recombinant hirudin unstable angina pectoris -...

1557

Recombinant Hirudin forUnstable Angina Pectoris

A Multicenter, Randomized Angiographic Trial

Eric J. Topol, MD; Valentin Fuster, MD, PhD; Robert A. Harrington, MD;Robert M. Califf, MD; Neal S. Kleiman, MD; Dean J. Kereiakes, MD; Marc Cohen, MD;

Anthony Chapekis, MD; Herman K. Gold, MD; Mark A. Tannenbaum, MD;A. Koneti Rao, MD; Darrell Debowey, MS; Darryl Schwartz, MD;

Marc Henis, MD; James Chesebro, MD*

Background Coronary artery thrombosis plays an impor-tant pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytictherapy has not provided complete or consistent benefit. Wehypothesized that recombinant hirudin, a direct thrombininhibitor, would prevent accumulation of coronary arterythrombus in a manner superior to heparin.Methods and Results Patients with rest ischemic pain, ab-

normal ECG, and baseline angiogram indicating a 260%stenosis of a culprit coronary artery or saphenous vein graftwith visual appearance of thrombus were randomized to one oftwo different doses of heparin (either a target activated partialthromboplastin time [aPTT] of 65 to 90 or 90 to 110 seconds)or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30mg * kg`-l h' infusion) in a dose-escalating protocol. After 72to 120 hours of study drug, a repeat coronary angiogram wasobtained, and the paired studies underwent quantitative anal-ysis. The primary end point was change in the average

Tnhe fundamental role of fissured coronary athero-sclerotic plaque and superimposed thrombus inthe pathogenesis of unstable angina and non-

Q-wave myocardial infarction has been demonstratedby pathological, angiographic, angioscopic, and bio-chemical studies.1-6 As a result, thrombolytic, antiplate-let, and antithrombotic agents have all been tried withvarying degrees of success. In these patients, severalcontrolled studies of intravenous thrombolytic therapyin conjunction with aspirin and heparin have collectivelyfailed to show a benefit of reduction of adverse events;paradoxically, such therapy appears to induce a higherrisk of myocardial infarction.7-12 Aspirin has been shown

Received October 25, 1993; revision accepted January 4, 1994.From the Department of Cardiology, Cleveland Clinic Founda-

tion, Cleveland, Ohio; Division of Cardiology, Duke UniversityMedical Center, Durham, NC; Division of Cardiology, Massachu-setts General Hospital, Boston; Division of Cardiology, BaylorCollege of Medicine, Houston, Tex; Hahnemann Hospital, Phila-delphia, Pa; Christ Hospital, Cincinnati, Ohio; Riverside Method-ist Hospital, Columbus, Ohio; the Iowa Heart Center, Des Moines;Mayo Clinic, Rochester, Minn; and the Thrombosis ResearchCenter, Temple University, Philadelphia, Pa.

Correspondence to Eric Topol, MD, Department of Cardiology,Cleveland Clinic Foundation, One Clinic Center, 9500 Euclid Ave,Desk F25, Cleveland, OH 44195.*A full list of the coinvestigators in the study group is provided

in the "Appendix."

cross-sectional area of the culprit lesion. Other efficacy endpoints also involved changes in culprit lesion dimensions andTIMI flow grade. Recombinant hirudin led to a dose-depen-dent elevation of aPTT that appeared to plateau at the0.2-mg/kg dose. A higher proportion of hirudin-treated pa-tients had their aPTT within a 40-second range (16% heparinversus 71% hirudin, P<.001). Overall, the 116 patients treatedwith hirudin tended to show more improvement than the 50patients receiving heparin relative to the primary efficacyvariable-the average cross-sectional area (P=.08)-as well asminimal cross-sectional area (P=.028), minimal luminal diam-eter (P=.029), and percent diameter stenosis (P=.07).

Conclusions Recombinant hirudin appears to be a promis-ing antithrombotic intervention compared with heparin forinhibition of coronary artery thrombus. Large-scale compara-tive trials are warranted. (Circulafion. 1994;89:1557-1566.)Key Words * angina * thrombosis * thrombin .

hirudin * anticoagulants

to reduce the incidence of serious events in patientswith unstable angina,1314 but the role of heparin is lessclearly defined. Theroux and colleagues15 conducted arandomized trial of heparin (1000 U/h IV titrated toactivated partial thromboplastin time [aPTT] 1.5 to 2times control), aspirin (325 mg BID), the combination,or placebo in 497 patients, with a clinical end point ofrefractory angina, myocardial infarction, or death at 5days. The results of this trial showed significant reduc-tions in these events with heparin, aspirin, or thecombination relative to placebo.15 However, there wereno differences among the three active treatments, andrebound phenomena (defined as myocardial infarctionor recurrent unstable angina after stopping therapy)occurred more frequently in the heparin group.16 TheRISC study group17 conducted a randomized trial ofplacebo, aspirin (75 mg/d), or intravenous heparin(3750- to 5000-U bolus every 6 hours) in 796 patientswith serial evaluation at 5 days and at 1 and 3 months.The results indicated a possible benefit of heparin whengiven in conjunction with aspirin but little benefit ofheparin by itself.These observations have raised the question of

whether more potent therapies, and particularly thosedirected toward thrombin, a pivotal mediator of plateletaggregation and fibrin accretion, could be developed for

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1558 Circulation Vol 89, No 4 April 1994

Chest Pain < 48 hours

Abnormal Electrocardiogram (ECG)

Baseline Angiographywith 2 60% Stenosis + Thrombus

Randomization

Heparin Hirudin3 to 5 day infusion 3 to 5 day infusion

l lRepeat Angiography

FIG 1. Protocol algorithm.

these patients. Hirudin, the most potent naturally oc-curring anticoagulant, derived from the leech Hirudomedicinalis, is a single polypeptide of 65 amino acids andhas been shown to be highly effective in preventingarterial thrombus formation in experimental models ofarterial thrombosis.18-22 Phase I studies have shown thesafety of short-term hirudin infusions, a close correla-tion of the aPTT with the plasma level of hirudin, and aplasma half-life of 2 to 3 hours in patients with coronaryartery disease.22 In the present trial, our hypothesis wasthat in patients with unstable angina, escalating doses ofrecombinant hirudin would be more effective thanheparin in preventing accumulation of coronary arterythrombus.

MethodsPatient PopulationAt 10 participating sites ("Appendix"), patients with rest

ischemic chest pain undergoing coronary angiography werescreened to determine eligibility for inclusion provided thatthe following criteria were met: (1) at least 5 minutes of restischemic pain, presumed to be myocardial in origin, occurringwithin the past 48 hours; (2) minimal angiographic stenosis.60% in a major epicardial coronary artery or saphenous veingraft interpreted as having an intraluminal thrombus andbelieved to represent the culprit vessel for the patient's clinicalpresentation; and (3) transient or fixed ECG abnormalitiessuggestive of ischemia. Patients more than 48 hours afterintravenous thrombolytic therapy for acute myocardial infarc-tion were eligible, as were patients receiving intravenousheparin, provided that entry criteria were met. Thrombus wasdefined as an intracoronary filling defect with convex or hazymargins or contrast staining as assessed visually at the time ofthe baseline angiogram (Fig 1).Reasons for exclusion were age >75 years, left main stenosis

>50%, hemodynamic instability including hypotension (<90mm Hg) or pulmonary edema, active bleeding or history ofsignificant bleeding in the past year, previous stroke or cere-brovascular disease, and serum creatinine >1.5 mg/dL. Allpatients gave informed consent to participate, and the protocolwas approved by the Institutional Review Board at each site.Recruitment began September 20, 1991, and ended March 22,1993.

Study Drug Dosing and AssignmentAs shown in Table 1, six groups of patients were enrolled in

the trial, with escalating doses of recombinant hirudin. Thedose of hirudin (CIBA-GEIGY, Summit, NJ) ranged from abolus of 0.15 mg/kg and infusion of 0.05 mg* kg h` to abolus of 0.9 mg/kg and an infusion of 0.3 mg kg1. h`.Porcine heparin was obtained from a single batch (Organon,Inc, West Orange, NJ) and was supplied in the appropriatestudy drug kits. The dose of heparin was a 5000-U bolus and

TABLE 1. Drug Dose Randomization Scheme in Six Groups of Patients

No. of PatientsGroup Bolus Infusion Enrolled

Hirudin 0.15 mg/kg 0.05 mg* kg-1 *h- 23Heparin 5000 U 1000 U/h 7

adjusted to PUT 65-90 s

11 Hirudin 0.30 mg/kg 0.1 mg* kg-' h-' 23Heparin 5000 U 1000 U/h 7

adjusted to PTT 65-90 s

iii Hirudin 0.60 mg/kg 0.2 mg* kg-'1 h-' 23Heparin 5000 U 1000 U/h 7

adjusted to PTT 65-90 sIV Hirudin 0.90 mg/kg 0.3 mg. kg1' . h-1 3

Heparin 5000 U 1000 U/h 0adjusted to PTT 65-90 s

V Hirudin 0.60 mg/kg 0.3 mg* kg-1 . h-1 23Heparin 5000 U 1000 U/h 7

adjusted to PTT 65-90 sVI Heparin 5000 U 1000 U/h 22

adjusted to PTT 90-1 10 sHirudin 0.6 mg/kg 0.3 mg* kg-1 . h-1 21

PTT indicates prothrombin time. Total heparin patients, 50; total hirudin patients, 116.


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Topol et al Hirudin in Unstable Angina 1559

1000 U/h adjusted to maintain the aPTT between 65 and 90seconds. In the last group of 42 patients assessed, the heparindose was raised to adjust the aPTT to 90 to 110 seconds toexamine whether the effects of hirudin and heparin wererelated to the extent of in vitro anticoagulant effect. For allgroups, the planned treatment duration was 72 to 120 hours.The treatments were prepared by site pharmacists on anopen-label basis. In the first five groups, the randomization wasplanned to be 23 patients assigned to hirudin and 7 assigned toheparin. In the last group, recruitment of 21 patients in boththe high-dose heparin group and the hirudin group wasplanned. The trial progressed in a sequential manner througheach dose group, with analysis of the data with respect tosafety and anticoagulation effect before proceeding to the nextdose level. Randomization was performed via telephone to theDuke University Coordinating Center on a 24-hour-per-day,7-day-per-week basis.

Conjunctive MedicationsAll patients received aspirin 160 to 325 mg/d PO and

triple-drug anti-ischemic therapy with a ,8-blocker, calciumchannel blocker, and long-acting nitrate. The recommendedmedications and minimal doses were metoprolol 50 mg every12 hours, diltiazem 30 mg every 8 hours, and isosorbidedinitrate 10 mg every 6 hours, respectively. However, it was leftto the discretion of the investigator to substitute for otheragents within each of these three classes and to regulate thedoses according to the level of myocardial ischemia and otherparameters such as heart rate, blood pressure, and medicationtolerance.

Paired Angiographic StudiesAt baseline, complete coronary angiography was performed

with specific attention to interrogation of the culprit vessel viaorthogonal views and multiple hemiaxial projections. Theangiograms were obtained after administration of 200 ,ug ofintracoronary nitroglycerin with the use of 7F or 8F catheters.Open-label heparin was given as a single 2500- to 5000-Ubolus during the procedure and withheld thereafter. Theinfusion of study drug was begun 1 to 2 hours after hemostasisfollowing sheath removal. After 72 to 120 hours of study drugadministration, a repeat angiogram was obtained using thesame technique with intracoronary nitroglycerin and withreplication of the key orthogonal views of the culprit vessel.Coronary revascularization was strongly discouraged untilafter completion of the second angiographic procedure unlessabsolutely necessary to manage recurrent ischemia unrespon-sive to medical therapy. After completion of the secondangiogram, patients were eligible for surgical or percutaneouscoronary revascularization based on coronary anatomy andclinical status.The cineangiograms were forwarded to the Core Angio-

graphic Laboratory of the Cleveland Clinic Foundation forindependent, blinded assessment of the initial and follow-upquantitative coronary angiograms. These assessments weremade from the paired initial and follow-up angiograms, withthe technicians unaware of the treatment assignments andwith any images that showed the procedural devices splicedout. The most severe hemiaxial view of the stenosis withoutforeshortening was selected for analysis. End-diastolic cineframes from orthogonal views were digitized with a cine-videoconverter and a computer-assisted edge-detection algorithm(Image Comm, Sunnyvale, Calif).

Clinical End PointsPatients were followed in-hospital and for 30 days. Recur-

rent angina was defined as ischemic chest discomfort occurringat rest or with exercise. Refractory angina was defined as restpain lasting more than 20 minutes, with ECG changes, despitemedical therapy and mandating urgent coronary revascular-

increase in creatine kinase myocardial band above the refer-ence site upper limit laboratory value. The decision for andtype of revascularization were left to the discretion of theinvestigator.

Hematologic StudiesPatients had serial measurement of aPTT and prothrombin

time (PT) at baseline and 4, 6, 8, 12, 16, 20, 24, 36, and 48hours into study drug infusion. The aPTT was determined atthe local sites by the CIBA-Corning 512 monitor (Biotrack,Inc, Mountainview, Calif). These values were used to adjustthe dose of heparin. In addition, serial blood samples were

drawn into 0.1 volume of 3.8% sodium citrate, and the plasmawas harvested by centrifugation and shipped on dry ice to a

core laboratory established at the Thrombosis Research Cen-

ter, Temple University School of Medicine, Philadelphia, Pa.The plasma samples were stored at -80°C until the time of

assay. The aPTTs were performed according to the manufac-turer's recommendations with a KoaguLab 32-S (Ortho Diag-nostic Systems, Raritan, NJ) instrument and partial thrombo-plastin from Organon Teknika Corp, Durham, NC (GeneralDiagnostics, automated aPTT reagent). The PTs were per-formed with the same instrument with a rabbit brain tissue

thromboplastin reagent, Simplastin Excel (Organon Teknika

Corp).All bleeding complications reported from the start of the

trial to 30 days of follow-up were classified as to whether or not

criteria for major bleed were met. Major bleeding was defined

as any intracranial bleed or a .15% decrease in hematocrit or

a 25-g/dL decrease in hemoglobin with transfusions factored

as 1 U equal to 1 g/dL hemoglobin.

Data AnalysisSummary statistics were computed for the variables ob-

tained in this study separately for each dose group. For thosevariables measured on a continuous scale, both medians and

means were computed, since in some cases differences be-

tween these reflected different aspects of the data; sampleproportions were computed for count or incidence variables.

Since this was a preliminary nondefinitive trial, sample sizes

were not determined on a statistical basis, and the trial was not

designed to address formal comparisons between individual

dose groups. When the data were examined, however, for

several variables the hirudin doses yielded results somewhatsimilar to each other and/or no clear dose response was

apparent. Under these conditions, it could be considered

justifiable to pool the data and perform statistical tests for

general comparative purposes, although the test results should

be interpreted with caution. Thus, several post hoc compari-sons were performed in which the combined groups of heparinand hirudin patients were compared with each other. For

those variables measured on continuous scales, Wilcoxonrank-sum tests were performed; for incidence data, Fisher's

exact test (two-tailed) was performed.

Results

The baseline characteristics are summarized in Table2. Three additional patients were studied at a hirudindose of 0.9-mg/kg bolus and 0.3-mg * kg-1 h`1 infusion,but this dose was changed to a 0.6-mg/kg bolus because

two of the three patients experienced minor bleedingcomplications (summarized below). Because this dose

group contained only three patients, it is not reportedseparately in this table. However, one of those patientsdeveloped a non-Q-wave myocardial infarction that is

included under clinical outcomes and the angiographicand clinical results factor in these three patients when-

ization. Reinfarction was defined as more than a twofold ever overall, intertreatment comparisons are made.


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TABLE 2. Baseline Characteristics

Heparin, Heparin, aPTT Hirudin, 0.05 Hirudin, 0.1 Hirudin, 0.2 Hirudin, 0.3aPTT 65-90 s 90-110 s mg*kg-1*h-1 mg*kg'1*h-1 mg*kg-1 h-1 mg*kg-'*h-

N 28 22 23 23 23 44

Age, y 60+8 60±11 61±10 62±8 60±10 58+9

Sex, % male 82 82 74 70 78 68

Weight, kg 83+12 87+20 83+22 90+16 85+12 86+15

Height, cm 171+9 170±17 174±10 175±9 175±10 171±11

Prior CABG, % 11 23 26 35 26 20

Prior PTCA, % 7 32 17 13 35 25

Prior Ml, % 39 64 43 43 61 57

Diabetes, % 18 14 26 26 26 32

Hypertension, % 61 45 48 52 39 50

Non-Q-wave Ml, % 11 14 17 26 30 14

Recent thrombolytic therapy, % 0 0 4 0 0 9

Angiographic features

Culprit vessel, %

LAD 25 14 26 35 17 27

LCx 21 23 35 17 13 18

RCA 46 45 22 17 43 34

SVG 7 18 17 26 26 20

LM 0 0 0 4 0 0

No. of diseased vessels, %

1 61 27 48 39 35 57

2 25 32 26 22 26 14

3 11 41 26 39 35 29

Indeterminate 4 0 0 0 4 0

aPTT indicates activated partial thromboplastin time; CABG, coronary artery bypass graft surgery; PTCA, percutaneous transluminalcoronary angioplasty; Ml, myocardial infarction; LAD, left anterior descending; LCx, left circumflex; RCA, right coronary artery; SVG,saphenous vein graft; and LM, left main.

In Fig 2, the effects of heparin and hirudin on aPTT(measured by CIBA-Corning 512 monitor) are pre-sented and demonstrate a plateau effect at the 0.2-mg . kg`1 h-1 infusion level. With further increase ofthe dose of hirudin, there was no further noticeableincrease in the aPTT value. Of note, the high-doseheparin group had an aPTT similar to the hirudin

12071

i 401/ Heparin Hirudin Doses

a205 -G--e Low Dose --_-- 0.15/0.05 -- -- 0.6/0.2to<> High Dose -_- - 0.3/0.1 * 0.6/0.3

o0,

infusion dose >0.2 mg* kg` h-i, although there werewider fluctuations. The aPTT was maintained within a40-second range much more frequently in the hirudingroups compared with both doses of heparin (Fig 3). Asshown in Fig 3, only 16% of patients receiving heparinmaintained the aPTT within a 40-second range com-pared with 71% of the patients receiving hirudin(P<.001). The proportions in the individual hirudin

U)c

'U

n

a.00,

0 4 6 8 12 16 20 24 36 48 60 72 84 96 108 120Time (hours)

FIG 2. Graph showing that during the hirudin or heparin pro-longed infusion there was a higher activated partial thromboplas-tin time (aPTT) value during serial measurement for increasingdoses of hirudin compared with heparin, with plateau at the0.2-mg/kg infusion level.

.uu .

1uU~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

80 73 7468 6

60-

40 I

4 26 I

20- 4 I

0- 777

65 - 90 90 - 110 0.15/0.05 0.30/0.10 0.60/0.20 0.60/0.30Heparin (sec) Hirudin (mg/kg/hr)

FIG 3. Bar graph showing the proportion of patients in whomthe activated partial thromboplastin time (aPTT) was within a40-second target range when serially assessed every 12 hours.The hirudin group had a more consistent prolongation of aPTT


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TABLE 3. Angiographic Outcomes

Hirudin, Hirudin, Hirudin, Hirudin,Heparin, Heparin, 0.15/0.05 0.3/0.1 0.6/0.2 0.6/0.365-90 s 90-110 s mg kg-1' h- mg kg-1' h-1 mg kg-1'* h-' mg*gkg-' *.h'

Average cross-sectional area,mm2

No. of patients 27 21 21 20 23 37

Median

Baseline 1.93 2.08 1.85 2.07 1.59 1.58

Repeat 2.19 1.72 1.95 2.32 1.76 1.74

Change 0.18 -0.18 0.10 0.39 0.13 0.13

Mean

Baseline 2.31 2.42 1.85 2.13 1.41 1.84

Repeat 2.56 2.28 2.11 2.58 1.93 2.04

Change 0.25 -0.14 0.25 0.44 0.52 0.19

SD 0.66 0.53 0.44 0.49 1.15 0.63

Minimum luminal diameter, mm

No. of patients 27 21 21 20 23 37

Median

Baseline 0.86 0.88 0.76 0.87 0.47 0.76

Repeat 0.80 1.00 0.89 1.04 0.78 0.93

Change 0.10 0.06 -0.03 0.24 0.08 0.11

Mean

Baseline 0.86 1.05 0.78 0.90 0.54 0.78

Repeat 0.92 1.03 0.89 1.09 0.78 0.96

Change 0.06 -0.01 0.11 0.19 0.24 0.17

SD 0.32 0.24 0.35 0.27 0.39 0.35

Minimum cross-sectionalarea, mm2

No. of patients 27 21 21 20 23 37

Median

Baseline 0.58 0.61 0.46 0.59 0.17 0.45

Repeat 0.50 0.78 0.62 0.85 0.48 0.68

Change 0.09 0.05 -0.05 0.28 0.09 0.20

Mean

Baseline 0.73 1.10 0.52 0.76 0.40 0.63

Repeat 0.88 1.12 0.71 1.08 0.70 0.96

Change 0.16 0.02 0.18 0.32 0.30 0.33

SD 0.62 0.31 0.54 0.48 0.50 0.66

Area stenosis, %

No. of patients 27 21 21 20 23 39

Median

Baseline 92.50 89.00 92.6 88.25 97.40 93.30

Repeat 90.20 89.40 92.6 87.40 94.20 89.90

Change -1.10 -0.60 -1.70 -4.25 0.00 -2.10

Mean

Baseline 90.19 87.10 91.86 87.19 93.96 89.86

Repeat 86.99 86.40 88.34 79.67 91.22 83.49

Change -3.20 -0.70 -3.52 -7.52 -2.74 -6.36

SD 12.08 5.12 8.29 17.98 4.99 15.19


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TABLE 4. Pooled Angiographic Outcomes

Average MinimumCross-Sectional Minimum Luminal Cross-Sectional Area

Area, mm2 Diameter, mm Area, mm2 Stenosis, %

All All All All All All All AllHeparin Hirudin Heparin Hirudin Heparin Hirudin Heparin Hirudin

No. of patients 48 104 48 104 48 104 48 106

Median

Baseline 1.95 1.70 0.87 0.76 0.60 0.45 92. 15 92.65Repeat 2.03 1.95 0.82 0.93 0.53 0.68 90.05 90.85

Change 0.01 0.14 0.07 0.10 0.09 0.17 -0.70 2.08Mean

Baseline 2.36 1.88 0.94 0.77 0.89 0.66 88.84 89.90Repeat 2.44 2.20 0.97 0.95 0.99 0.95 86.73 84.71Change 0.08 0.32 0.03 0.18 0.10 0.29 2.11 -519SD 0.63 0.73 0.29 0.34 0.51 0.55 9.66 12.80

Only patients with values on both the baseline and repeat angiograms are included in this summary.

dose groups were very consistent, ranging between 65%and 74%.Major efficacy end points included differences in angio-

graphic indexes between the baseline and follow-up pairedstudies of the culprit vessel. The detailed angiographicdata for each parameter by dose group are summarized inTable 3. As shown in Table 4 and in Figs 4 and 5, overallthe patients treated with hirudin consistently showedmore improvement than the heparin patients relative tothe primary efficacy variable-the average cross-sectionalarea (P=.08)-as well as with regard to the minimumcross-sectional area (P=.028), minimum luminal diameter(P=.029), percent diameter stenosis (P=.071), and TIMIflow grade (P=.441). When the dose groups were consid-ered individually, the small sample sizes and variability inthe data make precise comparisons difficult, but fromTable 3 and Figs 4 and 5 it can be seen that for theseangiographic parameters, the observed improvement inthe patients in the three highest hirudin dose groupsgenerally exceeded that of the heparin patients. For theprimary end point, average cross-sectional area, four ofthe five patients with the largest improvement from base-line in the entire study were in the 0.2-mg * kg`1 . h-1 dosegroup, reflected in Table 3 by the large mean differencefor this end point. This was also the dose group in whichthe greatest number of patients showed improvement asmeasured by TIMI flow grade (Fig 6). It should be notedthat the lesions treated in this dose group were moresevere at baseline than those of the other groups, includ-ing a number of patients with totally occluded arteries,which may have influenced the angiographic outcomes.The summary of the angiographic findings for overalltreatment groups is presented in Fig 7.The clinical outcomes at 30 days were not significantly

different between the heparin and hirudin treatmentgroups, including any difference in outcomes betweendose groups of hirudin or heparin considered sepa-rately. Because of the small numbers of patients in eachdose group and the limited numbers of patients whodeveloped an end point, the data are presented bypooling the hirudin and heparin patients (Table 5). Ofnote, there were no deaths. Overall, there tended to be

fewer myocardial infarctions among the hirudin patients(2.6%) than among the heparin patients (8.0%, P= .11).There tended to be less balloon angioplasty performedin the heparin group, but no difference was observed inthe overall rate of coronary revascularization proce-dures (Table 4).

` 0.50-

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= 0.30-00m 0.20-

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E 0.50-0.: 0.40-0 0.30-mE 0.20-0

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0,3901

0.10n ~~~~~~~~~~~~~~~~~~~~~~~~~~~i0.18

:L

0.13 0.13

---LI J--

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0.52

0.44

0.250.19ii


FIG 4. Bar graphs showing the median and mean improvementof average cross-sectional area (mm2) of the culprit vessel, fromangiography at 3 to 5 days compared with baseline, for heparinand hirudin at individual dose levels. Hirudin tended to achievea more substantial improvement (P=.08).

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I .\. Of f rEi::~11

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0.25-._

0.20-mo 0.15-

m 0.10-

0 0.05-CDCOU) 0.001

-0.01An ns

65 - 90 90 - 110 0.15/0.05 0.30/0.10 0.60/0.20 0.60/0.30

Heparin (sec) Hirudin (mg/kg/hr)

E,Ea)cC

(QU)mE0

CDc

0C5CDe

FIG 5. Bar graph showing mean change from baseline for theminimal luminal diameter for heparin and hirudin; hirudin led toa significantly greater diameter (P=.028).

No patients developed allergic reactions to hirudin. Noabnormal chemistries, including liver function tests or

renal function indexes, were attributed to study medica-tion. The bleeding complications are summarized in Table6. In the three patients receiving the 0.9-mg/kg bolus ofhirudin, one had lower gastrointestinal bleeding and re-

ceived a 2-U transfusion, and another had hematuriawithout the need for transfusion.A total of seven major bleeds occurred, with no more

than two occurring within any treatment group. Allmajor bleeding complications reported were either sec-

ondary to bleeding at peri-access sites or were associ-ated with coronary bypass grafting. None of the spon-

taneous bleeding complications reported in this trialmet the criteria for major bleeding. There were no

intracranial hemorrhagic events.

DiscussionThe present randomized, dose-ascending trial of re-

combinant hirudin demonstrated superiority in achiev-ing angiographic improvement of the culprit arteriallesion compared with heparin. The angiographic benefitappeared at hirudin doses .0.1 mg/kg, which wasassociated with a plateau effect of in vitro anticoagula-tion reflected by the aPTT. Importantly, the angio-graphic impact of hirudin was demonstrated to beindependent of its effect on in vitro anticoagulation bytesting heparin at a higher dose and thereby achievingan equivalent effect on the aPTT. Of note, hirudin wasnot associated with excessive bleeding or other unto-ward effects.

50-

43

40-

30QID

HeUar;n (Se) ;rd;n(m/k/h23 23

19 19

13

10-

065-90 90-110 0.1510.05 0.30/0.10 0.60/0.20 0.60/0.30

Heparin (sec) Hirudin (mg/kg/hr)

FIG 6. Bar graph showing percent of patients with TIMI flowgrade improvement for the individual heparin and hirudin dosegroups.

0.4- All Heparin

0.32 5 All Hirudin0.3 0.29

0.2- 0.18

0.10

0.1 0.08

0.03

U.UAvg. Cross Section Min. Lumen Diameter Min. Cross Section

FIG 7. Bar graph showing pooled angiographic average (Avg.)cross-sectional area improvement, minimal (min) luminal diam-eter (in mm), and area minimal cross-sectional data for allheparin-and hirudin-treated patients.

The major finding of angiographic improvement forhirudin compared with heparin is substantiated by theconsistency of benefit in several parameters, includinglesion cross-sectional area and vessel caliber. There isno consensus as to which of these indexes is more usefulin the setting of unstable angina and, in particular,whether any angiographic parameter will be proven asan adequate surrogate for clinically meaningful endpoints.The biology of the thrombin molecule has been

elucidated by several recent studies, and it is known thathirudin binds with high affinity to several key foci ofthrombin, including the catalytic site and the anionexosite. This direct inhibition of thrombin contrasts toheparin, which exerts its antithrombin action only via acofactor, antithrombin III, and can be inactivated in thebody by platelet factor 4, vitronectin, fibrin monomer II,and fibronectin.20-25 Importantly, hirudin is activeagainst clot-bound thrombin, whereas heparin is capa-ble of inhibiting predominantly soluble thrombin.26Moreover, hirudin is an effective inhibitor of thrombin-induced platelet activation,27-29 whereas heparin is not.This is particularly important in view of the role ofplatelets in arterial thrombosis.

In this trial, hirudin was shown to be advantageousover heparin in three main ways. First, hirudin achievedbetter improvement of the caliber (minimal luminal

TABLE 5. Clinical Outcomes and Revascularization byTreatment Assignment

Heparin Hirudin(N=50) (N=116) p

OutcomesDeath 0 0

Myocardial infarction 4 (8%) 3 (2.6%) .11

Recurrent angina 8 (16%) 15 (12.9%) .55

Any of the above 12 (24%) 17 (14.6%) .14

Coronary revascularizationprocedures

Balloon angioplasty 31 (62%) 87 (75%) .09

Other coronary intervention* 10 (20%) 22 (19%) .81

Bypass surgery 6 (12%) 15 (13%) .86

Any of the above 42 (84%) 105 (91%) .22

*Atherectomy, stenting, or laser.

0.24

0.190.17

0.11

0.06

0.30

A


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TABLE 6. Bleeding Complications*

Heparin, Heparin, Hirudin, 0.5 Hirudin, 0.1 Hirudin, 0.2 Hirudin, 0.3aPTT 65-90 s aPTT 90-110 s mg* kg- h-1 mg* kg-1 h-1 mg .kg1. h-1 mg .kg-1h-

No. of patients 28 22 23 23 23 44

Major bleeding complications

Intracranial 0 0 0 0 0 0

Spontaneous 0 0 0 0 0 0

Sheath site 0 1 (4.5%) 2 (8.7%) 0 0 1 (2.3%)Other bleedingAccess sites 10 (35.7%) 4 (18.2%) 3 (13.0%) 3 (13.0%) 8 (34.8%) 7 (15.9%)Pseudoaneurysm 1 (3.6%) 0 0 0 0 0

Rectal hemorrhage 0 0 0 0 0 1 (2.3%)Hematemesis 0 0 0 1 (4.3%) 0 0

Guaiac-positive stool 0 0 0 1 (4.3%) 2 (8.7%) 1 (2.3%)Epistaxis 0 0 2 (8.7%) 1 (4.3%) 1 (4.3%) 5 (11.4%)Hemoptysis 0 0 0 0 1 (4.3%) 0

Hematuria 2 (7.1%) 0 1 (4.3%) 2 (8.7%) 0 2 (4.5%)Ecchymosis 2 (7.1%) 1 (4.5%) 0 2 (8.7%) 3 (13.0%) 1 (2.3%)

Transfusion 0 1 (4.5%) 0 0 1 (4.3%) 2 (4.5%)*Patients may be categorized more than once.

diameter and minimal cross-sectional area) of the cul-prit vessel. This reflects dissolution or prevention ofcoronary artery thrombus, since not only was thereangiographic evidence of filling defect resolution, butthe time frame of improvement is too short for otherprocesses such as regression of atherosclerosis to con-tribute. The potential confounding variable of coronaryvasospasm was reduced by administration of intracoro-nary nitroglycerin at the time of both angiograms and byoral therapy with both nitrates and calcium channelblockers. Second, hirudin led to a more consistent andstable elevation of aPTT, suggesting that much lessadjustment of the infusion rates would be required tomaintain the level of anticoagulation within a prescribedrange. This observation is important on a practical basisbecause it suggests that a weight-adjusted dose wouldnot require much titration of the infusion level tomaintain a relatively constant aPTT effect. It should beunderscored, however, that the optimal aPTT for re-combinant hirudin still remains uncertain. The presentstudy does not address this particular issue but ratherprovides comparability data for heparin versus hirudinat a variety of different dose schedules for these twoagents. Third, the effect of hirudin on the culprit lesionwas not dependent on the extent of in vitro anticoagu-lation. The randomization between high-dose heparinand the upper dose of hirudin allowed for demonstra-tion of a persistent advantage of hirudin even at quitecomparable levels of in vitro anticoagulation.The plateau effect of hirudin with respect to antico-

agulant activity, reflected by aPTT, and angiographicefficacy was not expected. This may be attributed tosaturation of binding sites of thrombin by hirudin or,alternatively, to hirudin's interference with binding ofthrombin to thrombomodulin, thereby preventing acti-vation of protein C. This is an essential mechanisticdifferentiation that deserves careful evaluation.

The advantage of hirudin over heparin in this trial,with all patients receiving aspirin, may be related to thedifferences in their mechanisms of action. This benefitmay be linked to inactivation of clot-bound thrombin orthe direct inhibition of thrombin by hirudin. Anothermechanism is the ability of hirudin, but not heparin, toinhibit thrombin activation of platelets. Of particularinterest, there was no evidence of rebound of clinicalsymptoms in the 12- to 24-hour period after cessation ofhirudin, which has been documented for another throm-bin inhibitor, argatroban, in the setting of unstableangina.30 The number of clinical events in the trial waslow, however, and the study lacks adequate power todetermine whether rebound hypercoagulability will bean issue after hirudin therapy. This study was notintended to address whether there are differences inclinical outcomes at varying doses of hirudin or heparinbut rather was focused on angiographic and hemostaticparameters. The inability to distinguish a clear-cutdose-response relation for hirudin may be attributed, atleast in part, to the lack of statistical power of the trial.

In Table 7, the event rates for death and myocardialinfarction in the recent randomized trials710-12,31,32 ofthrombolytic therapy versus heparin are shown. Theevent rate exceeds 9% and is actually higher for thepatients who were assigned to thrombolytic therapy.Although the event rate of the present trial for theseprincipal end points was reduced compared with previ-ous studies, the selection bias for patients who would besuitable for 4 to 5 days of hirudin or heparin treatmentand for undergoing paired angiograms, in addition tothe relatively small number of patients studied, mayhave contributed. The event rates in previous trialsconfirm the importance of developing an improvedantithrombotic therapy in patients with unstable angina.This is a principal objective of the large-scale GlobalUse of Strategies to Open Occluded Arteries (GUSTO-


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TABLE 7. Major Event Rates of Patients in Contemporary Trials of Unstable Angina Pectoris

Thrombolytic+Heparin+Aspirin Heparin+Aspirin

Thrombolytic N Ml Death Ml Death

Williams et al 10 TPA 67 4.5% 0% 6.6% 0%

Nicklas et al 12 TPA 40 10% 0% 10% 10%

Freeman et al 11 TPA 70 2.8% 5.7% 5.7% 2.8%

Bar et al 31 APSAC 159 6.3% 12.5% 12.5% 3.7%

Schreiber et al 7 UK 149 3.8% 0% 8.3% 0%

TRIC32 TPA 205 10.0% 2.0% 7.6% 3.0%

Pooled 690 9.1% 11.3%

TPA indicates tissue-type plasminogen activator; APSAC, anisoylated plasminogen streptokinase activatorcomplex; and UK, urokinase.

II) trial, an ongoing effort comparinghirudin for clinical outcomes in 12000acute coronary syndromes.

heparin withpatients with

AppendixCoinvestigators in the Study Group(The number of patients enrolled for each clinical site is in

parentheses.) Cleveland Clinic, Cleveland, Ohio. (43) Eric J.Topol, MD; Stephen G. Ellis, MD; Patrick L. Whitlow, MD;Irving Franco, MD; Conrad Simpfendorfer, MD; RussellRaymond, DO; Michele Webb, RN. Duke University MedicalCenter, Durham, NC. (34) Robert Harrington, MD; RobertCaliff, MD; Eric Berrios, RN; Kirby Quintero, RN. Massachu-setts General Hospital, Boston, Mass. (18) Valentin Fuster,MD, PhD; Herman Gold, MD; Wendy Werner, RN. ChristHospital Medical Center, Cincinnati, Ohio. (15) Dean J.Kereiakes, MD; Karen Ibanez, RN. Methodist Hospital,Houston, Tex. (15) Neal S. Kleiman, MD; Dale Rose, BS;Kathy Trainor, RN. Hahnemann University Medical Center,Philadelphia, Pa. (14) Marc Cohen, MD; Kathy Stoakes, RN,BSN. Mayo Clinic, Rochester, NY. (10) James Chesebro, MD;Dawn Gaspar, RN. Riverside Methodist Hospital, Columbus,Ohio. (9) Anthony Chapekis, MD; Barry S. George, MD;Steven Yakabov, MD; Richard Candela, MD; Karla Rusk,RN. Iowa Heart Center, Des Moines, Iowa. (7) Phillip Bear,DO; Marc Polich, RN; Mark Tannenbaum, MD; Mary BethCraig, RN, BSN; Dawn Stangl, RN. Washington CardiologyCenter, Washington, DC. (1) Jeffrey J. Popma, MD; LeslieSweet, RN. Angiographic Core Laboratory, Cleveland Clinic,Cleveland, Ohio. Darrell Debowey, MS; Timothy D. Crowe,BS. Coagulation Core Laboratory, Temple University HealthSciences Center, Philadelphia, Pa. A. Koneti Rao, MD; LingSun, MD. CIBA-GEIGY, Summit, NJ. Marc Henis, MD;Malcolm MacNab, MD; Catherine Cabot, MD; DarrylSchwartz, MD. Continuous ECG Recording Core Laboratory,Mayo Medical Services, Rochester, Minn. Mary Coleman.

AcknowledgmentThis study was supported by CIBA-GEIGY, Summit, NJ.

References1. Fuster V, Chesebro JH. Mechanisms of unstable angina. N Engl J

Med. 1986;315:1023-1024.2. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibaya T, Arai

T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation ofcoronary artery thrombi in acute coronary syndromes. N Engl JMed. 1992;326:287-291.

3. Davies M, Thomas A. Plaque fissuring: the cause of acute myo-cardial infarction, sudden ischemic death, and crescendo angina.Br Heart J. 1985;53:63-73.

4. Falk E. Unstable angina with fatal outcome: dynamic coronarythrombosis leading to infarction and/or sudden death. Circulation.1985;71:699-708.

5. Ambrose JA, Hjemdahl-Monsen CE, Borrico S, Gorlin R, FusterV. Angiographic demonstration of a common link betweenunstable angina pectoris and non-Q wave acute myocardialinfarction. Am J Cardiol. 1988;61:244-247.

6. Chesebro J, Fuster V. Thrombosis in unstable angina. N Engl JMed. 1992;327:192-194.

7. Schreiber T, Rizik D, White C, Sharma G, Cowley M, Macina G,Reddy P, Kantounis L, Timmis G, Margulis A, Bunnell P, BarkerW, Sasahara A. Randomized trial of thrombolysis versus heparin inunstable angina. Circulation. 1992;86:1407-1414.

8. Waters D, Lam J. Is thrombolytic therapy striking out in unstableangina? Circulation. 1992;86:1642-1644.

9. The TIMI IIIA Investigators: Early effects of tissue-type plas-minogen activator added to conventional therapy on the culpritcoronary lesion in patients presenting with ischemic cardiac pain atrest: results of the Thrombolysis in Myocardial Ischemia (TIMIIIIA) Trial. Circulation. 1993;87:38-52.

10. Williams DO, Topol EJ, Califf RM, Roberts R, Mancini GBJ,Joelson JM, Ellis SG, Kleiman NS. Intravenous recombinanttissue-type plasminogen activator in patients with unstable anginapectoris. Circulation. 1990;82:376-383.

11. Freeman MR, Langer A, Wilson RF, Morgan CD, Armstrong PW.Thrombolysis in unstable angina: randomized double-blind trial oft-PA and placebo. Circulation. 1992;85:150-157.

12. Nicklas J, Topol E, Kander N, O'Neill W, Walton J, Ellis S,Gorman L, Pitt B. Randomized, double-blind, placebo-controlledtrial of tissue plasminogen activator in unstable angina. JAm CollCardiol. 1989;13:434-441.

13. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or bothin unstable angina. N Engl J Med. 1985;313:1369-1375.

14. Lewis HD, Davis JW, Archibald DG, Steinke WE, SmithermanTC, Doherty JE, Schnaper HW, Le Winter MM, Linares E, PougetJM, Sabharwal SC, Chesler E, DeMots H. Protective effects ofaspirin against acute myocardial infarction and death in men withunstable angina: results of a Veterans Administration CooperativeStudy. N Engl J Med. 1983;309:396-403.

15. Theroux P, Ouimet H, McCans J, Latour J, Joly P, Levy G, Pel-letier E, Juneau M, Stasiak J, de Guise P, Pelletier GB, Rinzler D,Waters DD. Aspirin, heparin, or both to treat acute unstableangina. N Engl J Med. 1988;319:1105 -1111 .

16. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivationof unstable angina after the discontinuation of heparin. N Engl JMed. 1992;327:141-145.

17. The RISC Group. Risk of myocardial infarction and death duringtreatment with low dose aspirin and intravenous heparin in menwith unstable coronary artery disease. Lancet. 1990;336:827-830.

18. Heras M, Chesebro JH, Penny WS, Bailey KR, Badimon L, FusterV. Effects of thrombin inhibition on development of acute platelet-thrombus deposition during angioplasty in pigs. Circulation. 1989;79:657-665.

19. Badimon L, Badimon JJ, Lassila R, Heras M, Chesebro JH, FusterV. Thrombin regulation of platelet interaction with damaged vesselwall and isolated collagen type I at arterial flow conditions in a


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porcine model: effects of hirudins, heparin, and calcium chelation.Blood. 1991;78:423-434.

20. Agnelli G, Pascucci C, Cosmi B, Nenci GG. The comparativeeffects of recombinant hirudin (CGP 39393) and standard heparinon thrombus growth in rabbits. Thromb Haemost. 1990;63:204-207.

21. Agnelli G, Renga C, Weitz J. Nenci G, Hirsh J. Sustainedantithrombotic activity of hirudin after its plasma clearance: com-parison with heparin. Blood. 1992;80:960-965.

22. Zoldhelyi P, Webster MWI, Fuster V. Grill DE, Gaspar D, EdwardsSJ, Cabot CF. Chesebro JH. Recombinant hirudin in patients withchronic stable coronary artery disease: safety, half-life and effect oncoagulation parameters. Circulation. In press.

23. Zoldhelyi P, Fuster V, Chesebro JH. Antithrombins as conjunctivetherapy in arterial thrombolvsis. Coronarx Artery Dis. 1992;3:1003-1009.

24. Kelly A, Maraganore J, Bourdon P. Hanson S, Harker L.Antithrombotic effects of synthetic peptides targeting various func-tional domains of thrombin. Proc Natl Acad Sci USA. 1992;89:6040-6044.

25. Topol EJ, Bonan R, Jewitt D, Sigwart U, Kakkar VV, Rothman M,de Bono D, Ferguson J, Willerson JT. Stronv J, Ganz P, CohenMD, Raymond R, Fox 1, Maraganore J. Adelman B. Use of a directantithrombin, Hirulog, in place of heparin during coronary angio-plasty. Circulation. 1993;87:1622-1629.

26. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J.Clot-bound thrombin is protected from inhibition by heparin-

antithrombin III but is susceptible to inactivation by antithrombinIll-independent inhibitors. J Clin Invest. 1990;86:385-391.

27. Markwardt F, Hoffmann A, Sturzebecher J. Influence of thrombininhibitors on the thrombin-induced activation of human bloodplatelets. Haemostasis. 1983;13:227-233.

28. Glusa E, Markwardt F. Platelet functions in recombinant hirudinanticoagulant blood. Haemostasis. 1990;20:112-118.

29. Glusa E. Hirudin and platelets. Semin Thromb Heniost 1991;17.122-125.

30. Gold HK, Torres FW, Garabedian HD. Evidence for a reboundcoagulation phenomenon after cessation of a 4-hour infusion of aspecific thrombin inhibitor in patients with unstable anginapectoris. JAm Coll Cardiol. 1992;211039-1047.

31. Bar F. Verheugt F, Materne P, Monassier J, Geslin P, Metzger J5Raynaud P, Foucault J, de Zwaan C Vermeer F. Thrombolysis inpatients with unstable angina improves the angiographic but notthe clinical outcome: results of UNASEM. a multicenter, ran-domized, placebo-controlled, clinical trial with anistreplase. Circu-lation. 1992;86:131-137.

32. Karlsson J, Berglund U, Bjorkholm A, Ohlsson J. Swahn E,Wallentin L, for the TRIC Study Group. Thrombolysis withrecombinant human tissue-type plasminogen activator duringinstability in coronary artery disease: effect on myocardialischemia and need for coronary revascularization. Am Heart f1992; 124:1419 -1426.


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Chapekis, H K Gold and M A TannenbaumE J Topol, V Fuster, R A Harrington, R M Califf, N S Kleiman, D J Kereiakes, M Cohen, A

angiographic trial.Recombinant hirudin for unstable angina pectoris. A multicenter, randomized

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