Antithrombotic Therapy in Patients with Acute Coronary Syndromes

REVIEW ARTICLE Antithrombotic Therapy in Patients With Acute Coronary Syndromes

Glenn N. Levine, MD; M. Nadir Ali, MD; Andrew I. Schafer, MD

he potential armamentarium of agents used in the treatment of acute coronary syndromes continues to expand, including such well-tested agents as aspirin, unfractionated heparin, and earlier-generation fibrinolytic agents, and newer agents such as low- molecular-weight heparins, direct thrombin inhibitors, thienopyridines, platelet Tglycoprotein IIb/IIIa receptor inhibitors, and bolus-administration fibrinolytic agents. Older and newer antithrombotic agents have undergone and continue to undergo intensive clinical investi- gation in patients with the clinical spectrum of acute coronary syndromes, which includes unstable angina, non–Q-wave (non–ST-segment elevation) myocardial infarction, and ST-segment elevation myocardial infarction. These studies, often conducted on an international scope and involving thousands of patients, provide data allowing practitioners to optimize the care of patients with acute coronary syndromes. In this article, studies of these established and newer agents in the treatment of patients with acute coronary syndromes are reviewed critically and summarized. Recommendations regarding use of antithrombotic agents in patients with acute coronary syndromes are then given. Arch Intern Med. 2001;161:937-948

UNDERSTANDING THE is the fact that Q waves may not develop NOMENCLATURE USED in some patients who present with ST- IN CLINICAL TRIALS segment elevation (probably as a result of early spontaneous, pharmacological, or Although older studies of antithrombotic mechanical reperfusion) and are later therapy have addressed unstable angina as termed to have non–Q-wave MI. Also, Q- a distinct condition, more recent studies wave MI may develop in a small propor- have recognized that unstable angina and tion of patients who present without ST- non–Q-wave myocardial infarction (MI) segment elevation. are part of a continuum of coronary throm- For the purposes of clarity in this re- botic disorders termed acute coronary syn- view, in studies in which patients labeled dromes and have assessed antithrombotic as presenting with unstable angina or non– therapy in these patients as a group (and Q-wave MI were enrolled and studied, the used acute coronary syndrome to refer to term non–ST-segment elevation acute coro- this group of patients). Acute coronary syn- nary syndromes will be used. The term dromes has also been used variably in the acute coronary syndrome will be reserved literature to also include those patients only for describing the broad spectrum of who present with ST-segment elevation patients that includes unstable angina, MI. Further confusing the nomenclature non–Q-wave MI, and ST-segment elevation MI.

From the Department of Medicine, Baylor College of Medicine (Drs Levine, Ali, and ANTIPLATELET AGENTS Schafer), the Section of Cardiology, Houston Veterans Administration Medical Center (Drs Levine and Ali), and Methodist Hospital (Dr Schafer), Houston, Tex. Dr Levine has received monetary compensation for speaking engagements on behalf of several Aspirin pharmaceutical companies, including Cor/Key, which markets eptifibatide (Integrilin), and Aventis, which markets enoxaparin sodium (Lovenox). Dr Ali has received Aspirin has been used medicinally since monetary compensation for speaking engagements on behalf of several pharmaceutical antiquity. Its antithrombotic action is due companies, including Merck & Co, Inc, which markets tirofiban hydrochloride to irreversible blockade of the formation (Aggrastat), and Aventis. of thromboxane A2, a potent mediator of

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 35 Ticlopidine and Clopidogrel Neither Aspirin 30 Heparin The thienopyridines ticlopidine hy- Aspirin + Heparin drochloride and clopidogrel block 25 adenosine diphosphate (ADP)–

20 mediated platelet activation and lead to irreversible inhibition of platelet 15 aggregation.7 The inhibitory effects % of Patients of the thienopyridines on platelet ag- 10 gregation may be synergistic to those 7 5 achieved with aspirin therapy. Like aspirin, the thienopyridines are rela- 0 tively weak inhibitors of platelet ac- Refractory MI Death Any Event Angina tivation compared with the platelet glycoprotein IIb/IIIa (GpIIb-IIIa) in- Figure 1. Results of the Montreal Heart Institute study of patients with unstable angina, showing the reduction in adverse events in patients treated with aspirin, heparin sodium, or both, compared with hibitors. those treated with neither agent. MI indicates myocardial infarction. Adapted from data in Theroux et al.4 Although the thienopyridines have become an integral part of phar- 600 fer a nonfatal or fatal MI (absolute Placebo macological therapy in patients un- rates, approximately 12% vs 3%, dergoing coronary stent implanta- 500 respectively). In the larger Re- tion, there remain only scant data on Aspirin search Group on Instability in Coro- the role of these agents in patients 400 Streptokinase nary Artery Disease (RISC) study of with acute coronary syndromes. In patients with unstable angina or an Italian study, 652 patients with 300 Aspirin + Streptokinase non–Q-wave MI, the risk for subse- unstable angina were treated with quent MI or death was reduced by ticlopidine hydrochloride (Ticlid), 200 aspirin therapy (75 mg/d) at 5-day 250 mg twice daily, plus conven- No. of Vascular Deaths No. of Vascular follow-up by 57% (from 5.8% to tional therapy or with conven- 100 2.5%).5 tional therapy alone during hospi- In the ISIS-2 (Second Interna- talization, with continued therapy 0 7 14 21 28 35 tional Study of Infarct Survival) trial, for approximately 6 months after Days From Randomization more than 17000 patients with sus- discharge.8 Treatment with ticlopi- Figure 2. Results of the Second International pected MI were randomized to aspi- dine decreased the incidences of Study of Infarct Survival (ISIS-2) in which rin therapy (160 mg/d), streptoki- nonfatal MI and vascular death by patients with suspected myocardial infarction nase, both therapies, or neither.6 The 46%. However, the conventional were treated with aspirin, streptokinase, both, or study included patients with ST- therapy arm did not include aspi- placebo. Aspirin or streptokinase therapy alone reduced vascular mortality by 23% to 25% segment elevation, ST-segment de- rin or heparin, and most of the re- compared with placebo therapy; treatment with pression, bundle-branch block, or duction in events with ticlopidine both agents reduced vascular mortality by 42%. other electrocardiographic (ECG) ab- therapy occurred not during the ini- Adapted with permission from the ISIS-2 Collaborative Group.6 normalities. Treatment with aspirin tial hospitalization but in the months decreased vascular mortality by 23%, after discharge. a reduction comparable to the 25% re- The relatively short onset of ac- platelet aggregation. The inhibi- duction achieved with streptokinase tion (in terms of platelet inhibitory effects of aspirin on platelet ag- therapy. Patients in the ISIS-2 trial tion) provided by a loading dose of gregation are rapid, with maximal ef- treated with streptokinase derived ad- clopidogrel (Plavix), the once- fects achieved within 15 to 30 ditional benefit from concomitant daily dosing schedule, and the minutes of oral administration of a therapy with aspirin. In those treated moderate degree of platelet inhibi- dose as low as 81 mg.1 with both agents, vascular mortality tion achieved might make this The beneficial effects of aspi- was decreased by 42%. The addi- agent a possible alternate therapy rin in patients with unstable an- tional beneficial effect of aspirin in in patients with acute coronary gina were demonstrated in several those receiving thrombolytic therapy syndromes who have true aspirin studies conducted in the 1980s,2-5 in- is believed to be due at least in part allergies. However, such a role has cluding a study conducted at the to aspirin’s decreasing the rates of ves- not been established or, at least in Montreal Heart Institute.4 In that sel reocclusion and thus of myocar- terms of published studies, evalu- study, 479 patients with unstable an- dial reinfarction. The result of these ated. Nevertheless, given the rec- gina were randomized to treatment treatment regimens on vascular mor- ognized importance of antiplatelet with aspirin (325 mg twice daily), tality in the ISIS-2 trial are shown in therapy in acute MI in patients intravenous heparin sodium, both, Figure 2. These trials thus firmly es- with true aspirin allergies, it has or neither (Figure 1). Compared tablished the clinically relevant ben- been recommended that other with patients who received neither eficial effect of aspirin therapy for the antiplatelet agents such as clopido- therapy, those who were treated with broad range of patients with acute grel or ticlopidine be considered as aspirin were 71% less likely to suf- coronary syndromes. alternate therapies.9

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 Platelet GpIIb-IIIa Inhibitors

Each platelet contains approximately 60000 to 80000 GpIIb-IIIa receptors for fibrinogen on its membrane. When platelets are activated, these GpIIb-IIIa complexes

undergo a conformational change Platelet that enables them to bind fibrino- Aggregation Fibrinogen Platelet gen. As illustrated in Figure 3, the Activation binding to GpIIb-IIIa receptors located on different platelets by the same fibrinogen dimer leads to platelet aggregation. The GpIIb-IIIa in- GpIIb-IIIa Inhibitor– Mediated hibitor molecules bind to the GpIIb- Inactive Activated Inhibition of Platelet GpIIb-IIIa GpIIb-IIIa Aggregation IIIa complex and thereby block the Receptors Receptors binding of fibrinogen to its recep- GpIIb-IIIa tor, leading to complete inhibition Inhibitors of platelet aggregation. There are currently 3 intrave- Figure 3. When the inactivated platelet becomes activated, there is a conformational change in the glycoprotein IIb/IIIa (GpIIb-IIIa) receptors, which are located on the platelet membrane. These activated nously administered approved GpIIb-IIIa receptors can then bind fibrinogen dimers, leading to platelet aggregation. The GpIIb-IIIa GpIIb-IIIa inhibitors. Abciximab receptor blockers can themselves bind to the GpIIb-IIIa receptors, and by doing so prevent (ReoPro) is the Fab fragment of a fibrinogen-mediated platelet aggregation. monoclonal antibody to GpIIb-IIIa that has been humanized to reduce as the initial or primary therapy in tients with non–ST-segment eleva- immunogenicity.10 As the antibody patients with non–ST-segment el- tion acute coronary syndromes were fragment binds tightly to the GpIIb- evation acute coronary syndromes. randomized to treatment with epti- IIIa receptor, the effective physi- Inclusion criteria for these trials fibatide (Integrilin) or placebo; hep- ological half-life of platelet inhibi- generally consisted of the presence arin therapy was encouraged but not tion is relatively long (approximately of (1) ischemic ST-segment depres- mandated. Patients could be treated 12 hours). Eptifibatide (Integrilin) sion, (2) transient and/or minor (Ͻ1 medically alone, or could undergo is a synthetic cyclic heptapeptide.11 mm) ST-segment elevation, (3) is- subsequent cardiac catheterization Tirofiban hydrochloride (Aggra- chemic T-wave inversions, or (4) el- and revascularization at the discre- stat) is a nonpeptide mimetic.12 Ep- evated levels of creatine phospho- tion of their physicians. Most pa- tifibatide and tirofiban are competi- kinase of muscle band (CPK-MB tients in the study were treated solely tive inhibitors of the GpIIb-IIIa levels) on admission. with medical therapy. Overall, the receptor. The half-lives of the smaller In the Platelet Receptor Inhibi- primary composite end point of death molecules eptifibatide and tirofi- tion in Ischemic Syndrome Manage- or MI at 30 days occurred in fewer ban, which are predominantly re- ment in Patients Limited by Unstable patients treated with eptifibatide nally cleared, are on the order of 90 Signs and Symptoms (PRISM-PLUS) than in those who received placebo to 120 minutes. Because these study,14 patientswithnon–ST-segment (14.2% vs 15.7%; P=.04); in those smaller molecules are predomi- elevation acute coronary syndromes patients in North America enrolled nantly renally cleared, the dose of were initially treated with heparin in PURSUIT, there was an approxi- these agents should be adjusted in alone, tirofiban alone, or tirofiban plus mate 22% reduction in death and MI patients with renal insufficiency. heparin for 48 hours before undergo- with eptifibatide therapy (11.7% vs At currently used doses, the ing cardiac catheterization and, when 15.0%). Those patients in PURSUIT GpIIb-IIIa receptors are able to in- appropriate, revascularization. The who underwent percutaneous revas- hibit platelet aggregation on the or- tirofiban-alone arm was terminated cularization had the greatest relative der of at least 80%.13 The contrain- prematurelyduetoanexcessofdeaths reduction in adverse outcome (11.6% dications to GpIIb-IIIa inhibitor use comparedwiththeheparin-alonearm. vs 16.7%; P=.01).15 are primarily related to bleeding The primary composite end point of In the Chimeric 7E3 Antiplate- risks, and are, in general terms, com- death, MI, or refractory ischemia at 7 let Therapy in Unstable Refractory parable to those of thrombolytic days was lower in those treated with Angina (CAPTURE) study of pa- therapy. Patients with platelet counts tirofiban plus heparin compared with tients with refractory unstable an- of less than 100ϫ10 9/L should not those treated with heparin alone gina who were found during car- be treated with these agents. (12.9%vs17.9%;P=.004).Mostofthis diac catheterization to have lesions Most trials of the GpIIb-IIIa in- benefit was maintained at the 30-day amenable to percutaneous translu- hibitors have been performed in the and 6-month follow-ups.14 minal coronary angioplasty (PTCA) setting of patients undergoing per- In the Platelet Glycoprotein IIb/ and were then subsequently treated cutaneous revascularization. Sev- IIIa in Unstable Angina: Receptor with abciximab or placebo for 18 to eral studies, however, have focused Suppresion Using Integrilin Therapy 24 hours before undergoing PTCA, on the use of GpIIb-IIIa inhibitors (PURSUIT) study,15 almost 11000 pa- treatment with abciximab was asso-

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6 ANTITHROMBIN AGENTS: N = 12 296 UNFRACTIONATED HEPARIN, 4 P = .001 N = 2 754 DIRECT THROMBIN P = .001 INHIBITORS, AND Death or Nonfatal MI, % 2 LOW-MOLECULAR-WEIGHT HEPARINS 0 +24 h +48 h +72 h 0 +24 h +48 h Unfractionated Heparin Start of GpIIb-IIIa Percutaneous Inhibitor or Coronary Placebo Therapy Intervention Commercial preparations of unfractionated heparin consist of a heter- Figure 4. Cumulative incidence of death or nonfatal myocardial infarction (MI; reinfarction) in patients with non–ST-segment elevation acute coronary syndromes randomized to treatment with a glycoprotein ogeneous mixture of glycosaminogly- IIb/IIIa (GpIIb-IIIa) inhibitor or placebo. From the Platelet Glycoprotein IIb/IIIa in Unstable Angina: cans, with molecular weights ranging Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet Glycoprotein IIb/IIIa in Unstable from approximately 3000 to 30000. Angina: Receptor Suppression Using Integrilin Therapy (PRISM-PLUS), and Chimeric 7E3 Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) studies. Adapted with permission from Boersma et al.19 Only about one third of the molecules in these products are antico- agulantly active. Heparin exerts its an- ciated with a lower incidence of dence of death or nonfatal MI dur- ticoagulant effect by interacting with adverse outcomes.16 The more gen- ing the first 48 hours after percuta- antithrombin III, dramatically increas- eral role of abciximab in the treat- neous coronary intervention in those ing its ability to bind to and neutral- ment of patients with non–ST- who subsequently underwent the pro- ize thrombin and other activated segment elevation acute coronary cedure was reduced by 41% with clotting factors. Thrombin that is syndromes is being evaluated as part GpIIb-IIIa therapy (absolute rates, already fibrin bound, however, is of the Global Use of Strategies to 4.9% and 8.0%, respectively; relatively protected from inactiva- Open Occluded Coronary Arteries PϽ.001).19 These findings are illus- tion by the heparin–antithrombin III (GUSTO) IV study. trated in Figure 4. complex.26 A fourth intravenously adminis- Given the overall positive re- In 1981, Telford and Wilson27 tered GpIIb-IIIa inhibitor, lamifiban, sults of trials of intravenous GpIIb- demonstrated that in patients with which has been evaluated as therapy IIIa inhibitors, and observations that unstable angina, intravenous admin- for non–ST-segment acute coronary a prothrombotic state may exist for istration of unfractionated heparin syndromes in the Platelet IIb/IIIa weeks or even several months after reduced the rate of progression to MI Antagonism for the Reduction of acute ischemic events, it was hypoth- from 15% to 3%, a relative reduc- Acute Coronary Syndrome Events esized that postdischarge longer- tion of 80%. In the Montreal Heart in a Global Organization Network term treatment with oral GpIIb-IIIa Institute trial, the incidence of non- (PARAGON)–A17 andPARAGON-B18 inhibitors would decrease ischemic fatal or fatal MI was reduced by treat- trials, has not been shown to be of events in patients with acute coro- ment with intravenous heparin significantbenefit,andisnotapproved nary syndromes. Despite initial en- therapy from a rate of 12% in those for clinical use. couraging results and high hopes for treated with placebo alone to a rate Boersma and colleagues19 an- these trials, the results of phase 3 stud- of only 0.8% in those treated with alyzed the combined data from ies thus far have been disappointing. heparin alone.4 the PURSUIT, PRISM-PLUS, and Treatment with oral GpIIb-IIIa in- The role of unfractionated hep- CAPTURE studies, examining the hibitors has been associated with in- arin in the treatment of MI in the benefits of GpIIb-IIIa therapy in pa- creased rates of bleeding complica- modern era is still not well resolved. tients with non–ST-segment eleva- tions and/or trends toward an Individual studies of heparin in the tion acute coronary syndromes dur- increased incidence of adverse ische- prethrombolytic era produced incon- ing pharmacological therapy alone mic events.20-24 Although the expla- sistent results.28 An overview of these and for the first 48 hours after per- nation(s) for the disappointing re- studies of heparin therapy for acute cutaneous coronary intervention in sults from these trials of oral GpIIb- MI found that patients who were not those patients who subsequently un- IIIa inhibitors remains speculative,23 treated with aspirin had an 18% re- derwent the procedure. During the a partial explanation may be production in reinfarction and a 23% re- period of pharmacological therapy vided from a substudy of the Oral duction in death; however, in those alone, those patients who received GpIIb-IIIa Inhibition With Orbo- patients who were also treated with GpIIb-IIIa therapy had a 34% rela- fiban in Patients With Unstable Coro- aspirin, the reductions were on the or- tive reduction in the incidence of nary Syndromes (OPUS)–Thrombin der of only 5% to 10%.29 death or nonfatal MI compared with Inhibition in Myocardial Ischemia The role of adjuvant heparin those who received placebo therapy (TIMI) 16 trial, in which it was found therapy in patients with acute MI (absolute event rates, 2.5% and 3.8%, that patients treated with the oral who are treated with thrombolytic respectively; PϽ.001). The inci- GpIIb-IIIa inhibitor orbofiban had therapy and aspirin is undergoing re-

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 evaluation. The Gruppo Italiano Death or MI Death, MI, or per lo Studio della Sopravvivenza Refractory Angina nell’Infarto Miocardico (ISIS-2)6 and 8 P = .08 P = .01 ISIS-330 studies included arms in which patients treated with throm- 6 bolytic therapy, most of whom presented with ST-segment elevation, 4 were randomized to adjunctive subcutaneous heparin sodium therapy % of Patients 2 (12500 U twice daily) or no hepa- Heparin rin therapy. When the results of both Hirudin

studies are combined, it appears that 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 subcutaneous heparin therapy mod- Days Days estly reduces the incidence of in- Figure 5. Results of the Organisation to Assess Strategies for Ischemic Syndromes (OASIS)–2 study hospital mortality, although this comparing hirudin with unfractionated heparin sodium therapy in patients with acute coronary benefit is no longer apparent at 5 syndromes. MI indicates myocardial infarction. Adapted with permission from OASIS Investigators.47 weeks and is associated with a small increased risk for bleeding compli- mittee recommendations, it may be coronary arterial flow, and were as- cations.30 In the GUSTO-1 trial, in reasonable to extrapolate this hepa- sociated with low rates of adverse patients treated with streptokinase, rin dosing regimen to patients treated outcomes.36-44 there were no significant differ- with reteplase (r-PA) (and possibly te- Several larger trials subse- ences in 90-minute coronary artery necteplase [TNK-tPA]). quently compared hirudin with patency or mortality between those unfractionated heparin in patients treated with subcutaneous heparin Direct Thrombin Inhibitors with non–ST-segment elevation and those treated with intravenous acute coronary syndromes. As part heparin.31,32 As their name implies, the direct of the GUSTO IIb Study, more than Although in patients treated thrombin inhibitors can inactivate 8000 patients were randomized to with tissue plasminogen-activator thrombin directly, without the need treatment with hirudin or unfrac- (tPA), intravenous heparin does for antithrombin III. The prototype tionated heparin. The primary end not appear to improve early vessel of the direct thrombin inhibitors is point of death or MI at 30 days patency when assessed angiographi- hirudin, a 65-amino acid polypep- was not notably different between cally 90 minutes after adminis- titde originally isolated from the sa- treatment groups (8.3% vs 9.1%; tration of the thrombolytic agent, it liva of the medicinal leech (but now P=.22).45 may have a role in maintaining ves- produced by recombinant DNA In the Organization to Assess sel patency in the 1 to 4 days after technology). Bivalirudin (Hirulog) Strategies for Ischemic Syndromes tPA administration.28 An overview is a synthetic 20–amino acid poly- (OASIS)–1 pilot study, the com- of randomized trials involving in- peptide. bined end point of death, MI, or re- travenous heparin therapy, how- The introduction of direct fractory angina occurred in 4.4% of ever, did not detect any significant thrombin inhibitors was accompa- patients treated with low-dose hi- effects of heparin therapy on rates nied by high hopes that these agents rudin (0.2-mg/kg bolus, then 0.1- or recurrent ischemia, reinfarction, would prove superior to unfraction- mg/kg per hour infusion), 3.0% of or mortality.33 ated heparin in the treatment of patients treated with moderate- The dosing recommendations acute ischemic heart disease. Un- dose hirudin (0.4-mg/kg bolus, then for intravenous heparin administra- like unfractionated heparin, direct 0.15-mg/kg per hour infusion) and tion in patients treated with tPA has thrombin inhibitors do not require 6.5% of patients treated with un- recently been revised by the Ameri- any cofactors, can neutralize clot- fractionated heparin.46 Based on can College of Cardiology–Ameri- bound thrombin, and are not inac- these findings, in OASIS-2, more can Heart Association (ACC/AHA) tivated by plasma proteins or plate- than 10000 patients were random- Committee on Management of Acute let factor 4.34,35 They also may ized to treatment with this moder- Myocardial Infarction. These recom- provide a more reliable degree of an- ate dose regimen of hirudin or un- mendations now call for even less ag- ticoagulation and enhance the rate fractionated heparin. The primary gressive heparin administration, with of thrombolysis with thrombolytic end point of death or new MI at 7 a bolus dose of 60 U/kg (maximum, therapy better than unfractionated days occurred in 3.6% of those 4000 U) at the initiation of tPA infu- heparin.34,35 Early, generally modest- treated with hirudin and 4.2% of sion and an initial maintenance infu- sized studies of these agents in pa- those treated with heparin (P=.08). sion of approximately 12 U/kg per tients who were and were not treated The composite end point of death, hour (maximum, 1000 U/h), subse- with thrombolytic therapy sug- myocardial infraction, or refrac- quently adjusted as needed to a tar- gested that the direct thrombin in- tory angina occurred in 5.6% of get activated partial thromboplastin hibitors were safe, led to dose- those treated with hirudin and 6.7% time (aPTT) of 1.5 to 2.0 times con- dependent and therapeutic degrees of those treated with heparin trol (50-70 seconds).9 Although not of anticoagulation, improved angio- (P=.01). These results are shown in specifically addressed in the Com- graphic findings and TIMI grade Figure 5. Major bleeding was more

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 10 Dalteparin Sodium Low-Molecular-Weight Heparin Heparin (Fragmin) [2.7:1] Hirudin RR = 0.90 P = .06 Nadroparin Calcium Low-molecular-weight heparins are (Fraxiparin) [3.6:1] 8 derived from enzymatic or chemical Enoxaparin cleavage of unfractionated heparin Sodium (Lovenox) [3.8:1] (Figure 7). The potential advan- 6 RR = 0.83 0.7 P = .004 tages of low-molecular-weight hepa- 0.6 rins (LMWHs) have made them at- 0.5 4 RR = 0.72 tractive subjects for study in acute P<.001 0.4 coronary syndromes. Compared with 0.3 LMWH Unfractionated unfractionated heparin, the LMWHs Patients With Adverse Event, % 2 0.2 Heparin

% of Composition have less nonspecific binding, greater 0.1 resistance to inactivation by platelet

0 5000 10 000 15 000 20 000 factor 4, greater anti–factor Xa activ- 0 72 h 7 d 35 d Molecular Weight, d ity (leading to greater “upstream” in- Greater Anti–Factor Greater Anti–Factor IIa; hibition of the coagulation cas- Figure 6. Combined results from the Global Use Xa Activity Less Anti–Factor Xa of Strategies to Open Occluded Coronary Resistant to PF4 Sensitive to PF4 cade), greater inhibition of thrombin Arteries IIb, Organisation to Assess Strategies Little Nonspecific Nonspecific Binding generation, longer half-lives, and a Binding Less Inhibition of for Ischemic Syndromes (OASIS)–1, and Greater Inhibition of Thrombin Generation more reliable anticoagulation ef- OASIS-2 studies comparing hirudin therapy with Thrombin Generation Figure 8 58,59 unfractionated heparin sodium therapy in fect ( ). In addition, the patients with acute coronary syndromes. RR Figure 8. Percentage of composition of LMWHs can be administered sub- indicates relative risk. Adapted with permission unfractionated and low-molecular-weight cutaneously and require no monitor- from OASIS-2 Investigators.47 heparin (LMWH) in terms of molecular weight. The 3 LMWHs that have been evaluated in ing of the aPTT. clinical trials of acute coronary syndromes are The incidence of heparin- shown, along with their respective anti–factor induced thrombocytopenia is much Xa/anti–factor IIa activity. The LMWHs have relatively greater anti–factor Xa activity, lower with LMWH than with un- 61,62 resistance to inactivation from platelet factor 4 fractionated heparin. However, Cleavage Isolation (PF4), less nonspecific binding, and greater it should be noted that LMWH inhibition of thrombin generation. Based on data from Weitz,59 Zed et al,60 and Antman and should not be administered to pa- Unfractionated LMWH Handin.58 tients with established heparin- Heparin induced thrombocytopenia because Figure 7. The low-molecular-weight heparins nial bleeding. The TIMI and GUSTO of a high degree of cross-reactivity (LMWH) are produced from chemical or trials were reconfigured (and were with the antibody associated with enzymatic degradation and cleavage of unfractionated heparin. Methods of cleavage and designated TIMI 9B and GUSTO unfractionated heparin–induced isolation vary for different commercially IIb), and compared lower doses of thrombocytopenia (a direct throm- produced LMWHs. Adapted with permission hirudin and unfractionated hepa- bin inhibitor or danaparoid so- from Fareed et al.57 rin. In the TIMI 9B trial, the com- dium should be used instead in such posite primary end point occurred patients).59 common with hirudin, although the in 12.9% of hirudin-treated pa- Clinical studies of these agents number of life-threatening epi- tients and 11.9% of heparin-treated have produced agent-dependent re- sodes and hemorrhagic strokes were patients (P=NS).51 In the GUSTO IIb sults (Table). Two studies of enoxa- similar.47 Pooled analysis of GUSTO trial, death or MI at 30 days oc- parin sodium (Lovenox) have de- IIb, OASIS-1, and OASIS-2, shown curred in 9.9% of those treated with termined that treatment with this in Figure 6, demonstrates that at hirudin and 11.3% of those treated LMWH may be superior to treat- 72 hours the risk for death due to with heparin (P=.06). Taken to- ment with unfractionated heparin in MI in patients with non–ST- gether, the TIMI 9B and GUSTO IIb patients with non–ST-segment el- segment acute coronary syn- findings suggest little if any benefit evation acute coronary syndromes. In dromes is reduced by 28% with hi- of routinely using hirudin over un- the Efficacy and Safety of Subcutane- rudin therapy, although some of this fractionated heparin as an adjunc- ous Enoxaparin in Non–Q-Wave early benefit is no longer present by tive therapy in patients treated with Coronary Events (ESSENCE) study, day 35.47 thrombolytic therapy and aspirin. the 14-day incidence of the com- Several recent, generally larger, Preliminary studies of other di- bined end point of death, MI, or re- trials have also evaluated the utility rect thrombin inhibitors as adjunc- current angina was lower in patients of direct thrombin inhibitors as ad- tive therapy in patients treated with treated with subcutaneous enoxapa- junctive therapy in patients with ST- thrombolytic agents have so far pro- rin sodium (1 mg/kg every 12 hours) segment elevation treated with duced mixed results.52-55 The Hiru- than with intravenous unfraction- thrombolytic therapy. In the TIMI log and Early Reperfusion/Occlu- ated heparin sodium (16.6% vs 9A,48 GUSTO IIA,49 and Hirudin for sion (HERO)–2 trial is currently 19.8%).62 The TIMI 11B study also Improvement of Thrombolysis– assessing clinical end points in found that treatment with enoxapa- III50 trials, the use of relatively high 17000 patients treated with strep- rin sodium (30-mg intravenous bo- doses of hirudin was associated with tokinase randomized to adjunctive lus then 1 mg/kg subcutaneously ev- unacceptably high rates of intracra- bivalirudin or heparin therapy.56 ery 12 hours) was superior to

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End Point End Point With Comparison Reference LMWH Dose End Point With LMWH, % Treatment, % P Gurfinkel et al,64 Nadroparin calcium 214 U/kg SQ twice daily Death, MI, recurrent 22 63 .07 1995 (Fraxiparine) angina, or major bleeding The FRAXIS Study Nadroparin calcium (1) 86 anti−factor Xa IU ϫ6d Death, MI, recurrent (1) 17.8 15.1 (1) .85 Group,65 1999 (Fraxiparine) (2) 86 anti−factor Xa IV ϫ 14 d angina (2) 20.0 (2) .25 Klein et al,66 1997 Dalteparin sodium 120 U/kg SQ twice daily Death, MI, or 9.3 7.6 .33 (Fragmin) recurrent angina Cohen et al,62 1997 Enoxaparin sodium 1 mg/kg SQ every 12 h Death, MI, or 16.6 19.8 .02 (Lovenox) recurrent angina Antman et al,63 1999 Enoxaparin sodium 30 mg IV then 1 mg/kg SQ Death, MI, or urgent 14.2 16.7 .03 (Lovenox) every 12 h revascularization

*LMWH indicates low-molecular-weight heparin; FRAXIS, Fraxiparine in Ischaemic Syndrome; SQ, subcutaneous; IV, intravenous; and MI, myocardial infarction.

treatment with intravenous hepa- Day Odds Ratio End Point P rin in reducing the 14-day compos- (95% Confidence Interval) I Reduction, % TIMI 11B ite end point of death, MI, or need 0.77 8 Essence 23 .02 (0.62-0.95) for urgent revascularization (14.2% Combined vs 16.7%).63 Meta-analysis of these TIMI 11B 0.79 2 trials showed an approximate 20% 14 Essence 21 .02 (0.65-0.96) reduction in death and cardiac is- Combined

chemic events with enoxaparin TIMI 11B 0.82 67 43 Essence 18 .02 therapy (Figure 9). An eco- (0.69-0.97) nomic analysis of the ESSENCE data, Combined shown in Figure 10, found treat- 0.5 0.75 1.0 2.0 Enoxaparin Unfractionated ment with enoxaparin to be cost- Better Heparin effective. Odds Ratio Although an earlier small study 64 Figure 9. Individual and combined results from the Thrombin Inhibition in Myocardial Infarction (TIMI) by Gurfinkel and colleagues found 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) that treatment with nadroparin studies comparing enoxaparin sodium (Lovenox) and unfractionated heparin in the treatment of patients with acute coronary syndromes. Results are shown for follow-up days 8, 14, and 43. Based on data from calcium (Fraxiparine) resulted in 67 lower incidences of adverse events Antman et al. Figure provided courtesy of Elliott M. Antman, MD. than treatment with placebo or intravenous unfractionated hepa- cant benefit for such routine outpa- including reteplase (r-PA) and te- rin, results from the larger Fraxip- tient therapy in patients with non– necteplase (TNK-tPA), were de- arine in Ischaemic Syndrome ST-segment elevation acute coronary signed to be more fibrin specific or (FRAXIS) study demonstrate that syndromes. clot specific, meaning that they outcome may be worse with nadro- would generate plasmin preferen- parin therapy when compared THROMBOLYTIC tially at the fibrin surface in a pre- with intravenous unfractionated (FIBRINOLYTIC) THERAPY formed thrombus, in the hopes that heparin therapy.65 In the Fragmin this would decrease bleeding com- During Instability in Coronary The thrombolytic (fibrinolytic) plications (a hope that was not found Artery Disease (FRIC) study, agents convert inactive plasmino- to be the case). The longer half- treatment with dalteparin sodium gen to active plasmin. Plasmin in lives of the next-generation throm- (Fragmin) proved no better than turn acts to degrade fibrin, al- bolytic agents, reteplase (r-PA) and that with unfractionated heparin, though plasmin is relatively sub- tenecteplase (TNK-tPA), allow them and in fact there were more deaths strate nonspecific and can degrade to be administered as bolus therapy. in those treated with dalteparin.66 other proteins, including fibrino- Studies of postdischarge, gen. The earliest thrombolytic agent Thrombolytic Therapy in longer-duration LMWH therapy in tested in clinical trials, streptoki- Non–ST-Segment Elevation patients with acute coronary syn- nase, was not fibrin specific or clot Acute Coronary Syndromes dromes have been generally discour- specific, meaning that it would lead aging.63,66,69 Despite the theoretical to indiscriminate systemic plasmin Pathological, angiographic, and benefits of continuing antithrom- production, a situation that could angioscopic studies performed bin therapy for 1 to several months lead to a systemic lytic state. The during the 1980s demonstrated that after discharge, no clinical trial has newer thrombolytic agents, begin- intracoronary thrombus was a demonstrated a statistically signifi- ning with the tPA alteplase and now common finding in patients with

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 70 8 16 000 Enoxaparin $14 357 60 Unfractionated Heparin $13 185 6 12 000 50

40 4 8000 Days

30 Costs, $ % of Patients 20 2 4000

0 0 0 Cath PTCA CABG Readmit ICU Stay Total Stay Hospital MD Total

Figure 10. Economic analyses from the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events study comparing resource use and costs in patients with acute coronary syndromes treated with enoxaparin sodium (Lovenox) or unfractionated heparin. Cath indicates coronary catheterization; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; ICU, intensive care unit; and MD, physician. Data from Mark et al.68

A B der of 25%-33%) in mortality with 40 60 thrombolytic therapy. Although initial studies relied on intracoronary ad-

30 40 ministrationofthethrombolyticagent, later studies demonstrated that the more practical intravenous admin- 20 20 istration of these agents was also efficacious. Thrombolytic agents that 10 0 have been shown in placebo-controlled landmark studies to be effica- Lives Saved per 1000 Patients Treated 0 Lives Saved per 1000 Patients Treated –20 cious include streptokinase (GISSI- 0-1 2-3 4-6 7-12 BBB Anterior Inferior ST-Segment Hours ST-Segment ST-Segment Depression 1, Intravenous Streptokinase in Acute Elevation Elevation Myocardial Infarction [ISAM], and Figure 11. Benefits in terms of lives saved per thousand patients with acute myocardial infarction treated ISIS-2), anistreplase (APSAC [an- with thrombolytic therapy in terms of time from chest pain onset to treatment (A) and electrocardiographic isoylated plasminogen streptokinase abnormality (B). BBB indicates bundle-branch block. Data from Fibrinolytic Therapy Trialists’ Collaborative 85 activator complex] Intervention Mor- Group. tality Study [AIMS]), and tPA (Anglo- unstable angina.70-74 This finding led segment depression or with nonspe- Scandinavian Study of Early Throm- to the hypothesis that thrombo- cific ECG abnormalities, there was no bolysis [ASSET], Estudio Multicen- lytic therapy would be of benefit in benefit with thrombolytic therapy trico Estreptoquinasa Republicas de 86 reducing adverse outcomes in pa- (Figure 11). If fact, those who pre- America del Sur [EMERAS], and tients with unstable angina. Early an- sented with ST-segment depression Late Assessment of Thrombolytic giographic and clinical studies pro- actually tended to worsen if treated Efficacy [LATE]87).85 duced conflicting results.73,75-83 These with thrombolytic therapy.85 Taken The relative benefit of thrombo- trials found that MI developed in a as a whole, analyses of studies in lytic treatment in terms of lives saved greater percentage of patients treated which thrombolytic therapy was ad- per 1000 patients treated based on with thrombolytic therapy than in ministered to patients with non–ST- time to treatment from chest pain on- those who were treated with hepa- segment elevation acute coronary syn- set and initial ECG findings are shown rin alone.84 dromes (unstable angina or non–ST- in Figure 11. Patients who are treated As part of the TIMI 3B trial, segment elevation MI) demonstrate within several hours of chest pain on- 1473 patients with unstable angina that thrombolytic therapy leads to no set derive the greatest benefit.85 or non–Q-wave MI were random- net benefit and may actually in- As most earlier trials of throm- ized to treatment with tPA or pla- crease the incidence of subsequent MI bolytic therapy had enrolled pa- cebo. All patients were treated with and death in such patients. tients who could be treated within aspirin and intravenous heparin. The 6 hours of chest pain onset, 2 trials composite primary end point of Thrombolytic Therapy in addressed whether treatment of pa- death, MI, or spontaneous recur- ST-Segment Elevation MI tients who presented later than 6 rent or inducible ischemia oc- hours after chest pain onset could curred in a similar percentage of the The role of thrombolytic therapy also derive benefit. In the EMERAS tPA- and placebo-treated patients in patients who present with ST- trial, which compared streptoki- (54.2% and 55.5%, respectively). segment elevation MI has been nase with placebo, there was a trend The Fibrinolytics Therapy Tri- demonstrated repeatedly and defini- toward decreased mortality in those alists’ Collaborative Group reviewed tively.Studiescomparingthrombolytic treated 7 to 12 hours after symp- the data from all large trials of throm- therapywithplacebohaveconsistently tom onset (11.7% vs 13.2%).86 In the bolytic therapy in suspected acute MI. shown a statistically and clinically sig- LATE study, which compared tPA In patients who presented with ST- nificant reduction (usually on the or- with placebo, there was a statisti-

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 cally significant 25.6% reduction in or combined end points between data, presented by James J. Fergu- mortality in those who were treated agents.90 In the Assessment of the son III, MD, at the European Soci- 6 to 12 hours after chest pain on- Safety and Efficacy of a New Throm- ety of Cardiology,92 suggested that set.87 These 2 trials,86,87 as well as an- bolytic (ASSENT)–2 trial includ- the combination of the LMWH other analysis,85 provided data that ing almost 17000 patients with acute enoxaparin and a platelet GpIIb- extended the therapeutic window for MI, tPA therapy was compared with IIIa inhibitor was safe and associ- thrombolytic therapy to 12 hours. another newer plasminogen activa- ated with a very low incidence of ma- Among patients with ECG find- tor, tenecteplase (TNK-tPA), a modi- jor adverse cardiac events (James J. ings of ST-segment elevation, those fied form of tPA that can be admin- Ferguson III, MD, written commu- with ST-segment elevation in the istered as a single bolus (30-50 mg, nication, November 1, 2000). anterior leads derive the greatest based on weight). Compared with Preliminary studies in pa- benefit. Those with inferior ST- tPA, tenecteplase (TNK-tPA) has tients with ST-segment elevation MI segment elevation derive a more slower plasma clearance, better fi- suggest that the combination of modest but still clinically impor- brin specificity, and higher resis- GpIIb-IIIa receptor inhibition with tant reduction in mortality.85 Se- tance to plasminogen-activator in- modified doses of thrombolytic lected patients who present with hibitor-1. The 30-day mortality rate agents can lead to a greater inci- symptoms highly suggestive of acute and the rate of intracranial hemor- dence of normal coronary blood flow MI and ECG findings demonstrat- rhage, however, were similar with (TIMI 3 flow) as assessed using 60- ing bundle-branch block obscur- tPA and tenecteplase (TNK-tPA).91 to 90-minute angiograms than with ing ST-segment analysis also derive Decisions about whether to use that achieved with thrombolytic significant benefit from thrombo- tPA or streptokinase can be based to therapy alone.93-95 Normal coro- lytic therapy.85,88 In particular, those some extent on such factors as rela- nary blood flow in the culprit coro- found to have a left bundle-branch tive mortality reductions, intracra- nary artery, as assessed using 90- block that is known or presumed to nial hemorrhage risk, and cost (tPA minute angiography, is restored with be new derive great benefit from is approximately 10 times more ex- thrombolytic therapy alone in ap- thrombolytic therapy. The benefits pensive than streptokinase). It has proximately 50% to 55% of treated of thrombolytic therapy based on been proposed that tPA be prefer- patients, whereas these prelimi- time to treatment and on ECG find- entially considered in patients who nary results have found that com- ings are shown in Figure 11. present early after symptom onset bining GpIIb-IIIa therapy with half- Several large trials have been per- with a large area of myocardium in dose thrombolytic therapy can result formed comparing the relative effi- jeopardy (eg, large anterior MI) and in restoration of normal blood flow cacy of different thrombolytic agents. low risk for intracranial hemor- in approximately 70% to 75% of In the GISSI-289 and ISIS-330 trials, no rhage, whereas streptokinase be con- treated patients.93,96,97 In general, re- significant differences in efficacy were sidered in those with less potential sults of combination therapy have found between streptokinase and tPA. for mortality benefit and greater risk been better with tPA or reteplase However, proponents of tPA have for intracranial hemorrhage.88 The (r-PA) than with streptokinase, as noted that in these trials, heparin was newer thrombolytic agents rete- therapy with streptokinase has administered subcutaneously (not in- plase (r-PA) and tenecteplase (TNK- resulted in lower rates of normal travenously) and was only started 4 tPA) appear to have similar overall coronary blood flow and a greater to 12 hours after thrombolytic ad- efficacy compared with tPA; how- incidence of bleeding complica- ministration. In the first GUSTO trial, ever, these newer agents are more tions.93-95,98 The results of larger there was a statistically significant easily administered and present the trials of combination GpIIb-IIIa lower mortality rate in those treated potential to treat selected patients and thrombolytic therapy, includ- with tPA and intravenous heparin with ST-segment elevation myocar- ing GUSTO IV–Acute Myocardial therapy (started at the time of throm- dial infraction before arrival in the Infarction (AMI) (abciximab+half- bolytic therapy) compared with those emergency department. dose reteplase [r-PA]), Integrilin and treated with streptokinase and intra- Tenecteplase in Acute Myocardial venous or subcutaneous heparin COMBINATION Infartion (INTEGRITI)–TIMI 20 (6.3% with tPA vs 7.3% with strep- ANTITHROMBOTIC THERAPY (eptifibatide+half-dose tenecteplase tokinase; P=.001).32 In these trials, [TNK-tPA]), and Fibrinolytic and tPA was associated with a small in- The demonstrated efficacy of newer Aggrastat ST Elevation Resolution creased risk for intracranial hemor- antithrombotic agents has led in- (FASTER)–TIMI 24 (tirofiban+half- rhage compared with treatment with vestigators to begin exploring the use dose tenecteplase [TNK-tPA]), streptokinase. of these newer agents in combina- should become available shortly, and The GUSTO-III trial com- tion with thrombolytic therapy. could have a significant impact on pared tPA with the newer recombi- As LMWHs and platelet GpIIb- our understanding of optimal treat- nant plasminogen activator (rete- IIIa inhibitors have been shown to ment of patients with acute MI (Her- plase [r-PA]), which is administered be of benefit in patients with non– bert B. Lee, PhD, written commu- in two 10-mg boluses given 30 min- ST-segment elevation MI, investiga- nication, March 3, 2000). utes apart. There were no statisti- tors have begun to explore using Preliminary data presented at cally significant differences in 30- these medications in combination. the 2000 Meeting of the American day mortality, overall stroke rates, Recent preliminary observational College of Cardiology from the

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 Heparin Aspirin Reperfusion Trial initial maintenance infusion dose of tients treated with reteplase (r-PA) (HART)–II study assessing the util- 18 U/kg, subsequently adjusted to or tenecteplase (TNK-tPA). The rou- ity of enoxaparin as antithrombin maintain the aPTT at 1.5 to 2.5 times tine use of heparin in patients treated therapy in patients with ST-segment control. The direct thrombin inhibi- with streptokinase is not recom- elevation MI treated with acceler- tor hirudin (possibly at a dose of a mended (although the use of hepa- ated tPA demonstrated trends to- 0.4-mg/kg bolus then an initial in- rin may be appropriate in such pa- ward greater 90-minute normal fusion dose of 0.15 mg/kg per hour, tients for other indications). No data coronary blood flow in the infarct- subsequently adjusted to an aPTT recommend the direct thrombin in- related artery and lower reocclu- level at 1.5-2.5 times control) can be hibitor hirudin compared with un- sion rates in patients who received considered instead of intravenous fractionated heparin in patients enoxaparin compared with those unfractionated heparin. Higher-risk treated with thrombolytic therapy; who were treated with standard un- patients (those with ischemic ECG results of the HERO-2 study may fractionated heparin. abnormalities or positive CPK-MB help to determine whether there is The Enoxaparin and TNK- or troponin levels) should be treated an adjunctive role for bivalirudin tPA With or Without GP-IIb/IIIa preferentially with enoxaparin (Hirulog) in patients treated with Inhibitor as Reperfusion Strategy in (Lovenox). It may be reasonable to streptokinase. Low-molecular- ST Elevation MI (ENTIRE)–TIMI 23 treat all patients with non–ST-ele- weight heparin therapy in patients trial will help tie together advances vation acute coronary syndrome pref- treated with thrombolytic agents ap- in antiplatelet, antithrombin, and erentially with such an LMWH, given pears promising, but further study thrombolytic therapy, and will com- other advantages including patient is necessary before its use in this set- pare treatment with tenecteplase comfort, ease of administration, and ting can be recommended. (TNK-tPA) and unfractionated hep- the fact that aPTT levels do not need Although preliminary studies arin or enoxaparin with therapy with to be monitored. combining GpIIb-IIIa inhibitors with tenecteplase (TNK-tPA) plus abcix- Thrombolytic therapy in pa- half-dose thrombolytic therapy are imab and unfractionated heparin or tients with non–ST-segment eleva- encouraging, such therapy cannot at enoxaparin. tion acute coronary syndromes is of present be recommended outside the no benefit (and indeed may be harm- setting of clinical trials, pending the RECOMMENDATIONS ful) and should not be used. results of planned and ongoing studies evaluating this combination Clinical studies now provide a ST-Segment Elevation MI therapy. wealth of information to guide treatment in patients with acute coro- All patients with ST-segment eleva- Accepted for publication November 21, nary syndromes. Planned and on- tion MI (as well as those with 2000. going studies should help serve to bundle-branch block obscuring ST- We thank Elliott M. Antman, MD, further refine and define these rec- segment evaluation) should be for creating and providing Figure 9. ommendations. treated with aspirin. No clinical data Corresponding author and exist as to whether thienopyridines reprints: Glenn N. Levine, MD, Sec- Non–ST-Segment Acute should be administered to those with tion of Cardiology 3C-330, Houston Coronary Syndromes true aspirin allergies, although this VA Medical Center (111b), 2002 seems to be a reasonable approach. Holcombe Blvd, Houston, TX 77030 All patients who present with un- In current practice, patients (e-mail: [email protected]). stable angina or non–ST-segment MI with ST-segment elevation and (non–Q-wave MI) should be treated treated with tPA as well as rete- REFERENCES with aspirin. Although there is scant plase (r-PA) (and tenecteplase clinical data, it seems reasonable to [TNK-tPA] when approved) are 1. Dabaghi SF, Kamat SG, Payne J, et al. Effects of treat those with true aspirin aller- treated with unfractionated hepa- low-dose aspirin on in vitro platelet aggregation gies with clopidogrel or ticlopi- rin also; studies of tenecteplase in the early minutes after ingestion in normal sub- dine. Patients who present with ST- (TNK-tPA) have also used intrave- jects. Am J Cardiol. 1994;74:720-723. segment depression, transient ST- nous heparin therapy. The recom- 2. Lewis HD, Davis JW, Archibald DG, et al. Protec- segment elevation, ischemic T-wave mended dose of heparin sodium in tive effects of aspirin against acute myocardial infarction and death in men with unstable angina: inversion, and/or positive cardiac en- patients treated with tPA has re- results of a Veterans Administration Cooperative zymes and without contraindica- cently revised to a gentler dosing Study. N Engl J Med. 1983;309:396-403. tions should be strongly consid- regimen of an initial bolus dose of 3. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfin- ered for additional antiplatelet 60 U/kg (up to a maximum dose of pyrazone, or both in unstable angina. N Engl J Med. therapy with a GpIIb-IIIa inhibitor. 4000 U) at the initiation of tPA in- 1985;313:1369-1375. 4. Theroux P, Ouimet H, McCans J, et al. Aspirin, hep- All patients without bleeding fusion and an initial maintenance in- arin, or both to treat acute unstable angina. N Engl contraindications should be treated fusion of approximately 12 U/kg per J Med. 1988;319:1105-1111. with antithrombin therapy. In those hour (maximum, 1000 U/h), sub- 5. The RISC Group. Risk of myocardial infarction and patients treated with unfraction- sequently adjusted to a target aPTT death during treatment with low dose aspirin and intravenous heparin in men with unstable coro- ated heparin, a weight-adjusted dos- of 1.5 to 2.0 times control (50-70 nary artery disease. Lancet. 1990;336:827-830. ing regimen should be used, with an seconds). It seems reasonable to ex- 6. ISIS-2 (Second International Study of Infarct Sur- initial 80-U/kg bolus followed by an trapolate this recommendation to pa- vival) Collaborative Group. Randomized trial of in-

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 travenous streptokinase, oral aspirin, both, or nei- let inhibitor, in patients undergoing PTCA or stent inhibitor, in unstable angina pectoris. Am J Car- ther among 17,187 cases of suspected acute placement. Paper presented at: 48th Annual Sci- diol. 1993;72:1357-1360. myocardial infarction: ISIS-2. Lancet. 1988;2: entific Session of the American College of Cardi- 39. Fuchs J, Cannon CP, and the TIMI 7 Investiga- 349-360. ology; March 8, 1999; New Orleans, La. tors. Hirulog in the treatment of unstable angina: 7. Sharis PJ, Cannon CP, Loscalzo J. The antiplate- 22. Cannon CP. Orbofiban in patients with unstable results of the Thrombin Inhibition in Myocardial let effects of ticlopidine and clopidogrel. Ann In- coronary syndromes. Paper presented at: 48th An- Ischemia (TIMI) 7 Trial. Circulation. 1995;92:727- tern Med. 1998;129:394-405. nual Scientific Session of the American College 733. 8. Balsano F, Paolo P, Violi F, et al. Antiplatelet treat- of Cardiology; March 10, 1999; New Orleans, La. 40. Topol EJ, Fuster V, Harrington RA, et al. Recom- ment with ticlopidine in unstable angina. Circu- 23. Heeschen C, Hamm CW. Difficulties with oral plate- binant hirudin for unstable angina pectoris: a mul- lation. 1990;82:17-26. let glycoprotein IIb/IIIa receptor antagonists. Lan- ticenter, randomized angiographic trial. Circula- 9. Ryan TJ, Antman EM, Brooks NH, et al. 1999 up- cet. 2000;355:330-331. tion. 1994;89:1557-1566. date: ACC/AHA guidelines for the management of 24. Newby LK. SYMPHONY-2 Results. Paper pre- 41. Lidon RM, Theroux P, Lesperance J, et al. A pi- patients with acute myocardial infarction: a re- sented at: 49th Annual Scientific Session of the lot, early angiographic patency study using a di- port of the American College of Cardiology/ American College of Cardiology; March 10, 2000; rect thrombin inhibitor as adjunctive therapy to American Heart Association Task Force on Prac- Anaheim, Calif. streptokinase in acute myocardial infarction. Cir- tice Guidelines (Committee on Management of 25. Holmes MB, Sobel BE, Cannon CP, Schneider DJ. culation. 1994;89:1567-1572. Acute Myocardial Infarction). J Am Coll Cardiol. Increased platelet reactivity in patients given or- 42. Theroux P, Perez-Villa F, Waters D, Lesperance 1999;34:890-911. bofiban after an acute coronary syndrome: an J, Shabani F, Bonan R. Randomized double- 10. Jordon RE, Mascelli MA, Nakada MT, et al. Phar- OPUS-TIMI 16 substudy. Am J Cardiol. 2000;85: blind comparison of two doses of Hirulog with hep- macology and clinical development of abciximab 491-493. arin as adjunctive therapy to streptokinase to pro- (c7E3 Fab, ReoPro). In: Sasahara AA, Loscalzo J, 26. Hirsh J, Warkentin TE, Raschke R, et al. Heparin mote early patency of the infarct-related artery in eds. Near Therapeutic Agents in Thrombosis and and low-molecular-weight heparin. Chest. 1998; acute myocardial infarction. Circulation. 1995;91: Thrombolysis. New York, NY: Marcel Dekker Inc; 114(suppl):489S-510S. 2132-2139. 1977:291-313. 27. Telford AM, Wilson C. Trial of heparin versus aten- 43. Cannon CP, McCabe CH, Henry TD, et al. A pilot 11. Goa KL, Noble S. Eptifibatide: a review of its use olol in prevention of myocardial infarction in in- trial of recombinant desulfatohirudin compared in patients with acute coronary syndromes and/or termediate coronary syndrome. Lancet. 1981;1: with heparin in conjunction with tissue-type plas- undergoing percutaneous coronary intervention. 1225-1228. minogen activator and aspirin for acute myocar- Drugs. 1999;57:439-462. 28. Levine GN, Stein B, Ali MN. Antithrombotic therapy dial infarction: results of the Thrombolysis in Myo- 12. Schafer AI. Antiplatelet therapy with glycopro- in cardiovascular disease. In: Loscalzo J, Scha- cardial Infarction (TIMI) 5 trial. J Am Coll Cardiol. tein IIb/IIIa receptor inhibitors and other novel fer AI, eds. Thrombosis and Hemorrhage. Balti- 1994;23:993-1003. agents. Tex Heart J. 1997;24:90-96. more, Md: Williams & Wilkins; 1998:1309- 44. Lee LV. Initial experience with hirudin and strep- 13. Keriakes DJ, Broderick TM, Roth EM. Time course, 1336. tokinase in acute myocardial infarction: results of magnitude, and consistency of platelet inhibition 29. Collins R, Peto R, Baigent C, Sleight P. Aspirin, the Thrombolysis in Myocardial Infarction (TIMI) by abciximab, tirofiban, or eptifibatide in pa- heparin, and fibrinolytic therapy in suspected acute 6 trial. Am J Cardiol. 1995;75:7-13. tients with unstable angina pectoris undergoing myocardial infarction. N Engl J Med. 1997;336: 45. Global Use of Strategies to Open Occluded Coro- percutaneous coronary intervention. Am J Car- 847-860. nary Arteries (GUSTO) IIb Investigators. A com- diol. 1999;84:391-395. 30. ISIS-3 (Third International Study of Infarct Sur- parison of recombinant hirudin with heparin for 14. PRISM-PLUS Study Investigators. Inhibition of the vival) Collaborative Group. ISIS-3: a randomised the treatment of acute coronary syndromes. N Engl platelet glycoprotein IIb/IIIa receptor with tirofi- comparison of streptokinase vs tissue plasmino- J Med. 1996;335:775-782. ban in unstable angina and non–Q-wave myocar- gen activator vs anistreplase and of aspirin plus 46. Organization to Assess Strategies for Ischemic dial infarction: platelet receptor inhibition in is- heparin vs aspirin alone among 41,299 cases of Syndromes (OASIS) Investigators. Comparison of chemic syndrome management in patients limited suspected acute myocardial infarction. Lancet. the effects of two doses of recombinant hirudin by unstable signs and symptoms. N Engl J Med. 1992;339:753-770. compared with heparin in patients with acute myo- 1998;338:1488-1497. 31. The GUSTO Angiographic Investigators. The ef- cardial ischemia without ST elevation: a random- 15. PURSUIT Investigators. Inhibition of platelet gly- fects of tissue plasminogen activator, streptoki- ized trial. Circulation. 1997;96:769-777. coprotein IIb/IIIa with eptifibatide in patients with nase, or both on coronary artery patency, ven- 47. Organisation to Assess Strategies for Ischemic acute coronary syndromes: Platelet Glycopro- tricular function, and survival after acute Syndromes (OASIS-2) Investigators. Effects of re- tein IIb/IIIa in Unstable Angina: Receptor Sup- myocardial infarction. N Engl J Med. 1993;329: combinant hirudin (lepirudin) compared with hep- pression Using Integrilin Therapy. N Engl J Med. 1615-1622. arin of death, myocardial infarction, refractory an- 1998;339:436-443 32. The GUSTO Investigators. An international ran- gina, and revascularisation procedures in patients 16. CAPTURE Investigators. Randomised placebo- domized trial comparing four thrombolytic strat- with acute myocardial ischaemia without ST el- controlled trial of abciximab before and during egies for acute myocardial infarction. N Engl J Med. evation: a randomised trial. Lancet. 1999;353: coronary intervention in refractory unstable an- 1993;329:673-682. 429-438. gina: the CAPTURE Study. Lancet. 1997;349: 33. Mahaffey KW, Granger CB, Collins R, et al. Over- 48. Antman EM, for the TIMI 9A investigators. Hiru- 1429-1435. view of randomized trials of intravenous heparin din in acute myocardial infarction: safety report 17. PARAGON Investigators. International, random- in patients with acute myocardial infarction treated from the thrombolysis and thrombin inhibition in ized, controlled trial of lamifiban (a platelet gly- with thrombolytic therapy. Am J Cardiol. 1996; myocardial infarction (TIMI) 9A trial. Circulation. coprotein IIb/IIIa inhibitor), heparin, or both in un- 77:551-556. 1994;90:1624-1630. stable angina. Circulation. 1998;97:2386-2395. 34. Cannon CP, Braunwald E. Hirudin: initial results 49. Global Use of Strategies to Open Occluded Coro- 18. Harrington RA. PARAGON-B Results. Paper pre- in acute myocardial infarction, unstable angina and nary Arteries (GUSTO) IIa Investigators. Random- sented at: 49th Annual Scientific Session of the angioplasty. J Am Coll Cardiol. 1995;25(suppl 7): ized trial of intravenous heparin versus recombi- American College of Cardiology; March 10, 2000; 30S-37S. nant hirudin for acute coronary syndromes. Anaheim, Calif. 35. Loscalzo J. Thrombin inhibitors in fibrinolysis: a Circulation. 1994;90:1631-1637. 19. Boersma E, Akkerhuis M, Theroux P, et al. Plate- Hobson’s choice of alternatives. Circulation. 1996; 50. Neuhaus KL, von Essen R, Tebbe U, et al. Safety let glycoprotein IIb/IIIa receptor inhibition in non– 94:863-865. observations from the pilot phase of the random- ST-elevation acute coronary syndromes: early ben- 36. Lidon RM, Theroux P, Juneau M, Adelman B, Ma- ized r-Hirudin for Improvement of Thrombolysis efit during medical treatment only, with additional raganore J. Initial experience with a direct anti- (HIT-III) study: a study of the Arbeitsgemein- protection during percutaneous coronary inter- thrombin, Hirulog, in unstable angina: anticoagu- schaft Leitender Kardiologischer Krankenhausar- vention. Circulation. 1999;100:2045-2048. lant, antithrombotic, and clinical effects. zte. Circulation. 1994;90:1638-1642. 20. The SYMPHONY Investigators. Comparison of si- Circulation. 1993;99:1495-1501. 51. Antman EM, for the TIMI 9B Investigators. brafiban with aspirin for prevention of cardiovas- 37. Fox KA. r-Hirudin in unstable angina pectoris: ra- Hirudin in acute myocardial infarction: Throm- cular events after acute coronary syndromes: a tionale and preliminary data from the APT pilot bolysis and Thrombin Inhibition in Myocardial randomised trial. Lancet. 2000;355:337-345. study. Eur Heart J. 1995;16(suppl D):28-32. Infarction (TIMI) 9B Trial. Circulation. 1996;94: 21. O’Neill WW, for the EXCITE Investigators. Effi- 38. Sharma GV, Lapsley D, Vita JA, et al. Usefulness 911-921. cacy and safety of xemilofiban, an oral IIb/IIIa plate- and tolerability of Hirulog, a direct thrombin- 52. Ferguson JJ. Meeting highlights: XIX Congress of

(REPRINTED) ARCH INTERN MED/ VOL 161, APR 9, 2001 WWW.ARCHINTERNMED.COM 947

Downloaded From: https://jamanetwork.com/ on 09/30/2021 the European Society of Cardiology. Circulation. 69. FRagmin and Fast Revascularisation during In- sults from all randomized trials of more than 1000 1997;96:3818-3821. Stability in Coronary artery disease (FRISC II) In- patients. Lancet. 1994;343:311-322. 53. Alderman EL. Results from late-breaking clinical vestigators. Long-term low-molecular-mass hep- 86. EMERAS (Estudio Multicentrico Estreptoqui- trials sessions at ACC ’98. J Am Coll Cardiol. 1998; arin in unstable coronary-artery disease: FRISC nasa Republicas de America del Sur) Collabora- 32:1-7. II prospective randomised multicentre study [pub- tive Group. Randomised trial of late thromboly- 54. Cody RJ. Results from late breaking clinical tri- lished correction appears in Lancet. 1999;354: sis in patients with suspected acute myocardial als session at ACC ’97. J Am Coll Cardiol. 1997; 1478]. Lancet. 1999;354:701-707. infarction. Lancet. 1993;342:767-772. 30:1-7. 70. Bresnahan DS, David JL, Holmes DR. Angio- 87. LATE Study Group: Late Assessment of Throm- 55. White HD, Aylward PE, Collins R, et al. Random- graphic occurrence of and clinical correlates of in- bolytic Efficacy (LATE) study with alteplase 6-24 ized, double-blind comparison of Hirulog versus traluminal coronary artery thrombus: role of un- hours after onset of acute myocardial infarction. heparin in patients receiving streptokinase and as- stable angina. J Am Coll Cardiol. 1985;6:285-289. Lancet. 1993;342:759-766. pirin for acute myocardial infarction (HERO). Cir- 71. Sherman CT, Litvack F, Grundfest W, et al. Coro- 88. Ryan TJ, Anderson JL, Antman EM, et al. ACC/ culation. 1997;96:2155-2161. nary angioscopy in patients with unstable angina AHA guidelines for the management of patients with 56. White HD. Direct thrombin inhibition and throm- pectoris. N Engl J Med. 1986;315:913-919. acute myocardial infarction: a report of the Ameri- bolytic therapy: rationale for the Hirulog and Early 72. Vetrovec GW, Cowley MJ, Overton H. Intracoro- can College of Cardiology/American Heart Associa- Reperfusion/Occlusion (HERO-2) trial. Am J Car- nary thrombus in syndromes of unstable myocar- tion Task Force on Practice Guidelines (Commit- diol. 1998;82:57P-62P. dial ischemia. Am Heart J. 1981;102:1202-1208. tee on Management of Acute Myocardial Infarction). 57. Fareed J, Jeske W, Hoppensteadt D, Clarizio R, 73. de Zwaan C, Bar FW, Janssen JHA, et al. Effects J Am Coll Cardiol. 1996;28:1328-1428. Walenga JM. Are the available low-molecular- of thrombolytic therapy in unstable angina: clini- 89. Gruppo Italiano per lo Studio della Sopravvive- weight heparin preparations the same? Semin cal and angiographic results. J Am Coll Cardiol. nza nell’Infarto Miocardico. GISSI-2: a factorial ran- Thromb Hemost. 1996;22(suppl 1):77-91. 1988;12:301-309. domized trial or alteplase vs streptokinase and hep- 58. Antman EM, Handin R. Low-molecular-weight 74. Falk E. Unstable angina with fatal outcome: dy- arin vs no heparin among 12,490 patients with heparins: an intriguing new twist with profound namic coronary thrombosis leading to infarction acute myocardial infarction. Lancet. 1990;336: implications. Circulation. 1998;98:287-289. or sudden death. Circulation. 1985;71:699-708. 65-71. 59. Weitz JI. Low-molecular-weight heparins. N Engl 75. Bar FW, Verheugt FW, Col J, et al. Thrombolysis 90. The Global Use of Strategies to Open Occluded J Med. 1997;337:688-698. in patients with unstable angina improves the an- Coronary Arteries (GUSTO III) Investigators. A 60. Zed PJ, Tisdate JE, Borzak S. Low-molecular- giographic but not the clinical outcome: results comparison of reteplase with alteplase for acute weight heparins in the management of acute coro- of UNASEM, a multicenter, randomized, placebo- myocardial infarction. N Engl J Med. 1997;337: nary syndromes. Arch Intern Med. 1999;159: controlled, clinical trial with anistreplase. Circu- 1118-1123. 1849-1857. lation. 1992;86:131-137. 91. Assessment of the Safety and Efficacy of a New 61. Warkentin TE, Levine MN, Hirsh J, et al. Heparin- 76. Freeman MR, Langer A, Wilson RF, et al. Throm- Thrombolytic (ASSENT-2) Investigators. Single- induced thrombocytopenia in patients treated with bolysis in unstable angina: randomized double- bolus tenecteplase compared with front-loaded low-molecular-weight heparin or unfractionated blind trial of t-PA and placebo. Circulation. 1992; alteplase in acute myocardial infarction: the heparin. N Engl J Med. 1995;332:1330-1335. 85:150-157. ASSENT-2 double-blind randomised trial. Lan- 62. Cohen M, Demers C, Gurfinkel EP, et al, for the 77. Gold HK, Johns JA, Leinbach RC, et al. A random- cet. 1999;354:716-722. Efficacy and Safety of Subcutaneous Enoxaparin ized, blinded, placebo-controlled trial of recom- 92. Ferguson JJ. NICE-3: National Investigators Col- in Non–Q-Wave Coronary Events Study Group. A binant human tissue-type plasminogen activator laborating on Enoxaparin 3: prospective, open- comparison of low-molecular-weight heparin with in patients with unstable angina pectoris. Circu- label non-randomized observational safety study unfractionated heparin for unstable coronary ar- lation. 1987;75:1192-1197. on the combination of LMWH and the clinically tery disease. N Engl J Med. 1997;337:447-452. 78. Ardissino D, Barberis P, de Servi S, et al. Recom- available IIb/IIIa inhibitors in 600 patients with 63. Antman EM, McCabe CH, Gurfinkel EP, et al. binant tissue-type plasminogen activator fol- acute coronary syndromes. Paper presented at: Enoxaparin prevents death and cardiac ischemic lowed by heparin compared with heparin alone for 22nd Congress of the European Society of Car- events in unstable angina/non–Q-wave myocar- refractory unstable angina pectoris. Am J Car- dial infarction: results of the Thrombolysis in Myo- diol. 1990;66:910-914. diology; August 30, 2000; Amsterdam, the Neth- cardial Infarction (TIMI) 11B trial. Circulation. 1999; 79. Williams DO, Topol EJ, Califf RM, et al. Intrave- erlands. 100:1593-1601. nous recombinant tissue-type plasminogen acti- 93. Ohman EM, Kleiman NS, Gacioch G, et al. Com- 64. Gurfinkel EP, Eustaquio EJ, Mejail RI, et al. Low vator in patients with unstable angina pectoris: re- bination accelerated tissue-plasminogen activa- molecular weight heparin vs regular heparin or as- sults of a placebo-controlled, randomized trial. tor and platelet glycoprotein IIb/IIIa Integrin re- pirin in the treatment of unstable angina and si- Circulation. 1990;82:376-383. ceptor blockade with Integrilin in acute myocardial lent ischemia. J Am Coll Cardiol. 1995;26:313- 80. Ambrose JAHC, Hjemdahl-Monsen CE, Borrico S, infarction: results of a randomized, placebo- 318. Gorlin R, Fuster V. Quantitative and qualitative ef- controlled, dose-ranging trial. Circulation. 1997; 65. The FRAXIS Study Group. Comparison of two fects of intracoronary streptokinase in unstable 95:846-854. treatment durations (6 days and 14 days) of a low angina and non–Q wave infarction. J Am Coll Car- 94. Giugliano RP, Antman EM, McCabe CH, et al. molecular weight heparin in the initial manage- diol. 1987;9:1157-1165. Abciximab+tPA improves coronary flow in a wide ment of unstable angina or non–Q wave myocar- 81. The TIMI-IIIA Investigators. Early effects of tissue- range of subgroups: results from TIMI 14 [ab- dial infarction: FRAXIX (FRAxiparine in Isch- type plasminogen activator added to conven- stract]. Circulation. 1998;98:I-560. aemic Syndrome). Eur Heart J. 1999;20:1553- tional therapy on the culprit coronary lesion in pa- 95. Ohman EM, Lincoff AM, Bode C, et al. Enhanced 1562. tients presenting with ischemic cardiac pain at rest: early reperfusion at 60 minutes with low-dose re- 66. Klein W, Buchwald A, Hillis SE, et al. Compari- results of the Thrombolysis in Myocardial Ische- teplase combined with full-dose abciximab in acute son of low-molecular-weight heparin with unfrac- mia (TIMI-IIIA) trial. Circulation. 1993;87:38-52. myocardial infarction: preliminary results from the tionated heparin acutely and with placebo for 6 82. Nicklas JM, Topol EJ, Kander N, et al. Random- GUSTO-4 pilot (SPEED) dose-ranging trail [ab- weeks in the management of unstable coronary ized, double-blind, placebo-controlled trial of tis- stract]. Circulation. 1998;98:I-504. artery disease. Circulation. 1997;96:61-68. sue plasminogen activator in unstable angina. 96. Antman EM, Giugliano RP, Gibson M, et al. Ab- 67. Antman EM, Cohen M, Radley D, et al. Assess- J Am Coll Cardiol. 1989;13:434-441. ciximab facilitates the rate and extent of throm- ment of the treatment effect of enoxaparin for un- 83. Schreiber TL, Rizik D, White C, et al. Random- bolysis: results of the Thrombolysis in Myocar- stable angina/non–Q-wave myocardial infarc- ized trial of thrombolysis versus heparin in un- dial Infarction (TIMI) 14 trial. Circulation. 1999; tion: TIMI 11B-ESSENCE meta-analysis. stable angina. Circulation. 1992;86:1407-1414. 99:2720-2732. Circulation. 1999;100:1602-1608. 84. Waters D, Lam JYT. Is thrombolytic therapy strik- 97. Califf RM. Combination therapy for acute myo- 68. Mark DB, Cowper PA, Berkowitz SD, et al. Eco- ing out in unstable angina? Circulation. 1992;86: cardial infarction: fibrinolytic therapy and glyco- nomic assessment of low-molecular-weight hep- 1642-1644. protein IIb/IIIa inhibition. Am Heart J. 2000; arin (enoxaparin) versus unfractionated heparin 85. Fibrinolytic Therapy Trialists’ Collaborative Group. 139(pt 2):S33-S37. in acute coronary syndrome patients: results from Indications for fibrinolytic therapy in suspected 98. Ronner E, van Kesteren HAM, Zijnen P, et al. Com- the ESSENCE randomized trial. Circulation. 1998; acute myocardial infarction: collaborative over- bined therapy with streptokinase and Integrilin [ab- 97:1702-1707. view of early mortality and major morbidity re- stract]. J Am Coll Cardiol. 1998;31:191A.

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