of anticoagulants in this setting (strength ofrecommendation B).22 A meta-analysis including14 randomized controlled trials investigated theuse of aspirin with warfarin versus aspirin alonein patients recovering from ACS to determinetheir effect on the incidence of ischemic eventsand the rate of bleeding (level of evidence 2). Intrials included in this meta-analysis that targetedan international normalized ratio (INR) of 23,the use of warfarin and aspirin was found toconfer a signicant reduction of major adverseevents including all-cause death, nonfatal MI,and nonfatal thromboembolic stroke (OR, 0.73;95% CI, 0.630.84; P .0001) versus the use ofaspirin alone (NNT of 33 patients to avoid onemajor adverse event). However, randomization towarfarin and aspirin was associated with a signi-cantly greater rate of major bleeds (OR, 2.32; 95%CI, 1.633.29; P .00001), representing an NNHof 100 patients to cause a major bleed.23 While notroutinely used in clinical practice, warfarin is FDAapproved for reducing the risk of death, recurrentMI, and thromboembolic events after MI.24 In thepast few years, three oral anticoagulants have beengranted FDA approval in the US, including dab-igatran (Pradaxa), rivaroxaban (Xarelto), and apixa-ban (Eliquis).2527 Each have been studied in thesetting of ACS but have not been granted FDAapproval for prevention of thrombotic events asso-ciated with ACS [Table 3].2832

    Adjuvant Agents-BlockersOral -blocker therapy should be initiated within24 hours of the onset of the event for patientspresenting with UA, NSTEMI, or STEMI ex-cluding patients with evidence of low-outputstate, signs of HF, increased risk for cardiogenicshock, or other contraindications to therapy(strength of recommendation A). The use of in-travenous -blockers is reasonable in patientswho are hypertensive and do not have any evi-dence of the states mentioned above. -blockersreduce myocardial contractility, sinus node rate,and AV node conduction velocity by blocking theeffects of catecholamines on -receptors locatedin the myocardium. The net benet of -block-ers is related to a decrease in cardiac work andreduction in myocardial oxygen demand. Studies

    doi: 10.3122/jabfm.2015.02.140189 Diagnosis and Management of Acute Coronary Syndrome 289

  • investigating the impact of -blockers on mor-tality in patients with ACS have variable resultsbased on differences in route of administration,time of administration from event onset, andpatient population.33,34 There is, however, suf-cient evidence to recommend -blockers as aroutine part of care in this patient population(strength of recommendation B).2,3 Effortsshould be made to start a -blocker in thepost-MI setting before discharge unless contra-indicated or not tolerated (strength of recommen-dation A). There is debate regarding the recom-mended duration of -blocker use in the post-MIsetting. The evidence suggesting the long-term useof -blockers post MI is largely from trials con-ducted before the widespread use of antiplateletagents and routine reperfusion therapy. Data

    suggests that the benets of -blockers emerge inthe early phase after MI and benets are moreprevalent among high-risk patients. The dura-tion of benet of long-term oral -blocker ther-apy is uncertain at this time. Many practitionerschoose to continue -blockers indenitely de-spite the lack of rm evidence. If patients areexperiencing side effects from -blocker use, itmay be reasonable to discontinue therapy at least1 year after an MI (strength of recommendationB).35 For patients who are unable to take-blockers and experience recurrent ischemia,consideration should be given to starting a non-dihydropyridine calcium channel blocker (ie, ve-rapamil or diltiazem) in the absence of clinicallysignicant left ventricular dysfunction (strengthof recommendation A).2,3

    Table 3. New Oral AnticoagulantsData in Acute Coronary Syndrome (ACS)

    Dabigatran (Pradaxa) Rivaroxaban (Xarelto)* Apixaban (Eliquis)

    Clinical trial RE-DEEM (phase II)28 ATLAS-ACS-2-TIMI-51 (phaseIII) 29

    APPRAISE-2 (phase III)32

    Patient population 1861 patients presenting withSTEMI or NSTEMI

    7817 patients presenting withSTEMI

    7392 patients with recent ACSand 2 additional riskfactors for recurrentischemic events

    Primary outcome Composite of major or clinicallyrelevant minor bleeding

    Composite of CV death, MI, orstroke

    Efcacy: a composite of CVdeath, MI, or stroke

    Safety: major TIMI bleedingResults There was a dose-dependent

    increase in bleeding withdabigatran compared withplacebo: HR, 1.77 (95% CI,0.704.50) for 50 mg; HR,2.17 (95% CI, 0.885.31) for75 mg; HR, 3.92 (95% CI,1.728.95) for 110 mg; andHR, 4.27 (95% CI, 1.869.81)for 150 mg (all given twicedaily)

    Rivaroxaban reduced the primaryefcacy endpoint of CV death,MI, or stroke compared withplacebo (8.4 vs 10.6%; HR,0.81; 95% CI, 0.670.97; P .019)

    There was no signicantreduction in the occurrenceof ischemic events whencomparing apixaban toplacebo (7.5 vs 7.9%; HR,0.95; 95% CI, 0.801.11;P .51)

    Rivaroxaban increased non-CABG TIMI major bleeding(2.2 vs 0.6%; P .001) andICH (0.6 vs 0.1%; P .015)without a signicant increasein fatal bleeding (0.2 vs 0.1%,P .51)

    Apixaban demonstrated anincrease in major TIMIbleeding compared withplacebo (1.3 vs 0.5%; HR,2.59; 95% CI, 1.504.46;P .001)

    Conclusions Dabigatran was associated with adose-dependent increase inbleeding events in this patientpopulation when compared toplacebo

    Rivaroxaban reduced CV eventsin this patient populationwhen compared with placebo,albeit at an increased risk ofbleeding

    Apixaban increased thefrequency of major bleedswithout a signicantreduction in ischemic eventscompared with placebo

    *The FDA has denied the proposed expanded indication for rivaroxaban as a treatment for patients with ACS to reduce the risk ofMI, stroke, death, or stent thrombosis.30 Rivaroxaban 2.5 mg twice daily is approved in Europe for secondary prevention of ACS incombination with standard antiplatelet therapy.31

    APPRAISE-2, Apixaban for Prevention of Acute Ischemic Events 2; ATLAS-ACS-2-TIMI-51, Anti-Xa Therapy to Lower Cardio-vascular Events in Addition to Standard Therapy in Subjects with Acute Coronary SyndromeThrombolysis In MyocardialInfarction-51; CABG, coronary artery bypass grafting; CV, cardiovascular; HR, hazard ratio; ICH, intracranial hemorrhage; MI,myocardial infarction; RE-DEEM, The Randomized Dabigatran Etexilate Dose Finding Study in Patient with Acute CoronarySyndromes Post Index Event with Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel.STEMI, ST-elevated myocardial infarction; NSTEMI, non-ST elevated myocardial infarction; TIMI, thrombosis in myocardialinfarction; CI, condence interval.

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  • Inhibitors of the Renin-Angiotensin SystemAn angiotensin-converting enzyme (ACE) inhibi-tor or angiotensin receptor blocker (ARB) shouldbe initiated within the rst 24 hours of patientspresenting with ACS who have pulmonary conges-tion, HF, STEMI with anterior location, or leftventricular ejection fraction (LVEF) 40% in theabsence of contraindications to therapy (strength ofrecommendation A).2,3 ACE inhibitors have beenshown to reduce mortality in a broad spectrum ofpatients following MI, including those with andwithout left ventricular dysfunction (level of evi-dence 1).3639 ACE inhibitors have also been stud-ied in patients with stable CAD, which have shownconicting effects on mortality and vascular events(level of evidence 2).4042 Patients with stable CADwho are not medically optimized (ie, cannot toler-ate a -blocker or statin), who are not able to berevascularized, and/or who have poorly controlleddiabetes have shown mortality benet with contin-ued treatment with ACE inhibitors.40 On the con-trary, revascularized patients with stable CAD,without signicant comorbidities, who are on op-timal medication management, have not shown thislong-term benet.42 The decision to continue anACE inhibitor long-term in patients with a historyof ACS should be individualized with concomitantdisease states considered. Aldosterone antagonists(ie, spironolactone, eplerenone) have also beenstudied in the post-ACS setting and have beenfound to reduce morbidity and mortality in selectpatient populations (level of evidence 1).43,44 Initi-ation of an aldosterone antagonist is recommendedafter an ACS event for patients who are on thera-peutic doses of an ACE inhibitor or ARB and-blocker with an LVEF 40% and either symp-tomatic HF or diabetes mellitus (strength of rec-ommendation A). When initiating inhibitors of therenin-angiotensin system, it is important to moni-tor for adverse effects associated with these agentsincluding hyperkalemia, elevations in serum creat-inine, and hypotension.2,3

    HmGcoenzyme A Reductase InhibitorsIt is recommended to initiate or continue statintherapy in all patients presenting with ACS and nocontraindications to its use (strength of recommen-dation A).2,3 High-intensity statin therapy follow-ing an ACS event was shown to confer an absoluterisk reduction of 3.9% as compared with a moder-ate intensity statin for the composite endpoint of

    death from any cause, recurrent MI, UA requiringrehospitalization, revascularization, and stroke(22.4 vs 26.3%; RR, 16%; 95% CI, 526%; P .005), representing an NNT of 26 for a time periodof 2 years (level of evidence 1).45 Statin therapy hasbeen shown to be benecial following ACS even inpatients with baseline low-density lipoprotein cho-lesterol levels of70 mg/dL.2,3 Recently publishedAmerican College of Cardiology and AmericanHeart Association Guidelines on treatment of cho-lesterol recommend high intensity statins (ie, ator-vastatin, 40 mg daily or rosuvastatin, 20 mgdaily) for high-risk patients, which include pa-tients who have an ACS event. Lower-dose st-atins can be considered if patients are 75 yearsold or if patients cannot tolerate high-intensitystatins (strength of recommendation A).46

    ConclusionACS is a potentially life-threatening condition thataffects millions of individuals each year. Despitedeclining rates of hospitalization for MI, the iden-tication and prevention of ACS continues to be animportant public health concern. Over the pastseveral years, studies have led to an improved un-derstanding of the pathophysiology of ACS andadvancements have been made in the medical man-agement of this condition. Initial ACS managementshould include risk stratication, appropriate phar-macologic management including DAPT, antico-agulation and appropriate adjuvant therapies, and adecision to pursue an early invasive or conventionaltreatment strategy. Long-term management fol-lowing an ACS event should follow evidence-basedrecommendations and should be individualized toeach patient.

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