antiplatelet agents in acute non-st elevation acute coronary syndromes

8/13/2019 Antiplatelet Agents in Acute Non-ST Elevation Acute Coronary Syndromes

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Antiplatelet agents in acute non-ST elevation acute coronarysyndromesAuthorsMichael Simons, MDDonald Cutlip, MD

A Michael Lincoff, MDSection EditorsChristopher P Cannon, MDFreek Verheugt, MD, FACC, FESCDeputy EditorGordon M Saperia, MD, FACCDisclosures

All topics are updated as new evidence becomes available and ourpeerreview processis complete.

Literature review current through:Oct 2013. | This topic last updated:oct 3, 2013.

INTRODUCTIONRupture of an atherosclerotic plaque is the usualinitiating event in an acute coronary syndrome (ACS). Plaque rupture oftenleads to thrombus formation and persistent thrombotic occlusion results inacute myocardial infarction (MI). (See"The role of the vulnerable plaque inacute coronary syndromes".)

The role of platelets in thrombus formation during ACS is discussed indetail elsewhere (figure 1). (See"Congenital and acquired disorders ofplatelet function", section on 'Normal platelet function'and"The role ofplatelets in coronary heart disease".)

This topic will discuss the use of antiplatelet agents in unstable angina andnon-ST elevation myocardial infarction, which together are referred to asnon-ST elevation ACS. All patients with non-ST elevation ACS should betreated withaspirinand a platelet P2Y12receptor blocker. The use ofantiplatelet agents in ST-elevation MI is discussed separately. (See"Antiplatelet agents in acute ST elevation myocardial infarction".)

CLASSIFICATION OF ANTIPLATELET AGENTSAntiplatelet agentsinterfere with a number of platelet functions, including aggregation, releaseof granule contents, and platelet-mediated vascular constriction. They canbe classified according to their mechanism of action (figure 2):

Aspirinblocks cyclooxygenase (prostaglandin H synthase), the
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enzyme that mediates the first step in the biosynthesis ofprostaglandins and thromboxanes (including TxA2) from arachidonicacid (algorithm 1).

The P2Y12receptor blockers,clopidogrel,ticlopidine,prasugrel,ticagrelor,and cangrelor block the binding of adenosine diphosphate(ADP) to a platelet receptor P2Y12, thereby inhibiting activation of theglycoprotein (GP) IIb/IIIa complex and platelet aggregation [1].

Anti-GP IIb/IIIa antibodies and receptor antagonists inhibit the finalcommon pathway of platelet aggregation (the cross-bridging ofplatelets by fibrinogen binding to the GP IIb/IIIa receptor) and mayalso prevent adhesion to the vessel wall.

ASPIRINAspirinhas an established benefit in a variety ofcardiovascular disorders including primary and secondary prevention ofcoronary heart disease, transient ischemic attack, and stroke, and in theacute therapy of patients with an acute coronary syndrome (ACS). (See"Benefits and risks of aspirin in secondary and primary prevention ofcardiovascular disease".)

The antiplatelet activity ofaspirinappears to be mediated principallythrough inhibition of the synthesis of thromboxane A2 (TxA2), a potentstimulator of platelet aggregation (see"Overview of hemostasis", sectionon 'Platelet aggregation')[2]. Since platelets do not synthesize newenzymes, the functional defect induced by aspirin persists for the life of theplatelet. (See"Benefits and risks of aspirin in secondary and primaryprevention of cardiovascular disease", section on 'Mechanisms of action'.)

Evidence of benefitThe Antithrombotic Trialists' Collaborationreviewed the effect of antiplatelet therapy, mostlyaspirin(in doses rangingfrom 75 to 1500 mg daily) in nearly 200,000 patients [3]. Antiplatelet

therapy produced a significant 46 percent reduction in the combined endpoint of subsequent nonfatal myocardial infarction (MI), nonfatal stroke, orvascular death (8.0 versus 13.3 percent) in patients with unstable angina,and a 30 percent reduction in patients with acute myocardial infarction(10.4 versus 14.2 percent) (table 1). There was no significant difference inefficacy between lower and higher daily doses (75 to 325 versus 500 to1500 mg). Another important contribution of this analysis was the finding
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that the addition of a second antiplatelet agent (eg,dipyridamole,ticlopidine,or intravenous glycoprotein IIb/IIIa inhibitor) significantlylowered the combined end point.

DoseAn initial loading dose of 162 to 325 mg of uncoatedaspirin

should be given as soon as possible to any patient thought to have anACS. At this dose, aspirin produces a rapid antithrombotic effect due toimmediate and almost complete inhibition of thromboxane A2 production.The first tablet should be chewed or crushed to establish a high blood levelquickly. More rapid absorption occurs with nonenteric coated formulations.There is no evidence that higher doses are more effective but they maylead to greater gastric irritation. Aspirin (75 to 100 mg once a day) shouldbe continued indefinitely for secondary prevention [4]. The upper limit of100 mg is based on the observation of a dose dependent increase in therate of major bleeding in the CURE trial: 2, 2.3, and 4 percent at doses of

than 100, 100 to 200, and greater than 200 mg daily [5]. (See"Benefitsand risks of aspirin in secondary and primary prevention of cardiovasculardisease", section on 'Dosing and cardiovascular benefit'and"Benefits andrisks of aspirin in secondary and primary prevention of cardiovasculardisease", section on 'Dosing and bleeding risk'and 'Clopidogrel'below.)

We recommend that ACS patients be discharged on 75 to 100 mg/day ofaspirin,based principally on CURRENT OASIS 7 trial, in which there wasno significant difference in cardiovascular outcomes between high or lowdose aspirin irrespective of whether ACS patients received percutaneouscoronary intervention or not, while gastrointestinal bleeding rates were

increased with higher dose aspirin. For patients takingticagrelor,werecommend not using doses greater than 100 mg daily. (See 'Ticagrelor'below.)

Side effects and allergyAspirintherapy may be associated withgastrointestinal intolerance or bleeding, allergy (primarily manifested asbronchospasm or asthma), and worsening of pre-existent bleeding.Gastrointestinal side effects such as dyspepsia and nausea are infrequentwith the low doses. Patients who develop gastrointestinal side effectsshould be treated with a proton pump inhibitor and are usually able totolerate a lower and probably still effective dose (80 to 100 mg of aspirinper day) [6]. Enteric-coated aspirin may be of some benefit, but it does notprotect against gastrointestinal bleeding. (See"Benefits and risks of aspirinin secondary and primary prevention of cardiovascular disease", section on'Aspirin formulation'and"Periprocedural and long-term gastrointestinalbleeding in patients undergoing percutaneous coronary intervention"and"Diagnostic challenge and desensitization protocols for NSAID reactions".)
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Summary

An initial loading dose of 162 to 325 mg of uncoatedaspirinshouldbe given as soon as possible to any patient thought to have an ACS.

We recommend that ACS patients be discharged on 75 to 162mg/day ofaspirin.For patients takingticagrelor,we suggest aspirin ata dose between 75 and 100 mg daily. (See 'Ticagrelor'below.)

PLATELET P2Y12 RECEPTOR BLOCKERSClopidogrel,ticlopidine,prasugrel,ticagrelor,and cangrelor block the adenosine diphosphatereceptor P2Y12on platelets. (See"Platelet biology".) The evidence

presented below supports a strong recommendation for at least one yearof dual antiplatelet therapy withaspirinand a P2Y12receptor blocker in allpatients with acute coronary syndrome (ACS). This recommendation isbased principally on the results of the CURE trial, which compared dualantiplatelet therapy with aspirin and clopidogrel to aspirin alone. Evidencefor the role of ticagrelor and prasugrel comes from studies which comparedthese newer agents to clopidogrel.

Ticlopidineis rarely chosen due to the risk of thrombocytopenia. Threelimitations to the use ofclopidogrel(delayed onset of action, large between

individual variability in platelet response, and irreversibility of its inhibitoryeffect on platelets) led to the development of other agents, includingprasugrelandticagrelor[7]. Both prasugrel and ticagrelor induce moreintense platelet inhibition than clopidogrel and have been found to be bothmore effective and associated with higher rates of bleeding. All trials ofP2Y12receptor blockers have given these drugs in conjunction withaspirin.

ClopidogrelThe benefit of dual antiplatelet was established in theCURE trial, which randomly assigned 12,562 patients who presentedwithin 24 hours after the onset of a non-ST elevation ACS toaspirinalone

(75 to 325 mg/day) or withclopidogrel(300 mg loading dose immediatelyfollowed by 75 mg/day) for 9 to 12 months; both were given immediatelyon presentation. The majority of patients were at increased risk of anadverse outcome because of electrocardiogram (ECG) changes (mostlyST depression 1 mm or T wave inversion 2 mm) or elevated cardiacenzymes [5]. Over 60 percent did not receive revascularization. Theprimary endpoint was cardiovascular death, myocardial infarction, or
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stroke.

At an average follow-up of nine months, combination therapy led to asignificant reduction in the combined primary endpoint of cardiovasculardeath, nonfatal myocardial infarction (MI), or stroke (9.3 versus 11.4

percent), which was largely due to fewer MIs (5.2 versus 6.7 percent)(figure 3). However,clopidogreltherapy significantly increased the rate ofmajor bleeding (3.7 versus 2.7 percent) but not in life-threatening bleedingor hemorrhagic stroke.

Clopidogreltherapy produced a similar relative risk reduction in patientswho were treated medically or underwent revascularization [8]and in low-,intermediate-, and high-risk patients as defined by the TIMI risk score(calculator 1)[9]. High-risk patients derived the greatest absolute benefit.

A subsequent analysis from CURE evaluated the time course of benefit of

clopidogrel[10]. Evidence of benefit began to emerge within 24 hours andgradually increased in magnitude during the first 30 days (4.3 versus 5.4percent incidence of the primary endpoint, relative risk 0.79). The benefitcontinued to increase from 31 days to one year (5.2 versus 6.3 percentincidence of new events, relative risk 0.82) (figure 4). There was nosignificant excess of late life-threatening bleeding, but there was a smallexcess of major bleeds (5 per 1000) that was much smaller than the totalcardiovascular benefit at one year (22 per 1000).

Subgroup analyses of the CURE (PCI-CURE) [8]and the CREDO trials[11]have confirmed the benefit of dual antiplatelet therapy withaspirinandclopidogrelin ACS patients undergoing percutaneous coronaryintervention (PCI) with stenting. (See"Antithrombotic therapy forintracoronary stent implantation: Clinical trials", section on 'Timing anddose'.)

DoseThe standardclopidogrelregimen in patients with a non-STelevation ACS, which was used in CURE and CREDO, has been a 300 mgloading dose followed by a maintenance dose of 75 mg/day [5,8,11].However, the benefit in CREDO was only seen in patients who had beentreated at 15 hours before PCI [12]. This concern existed for non-ACS

patients as well and led to the following studies that compared a 300 mg toa 600 mg loading dose (see"Antithrombotic therapy for intracoronary stentimplantation: Clinical trials", section on 'Timing and dose'):

In the ARMYDA-trial in which 255 patients (75 percent stable angina,25 percent non-ST elevation ACS) scheduled to undergo PCI wererandomly assigned to a 300 or 600 mg loading dose four to eight
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hours before the procedure [13]. The primary end point (death, MI, ortarget vessel revascularization) occurred significantly less often withthe 600 mg loading dose (4 versus 12 percent).

In a single center trial in which 292 patients with non-ST elevation

ACS were randomly assigned to either 300 or 600 mg at least 12hours before scheduled stenting, the rate of recurrent cardiovascularevents at 30 days was significantly lower with the 600 mg dose (5versus 12 percent) [14].

The optimal loading dose ofclopidogrelin patients with ACS was bestaddressed in the CURRENT-OASIS 7 trial, which randomly assigned25,086 patients with an ACS (70.8 percent unstable angina or non-STelevation myocardial infarction [NSTEMI]) referred for an invasive strategyto either clopidogrel 600 mg loading dose on day one followed by 150 mgdaily for six days (and 75 mg thereafter) or clopidogrel 300 mg loadingdose followed by 75 mg daily [15]. The interval between randomization andPCI was 3.4 hours. The following findings were noted:

The rate of the primary outcome (cardiovascular death, MI, or strokeat 30 days) was not statistically different (4.2 versus 4.4 percentrespectively). However, in the subgroup of patients who underwent

PCI (n = 17,263) the higher dose ofclopidogrelsignificantly reducedthe rate of the primary outcome, 3.9 versus 4.5 percent; adjustedhazard ratio 0.86, 95% CI 0.74-0.99.

Major bleeding occurred significantly more often in patients whoreceived the higherclopidogreldose (2.5 versus 2.0 percent in theoverall population and 1.6 versus 1.1 in the PCI subgroup).

The higher dose ofclopidogrelwas associated with a significantreduction in the secondary outcome of definite or probable stentthrombosis among the 17,263 patients who underwent PCI (1.6versus 2.3 percent) [16]. (See"Antiplatelet therapy after coronaryartery stenting".)
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We recommend a 600 mg loading dose in patients who will undergoangiography and possible revascularization within 24 hours of diagnosis.(See"Antithrombotic therapy for percutaneous coronary intervention:General use"and"Antithrombotic therapy for intracoronary stentimplantation: Clinical trials", section on 'Timing and dose'.)

We prefer the maintenance dose of 75 mg daily, as opposed to the higherdose of 150 mg for six days. As the evidence supporting the 150 mg dose(for one week) comes from a subgroup analysis of a negative trial(CURRENT-OASIS 7), the lower dose is preferred until further evidence isavailable. We are concerned of an increase in the frequency of bleedingwith the higher dose.

Patients already taking clopidogrelThe issue ofclopidogrelreloadingis discussed separately. (See"Antithrombotic therapy for percutaneouscoronary intervention: General use", section on 'Patients already taking

clopidogrel'.)

Duration of therapyThe CURE trial discussed above providesevidence that dual antiplatelet therapy withaspirinandclopidogrelshouldbe continued for 9 to 12 months. While studies have not compared oneduration of therapy to another, the continued separation of events in CUREup to 9 to 12 months (figure 3)makes us reasonably confident about thisduration.

This minimum duration is supported by a retrospective cohort study of ACSpatients treated with stents (1569, 63 percent received bare metal stents)and without stents (1568) which evaluated the frequency and timing ofboth all-cause mortality or acute MI afterclopidogrelcessation [17]. Themean duration of clopidogrel therapy was 278 and 302 days, respectively.In multivariate analysis, including adjustment for duration of clopidogreltreatment, the first 90-day interval after stopping clopidogrel treatment wasassociated with a small risk of adverse events in both medical and PCIgroups (1.31 and 0.57 per 1000 patient-days, respectively) that wassignificantly higher than in the interval of 91 to 180 days (incidence rateratios 1.82 and 1.98). This early incidence of adverse events wasconsistent whether patients took clopidogrel for three, six, or nine or more

months.

Evidence from randomized trials in favor of continuedclopidogreluse forlonger than one year in non-ST elevation ACS is lacking. However, somesupport comes from the CAPRIE trial, which compared clopidogrel toaspirin(but not the combination) in patients with atherosclerosis not limitedto acute coronary syndromes [18]. Clopidogrel therapy was associatedwith a significant reduction in fatal or nonfatal MI; the magnitude of this
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benefit increased progressively over the three-year period of the study[19]. Support also comes from subgroup analyses from CHARISMA, wherebenefit was seen in patients with prior MI or stroke [20].

Some physicians recommend continuingclopidogrelbeyond one year or

even indefinitely given a continued benefit over time observed in CURE,PCI-CURE (figure 5), and CREDO (figure 6)[5,8,11]. This approachshould be considered in patients with more severe vascular disease (eg,prior MI or cerebrovascular event or peripheral vascular disease) or inthose with drug-eluting stents. (See"Antiplatelet therapy after coronaryartery stenting"and"Antiplatelet therapy after coronary artery stenting",section on 'Duration'.)

After CABGThe use ofclopidogrelin patients with non-ST elevationACS undergoing urgent coronary artery bypass graft surgery is discussedseparately. (See"Medical therapy to prevent complications after coronary

artery bypass graft surgery", section on 'Platelet P2Y12 receptor blockertherapy'.)

TiclopidineTiclopidinecompared to placebo improves outcomes inpatients with unstable angina who are not treated withaspirin[21]. Notrials have compared ticlopidine to aspirin or assessed the role ofcombined therapy. Side effects have limited its use compared toclopidogrel.(See"Antithrombotic therapy for percutaneous coronaryintervention: General use", section on 'Ticlopidine'.)

PrasugrelPrasugrelhas a more rapid onset of action and is able toachieve higher degrees of platelet inhibition thanclopidogrel[22,23].Furthermore, prasugrel effectively suppresses platelet activity in a largernumbers of patients than clopidogrel, since 20 to 25 percent of patientsappear to be clopidogrel-resistant. (See"Clopidogrel resistance andclopidogrel treatment failure", section on 'Definitions'.)

Patients undergoing PCIThe TRITON-TIMI 38 trial directly comparedprasugreltoclopidogrelin 13,608 moderate- to high-risk ACS patientsundergoing PCI, including 10,074 with non-ST elevation ACS [24].Prasugrel was given with a loading dose of 60 mg and maintenance dose

of 10 mg/day while clopidogrel was given with a 300 mg loading dose anda 75 mg/day maintenance dose; the median duration of therapy was 14.5months. For patients with unstable angina or NSTEMI, the coronaryanatomy had to be known before randomization. Thus, in the majority ofcases both clopidogrel and prasugrel were given after coronaryangiography.

At 15-month follow-up, the following findings were noted (the overall data
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are given since the benefits were similar in non-ST elevation and STelevation syndromes):

The primary efficacy end point (cardiovascular death, nonfatal MI, or

nonfatal stroke) occurred significantly less often in patients treatedwithprasugrel(9.9 versus 12.1 percent; hazard ratio [HR] 0.81; 95%CI 0.73-0.90) irrespective of whether or not they underwent PCI withstenting [24,25]. This was driven primarily by a significant reduction innonfatal MI (7.4 versus 9.7 percent).

Among patients who sustained a nonfatal MI or stroke, the likelihoodof a recurrent primary end point was significantly reduced withprasugrelcompared toclopidogrel(10.8 versus 15.4 percent), as wasthe likelihood of cardiovascular death following the nonfatal first event(3.7 versus 7.1 percent) [26]. This benefit was found in patients witheither procedure-related or non-procedure related MIs and was seenirrespective of MI size or timing [27].

The safety end point of a major bleeding event not associated withcoronary artery bypass graft surgery (CABG) occurred significantlymore often in patients treated withprasugrel(2.4 versus 1.8 percent;

HR 1.32; 95% CI 1.03-1.68). This difference was attributable to anincrease in bleeding events with prasugrel after (but not before) thefirst three days [28]. The rate of life-threatening bleeding was alsosignificantly increased with prasugrel.

Post hoc analysis identified three predictors of less net clinicalefficacy and greater absolute levels of bleeding withprasugrel:Ahistory of stroke or transient ischemic attack (TIA); age 75 years of

age; and body weight 60 kg. In those with stroke or transientischemic attack, the use of prasugrel was associated with harm. TheUnited States Food and Drug administration states the following:Prasugrel use is contraindicated in patients with active pathologicbleeding or history or TIA or stroke.
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in Myocardial Infarction (TIMI) major bleeding increasedprogressively with age and were twoto threefold higher in olderindividuals [30]. Similar to the entire study population, there was nosignificant difference in these outcomes between the twointerventions in these older patients.

A prespecified subgroup analysis evaluated outcomes based onwhether or not diagnostic angiography had been performed [31].

Although the primary end point was lower in theprasugrelgroup thanin theclopidogrelgroup for those who had angiography (10.7 versus14.9 percent; adjusted hazard ratio 0.77, 95% CI 0.61-0.98), thefinding of this positive result in an overall negative trial may bespurious.

Dosing in elderlyThe optimal dose of P2Y12receptor blockers inelderly patients who are at increased bleeding risk is not known. Thepharmacokinetic and pharmacodynamic (phase 1b) GENERATIONS trialof stable patients found thatprasugrel5 mg in 79 elderly patients (meanage of 79 years) was noninferior to prasugrel 10 mg in 56 nonelderlypatients (mean age of 56 years) for the primary end point of maximumplatelet aggregation [32]. Bleeding rates were comparable, but the studywas not powered for clinical effectiveness or safety outcomes.

TicagrelorTicagrelordiffers from the thienopyridines (clopidogrelandprasugrel)in that it binds reversibly rather than irreversibly to P2Y12platelet receptor and has a more rapid onset of action than clopidogrel [7].It has been assigned to a new chemical class of antiplatelet agents, thecyclopentyltriazolopyrimidines. Similar to prasugrel, treatment withticagrelor leads to more intense platelet inhibition than clopidogrel.

The efficacy and safety ofticagrelorwere evaluated in the PLATO trial inwhich 18,624 patients with ACS were randomly assigned to eitherticagrelor (180 mg loading dose followed by 90 mg twice daily) orclopidogrel(300 to 600 mg loading dose followed by 75 mg daily) [33].Treatment was started as soon as possible after hospital admission(median of five hours), but many patients received the drug after coronaryangiography. The median time from the first dose of the study drug to PCIwas approximately 4 hours (interquartile range [approximately] 0.45-50.8hours).

All patients received a loading dose ofaspirin,which was usually 325 mg.
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