Tenecteplase and tirofiban in ST-segment elevation acute myocardial infarction: Results of a randomized trial

Clinical Investigations

Acute Ischemic Heart Disease

Tenecteplase and tirofiban in ST-segment elevation acute myocardial infarction: Results of a randomized trial E. Magnus Ohman, MD,a Frans Van de Werf, MD,b Elliott M. Antman, MD,c Robert M. Califf, MD,d James A. de Lemos, MD,e C. Michael Gibson, MD, MS,f Renee L. Oliverio, RN, MA,d Lynn Harrelson, MS,d Carolyn McCabe, BS,f Peter DiBattiste, MD,g and Eugene Braunwald MD,f for the FASTER (TIMI 24) Investigators Chapel Hill and Durham NC, Boston, Mass, Leuven, Belgium, Dallas, Tex, and Whitehouse Station, NJ

Background The combination of older reduced-dose fibrinolytic agents and platelet glycoprotein IIb/IIIa inhibitors has shown modest improvements in reperfusion and more striking improvements in ST-segment resolution after acute myocardial infarction. We performed a multicenter dose-ranging study of reduced doses of a newer fibrinolytic (tenecteplase) combined with tirofiban, a glycoprotein IIb/IIIa inhibitor. Methods

The first goal of the trial was to identify a dose or doses of tirofiban that, when combined with reduced-dose tenecteplase, would result in a higher incidence of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 60 minutes versus full-dose tenecteplase alone. The second goal was to assess whether the optimum dose(s) from the first stage also would result in greater resolution of ST-segment elevation.

Results In all, 409 patients aged 18 to 75 years with myocardial infarction were enrolled. The incidence of TIMI grade 3 flow at 60 minutes did not differ significantly among dose groups, ranging from 50% to 68%. The corrected TIMI frame count likewise did not differ substantially (range 34 - 42). More patients given combined therapy had complete resolution of ST-segment elevation at 60 minutes compared with patients given tenecteplase alone. Major bleeding was infrequent, and no strokes occurred. Based on angiographic results of the first stage, the second planned stage of the study was not performed. Conclusions Although combination therapies were not associated with increased reperfusion compared with full-dose tenecteplase alone, similar TIMI flow grades were achieved despite reductions in tenecteplase doses. ST-segment resolution was more rapid and complete with combination therapy versus full-dose tenecteplase, suggesting enhanced microcirculatory perfusion to the infarct zone in this dose-ranging trial. (Am Heart J 2005;150:79- 88.) Platelets play a pivotal role in the response to disruption of a coronary artery plaque. Platelets also are activated in response to fibrinolysis, and platelet-rich thrombi are more resistant to fibrinolysis. Although aspirin is now a fundamental element in the medical

From the aDivision of Cardiology, University of North Carolina at Chapel Hill, UNC Heart Center, Chapel Hill, NC, bDepartment of Cardiology, University of Leuven, Leuven, Belgium, cTIMI Study Group, Brigham and Women’s Hospital, Boston, Mass, d Duke Clinical Research Institute, Durham, NC, eDonald W. Reynolds Cardiovascular Clinical Research Center, University of Texas–Southwestern, Dallas, Tex, fHarvard Clinical Research Institute, Boston, Mass, and gMerck & Company, Whitehouse Station, NJ. This work was supprted by grants from Merck & Company, Whitehouse Station, New Jersey and Genentech, Inc., South San Francisco, California. Submitted September 3, 2003; accepted January 7, 2005. Reprint requests: E. Magnus Ohman, MD, 130 Mason Farm Road, Bioinformatics Building, CB 7075, Chapel Hill, NC 27599. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.01.007

treatment of acute ST-segment elevation myocardial infarction (STEMI), inhibition of platelet activation with aspirin is incomplete, given that only the thromboxane A2 pathway is blocked. Intravenous agents that block the platelet glycoprotein (GP) IIb/IIIa receptor on activated platelets are attractive because they block the final common pathway leading to platelet aggregation. Investigating the therapeutic potential of GPIIb/IIIa inhibitors for myocardial infarction (MI) has taken 2 broad paths: incorporating them into pharmacological reperfusion regimens and using them as supportive therapy during primary percutaneous coronary intervention (PCI). Initial attempts to amplify pharmacological reperfusion regimens combined full doses of fibrinolytic drugs with GPIIb/IIIa inhibitors. Although these initial efforts provided proof of the concept that augmentation of antiplatelet therapy beyond aspirin appeared to enhance epicardial flow in the infarct artery and improve myocardial perfusion, concerns arose over increased rates of major bleeding.

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Table I. Dosing regimens per phase and arm Phase 1 Arm Agent

A n = 43

Tirofiban

Tenecteplase Heparin

Phase 2 B n = 84

–

10-Ag bolus 0.15-Ag/kg infusion Low dose 0.27 mg/kg 50% dose 40-U/kg bolus 7-U/kg/h infusion

0.53 mg/kg 100% dose 60-U/kg bolus 12-U/kg/h infusion High dose

A n = 30 –

100% dose High dose

Phase 3

B n = 62

C n = 59

12.5-Ag bolus 0.15-Ag/kg infusion Medium dose

A n = 33

Low dose

0.36 mg/kg 67% dose Low dose

50% dose Low dose

–

100% dose High dose

B n = 98 15-Ag bolus 0.15 Ag/kg infusion High dose 50% dose Low dose

Low dose

Table II. Baseline characteristics, efficacy - evaluable patients Phase 1

Characteristics Age (y) Female sex (%) Weight (kg) Location of infarct (%) Anterior Nonanterior Killip class (%)T I II III IV

A n = 30

B n = 59

Phase 2 A n = 23

B n = 49

Phase 3 C n = 47

Pooled data*

A n = 32

B n = 84

All A arms n = 85

All B arms n = 192

58 23 75

59 20 80

57 39 75

55 18 78

54 11 80

56 16 79

55 23 75

57 25 77

56 21 78

33 67

37 63

39 61

35 65

32 68

38 63

35 66

37 64

35 65

83 17 0 0

91 8.6 0 0

91 9.1 0 0

91 8.7 0 0

96 2.2 0 2.2

87 13 0 0

90 10 0 0

87 13 0 0

91 9.2 0 0

Data are medians or percentages. *All bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban.

The combination of a reduced-dose fibrinolytic and a GPIIb/IIIa inhibitor then was tested in a series of trials. These studies involved combinations of lower doses of alteplase or reteplase with abciximab and lower doses of alteplase or tenecteplase with eptifibatide or abciximab.1-5 The incidence of TIMI grade 3 flow was modestly improved, along with somewhat more striking improvements in ST-segment resolution, suggesting enhanced myocardial perfusion.6 The FASTER trial was a dose-ranging study of reduced doses of tenecteplase combined with tirofiban. The primary objective of the initial portion of the trial was to identify a dose or doses of tirofiban that, combined with reduced-dose tenecteplase, would result in an increased incidence of TIMI grade 3 flow at 60 minutes versus fulldose tenecteplase alone. Secondary objectives included identification of tirofiban dose(s) that would improve the

TIMI frame count and enhance ST-segment resolution and be associated with acceptable rates of major bleeding. To accomplish these objectives, we explored a series of dose panels that modified both the dose of tenecteplase and the bolus dose of tirofiban in the experimental arms.

Methods Patients Men and women aged 18 to 75 years were eligible for randomization if they (1) had ischemic pain at rest for z20 minutes but b6 hours, (2) had ST-segment elevation z0.15 mV (0.08 seconds after the J point) in 2 or more contiguous limb leads or z0.2 mV elevation in 2 or more contiguous precordial leads, and (3) were able to provide written informed consent and agreed to comply with all protocol-specific procedures. Patients were excluded for any prior bypass surgery; fibrinolytic therapy, angiography, or PCI b7 days before entry;

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Table III. Treatment characteristics, efficacy - evaluable patients Phase 1

Characteristics

A n = 30

Phase 2

Phase 3

Pooled data*

B n = 59

A n = 23

B n = 49

C n = 47

A n = 32

B n = 84

All A arms n = 85

All B arms n = 192

3.2

2.5

3.0

2.4

2.6

2.7

2.5

2.9

84 11 5.3 6.8

– – – –

83 8.5 8.5 12

89 4.3 6.4 19

– – – –

81 16 3.7 19

– – – –

82 12 5.4 14

Time to treatment (h) 2.5 Time tirofiban given versus tenecteplase (%) V10 min before – Same time – V10 min after – Tirofiban stopped early (%) –

Data are medians or percentages. *All bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban.

Table IV. Baseline angiographic characteristics, efficacy-evaluable patients Phase 1

Characteristics Time to angiogram (min) Infarct artery (%) LAD Left circumflex Right coronary artery Left main Diagonal Unknown Normal coronaries PCI of IRA performed (%)

A n = 30

B n = 59

Phase 2 A n = 23

B n = 49

Phase 3 C n = 47

A n = 32

B n = 84

Pooled data* All A arms n = 85

All B arms n = 192

60

62

64

61

61

62

61

62

61

37 13 50 0 0 0 0 70

34 14 49 0 1.7 1.7 0 59

44 17 39 0 0 0 0 52

35 14 49 0 2 0 0 67

34 8.5 55 0 2.1 0 0 68

34 6.3 56 0 3.1 0 0 81

31 17 51 0 1.2 0 0 68

38 12 49 0 1.2 0 0 69

33 15 50 0 1.6 0.5 0 65

Data are medians or percentages. IRA, infarct-related artery. *All bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban.

left bundle-branch block, intraventricular conduction defect, or paced rhythm; cardiogenic shock; acute pulmonary edema requiring diuretics (rales N50% of lung fields) or Killip class IV heart failure; acute pericarditis; systolic blood pressure N180/100 mm Hg between symptom onset and enrollment; prior stroke or transient ischemic attack; active bleeding disorder within the past year, known coagulopathy, platelet disorder, or previous thrombocytopenia; severe trauma, major surgery; traumatic or prolonged cardiopulmonary resuscitation within 2 weeks before entry; or active peptic ulcer disease within 3 months before entry. Patients also were excluded for suspected or known pregnancy; medical conditions that, in the investigator’s opinion, reduced the likelihood of survival during the study or would produce a significant risk to the patient; other serious illness; weight N120 kg; treatment with abciximab within the previous 14 days or eptifibatide or tirofiban b48 hours before entry; use of low–molecular-weight heparin b12 hours before entry; required chronic warfarin therapy or warfarin use b1 week before entry; known allergy or intolerance to

tirofiban, aspirin, heparin, or tenecteplase; use of N6000 U heparin b1 hour before entry; clopidogrel or ticlopidine use b 7 days before randomization; participation in another trial of an investigational agent or device within 4 weeks before entry; serum creatinine N2.5 mg/dL or creatinine clearance b30 mL/min; hemoglobin b11 g/dL or hematocrit b34%; or platelet count b150 000/mm3.

Study design and treatments This was a multicenter, randomized, open-label, doseranging study of various doses of tirofiban (see below) and various doses of tenecteplase. Table I details the study-drug doses among the 3 phases of the trial. Patients were randomized to receive 0.53 mg/kg of tenecteplase (Genentech, Inc, South San Francisco) alone (100% dose; all bAQ arms among the phases) or reduced doses of tenecteplase with tirofiban (Merck & Company, Whitehouse Station) (patients in the bBQ arms [50% tenecteplase dose] and bCQ arm [67% tenecteplase dose]). All patients also received intravenous unfractionated heparin, aspirin 300 to 325 mg immediately

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Table V. Angiographic efficacy results Phase 1

Variable

A n = 30

60-min TIMI flow grade (%)z 3 2 1 0 TIMI grade 3 flow, IRA (%) LAD Other coronary artery Median CTFC

Phase 2

Phase 3

Pooled data*

B n = 59

A n = 23

B n = 49

C n = 47

A n = 32

B n = 84

All A arms n = 85

All B arms n = 192

60 17 0 23

68 25 0 6.8

57 30 4.3 8.7

55 27 6.1 12

68 8.5 4.3 19

56 22 3.1 19

50 29 7.1 14

58 22 2.4 18

57 27 4.7 12

.389

55 63 37

65 69 34

50 62 38

71 47 38

69 68 36

46 62 35

50 50 42

50 62 37

60 55 37

.337 .371

Pyy

CTFC, corrected TIMI frame count; for other abbreviations, see text and Table IV. *All bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban. yStatistical test for pooled data only. zCore laboratory assessment of angiogram obtained 55 to 75 minutes after study-drug initiation.

and daily unless contraindicated, and nitroglycerin as clinically indicated. For patients who had not received heparin before and who were randomized to receive tenecteplase alone, the heparin dose was as follows: for patients weighing N67 kg, a 5000-U bolus and 1000-U/h infusion, and for patients weighing V67 kg, a 4000-U bolus and 800-U/ h infusion. For patients who had not received heparin before and who were randomized to receive combination therapy, a heparin bolus of 60 U/kg (4000 U maximum) was given, followed by infusion of 7 U/kg/h (800 U/h maximum). For patients randomized to receive combination therapy, heparin and tirofiban were started concomitantly within 15 to 20 minutes after randomization. The tenecteplase bolus then was given within 5 minutes after the tirofiban/heparin. Tirofiban infusions continued for z24 hours and could be extended for later angiography and PCI. Heparin therapy continued for z4 hours, and its use was discouraged after PCI unless clinically indicated.

End point definitions and assessments The primary efficacy end points were the incidence of TIMI grade 3 flow7 in the infarct-related artery and the corrected TIMI frame count8 on 60-minute angiography (which could be performed between 55 and 75 minutes after fibrinolysis began). Key secondary end points included category of resolution (compared with baseline) of ST-segment elevation at 60 minutes (time window of 50 to 75 minutes) and at 3 hours (window of 160 to 200 minutes). The categories of resolution were defined as complete (N70% resolution), partial (30% to 70% resolution), and none (b30% resolution). The primary safety measurements were the incidence of major bleeding b48 hours after study-drug initiation, according to the TIMI criteria,1,9 and the incidence of intracranial hemorrhage. Additional safety measurements included minor bleeding events (by the TIMI criteria) and the use of blood transfusions within 30 days. Clinical events (death, reinfarction, congestive heart failure, resuscitated cardiac arrest,

bypass surgery, and severe ischemia requiring urgent revascularization) also were collected from enrollment through 30 days. The primary efficacy end point variables were assessed at core angiographic and electrocardiographic laboratories by personnel unaware of treatment assignment. The primary safety variable (the incidence of major TIMI bleeding) was confirmed by a blinded safety monitor.

Statistical analysis The first goal was to identify combined doses of tenecteplase and tirofiban that would have a high probability of attaining a 20% absolute increase above the approximately 50% incidence of TIMI grade 3 flow at 60 minutes achieved with full-dose tenecteplase alone.1,10 A decision algorithm for dose acceptance/rejection was developed. With a maximum of 70 evaluable patients per dose, this algorithm provided (1) a N95% probability of selecting doses associated with a true incidence of TIMI grade 3 flow at 60 minutes of z70% and (2) a N80% probability of rejecting doses associated with a true incidence of TIMI grade 3 flow of V55%. The second goal was to show that the dose(s) resulting in optimal TIMI grade 3 flow also was (were) superior to tenecteplase alone in resolution of ST-segment elevation. Assuming that the true distribution of responses in the full-dose tenecteplase group would be 35% complete resolution, 20% partial resolution, and 45% no resolution,6 and that tirofiban treatment would double the odds of complete resolution (leading to a distribution of responses in the tirofiban group of 52% complete resolution, 19% partial resolution, and 29% no resolution), a total of 150 evaluable patients per treatment group would provide 90% power (2-sided P = .05) to detect an improvement in ST-segment resolution as identified by a shift in the distributions.6 For analysis of the primary end point (TIMI grade 3 flow at 60 minutes), we included patients who received any valid dose of study drug and had a 60-minute TIMI flow grade reading

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Figure 1

100%

Patients

80%

60%

40%

20% TIMI Grade 3

Grade 2

Grade 1

Grade 0

0% A

B Phase 1

A

B Phase 2

C

A Phase 3

B

A

B Pooled

TIMI flow grades at 60-minute angiography.

available (befficacy-evaluable patientsQ). Analysis of ST-segment resolution included patients who received any valid dose of study drug and had ST-segment resolution measured 60 minutes and 3 hours after study drug began, including those who had had PCI performed during the interval. For assessments of clinical events and bleeding, we included all randomized patients by intention-to-treat analysis. The original protocol called for a dose-confirmation phase testing a larger sample of patients without angiography and with ST-segment resolution as the primary end point after the initial dose-finding stage. The best combination dosing regimen(s) from the dose-finding stage was to be tested against the control arm in a larger sample of patients. When the results of the dose-ranging study emerged, however, the Steering Committee decided to terminate the trial early. It was evident, based on the results of the dose-ranging phase and those of recent trials of combination GPIIb/IIIa inhibition and fibrinolysis, that detecting a clinically significant difference between treatments would have been very difficult in a doseconfirmation stage.2-4,11

Results Between May 2000 and February 2001, 409 patients were enrolled at 44 sites in 15 countries: 127 during phase 1, 151 during phase 2, and 131 during phase 3. Of these, 89 (70%), 119 (79%), and 116 (89%), respectively, were included in the angiographic efficacy analyses. The median age of the patients ranged from 26 to 81 years (Table II). The C arm in phase 2 included only

about half as many women as the other dose arms, but the proportions of women in the pooled groups did not differ substantially. About one third of the patients overall had anterior MI, and all but 1 patient fell under a Killip classification of I or II. More than 90% of the patients in each tirofiban group received that drug simultaneously with or within 10 minutes before starting tenecteplase. Study drug was started a median 2.4 to 3.2 hours after MI symptom onset (Table III). Tirofiban was stopped early in 7% (phase 1, arm B) to 19% of patients (phase 2, arm C and phase 3, arm B), almost always because of bleeding. The initial angiogram was performed between 60 and 64 minutes (median) after study drug initiation (Table IV). The infarct-related artery was most often the left anterior descending (LAD) or right coronary artery. PCI was performed in between 52% (phase 2, arm A) and 81% of patients (phase 3, arm A). Angiographic efficacy results are presented in Table V and Figure 1. The incidence of TIMI grade 3 flow at 60 minutes did not differ significantly among groups. This finding persisted when the analysis was repeated among all patients, not just those who were efficacyevaluable (59% incidence of TIMI grade 3 flow among all full-dose tenecteplase [A] arms vs 57% incidence among all half-dose tenecteplase/tirofiban [B] arms; P = .780). The corrected TIMI frame count likewise did not differ

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84 Ohman et al

Table VI. ST-segment resolution results, all patients with dataT Phase 1 Variable 60 min (%) Complete Partial None Median resolution (%) 3 h (%) Complete Partial None Median resolution (%)

Phase 2

Phase 3 A n = 29

Pooled dataT

A n = 18

B n = 53

A n = 22

B n = 38

C n = 38

B n = 68

22 33 44 35

49 26 25 69

27 23 50 36

34 45 21 63

32 45 24 62

n = 20

n = 44

n = 20

n = 38

n = 28

n = 26

n = 60

n = 66

n = 142

55 20 25 83

77 14 9.1 94

55 25 20 74

74 18 8 85

71 11 8 94

81 3.8 15 81

78 13 8.3 91

65 15 20 79

77 15 8.5 90

35 31 35 53

All A arms n = 69

43 19 38 57

All B arms n = 159

29 29 42 47

Pzz

43 28 30 64

.098

.031

.062

.003

TCompared with baseline ECG; includes patients who received a valid dose of study drug and had ST-segment resolution measured within 50 to 75 minutes (60-minute analysis) or 160 to 200 minutes (3-hour analysis). yAll bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban. zStatistical test for pooled data only.

Table VII. Clinical events and bleeding complications through 30 days, all patients with data Phase 1

Outcome (%) Mortality Congestive heart failure Reinfarction Resuscitated arrest Bypass surgery Severe ischemiay Any of the above Bleeding events Major§ Intracranial Spontaneous Trauma-related Unknown Minor Red cell transfusion

Phase 2

Phase 3

Pooled dataT

A n = 43

B n = 84

A n = 30

B n = 62

C n = 59

A n = 33

B n = 98

All A arms n = 106

All B arms n = 244

0 12 7.0 4.7 9.3 4.7 26

3.6 4.8 3.6 4.8 9.5 6.0 23

0 10 3.3 3.3 13 6.7 23

0 6.6 6.6 0 4.8 6.6 16

6.8 14 3.4 8.5 1.7 3.4 27

6.1 3.0 3.0 0 0 6.1 18

4.1 7.1 5.1 2.0 7.1 7.1 24

1.9 8.5 4.7 2.8 7.5 5.7 23

2.9 6.2 4.9 2.5 7.4 6.6 21z

9.3 0 2.3 4.7 2.3 2.3 9.3

3.6 0 1.2 2.4 0 6.0 12

3.3 0 0 3.3 0 13 17

6.5 0 4.8 1.6 0 6.5 6.5

10 0 3.4 6.8 0 12 6.8

0 0 0 0 0 6.1 9.1

9.2 0 5.1 4.1 0 10 11

4.7 0 0.9 2.8 0.9 11 6.6

6.6b 0 3.7 2.9 0 10 7.8

TAll bAQ arms included full-dose tenecteplase; all bBQ arms included 50% tenecteplase dosing plus tirofiban. yRequiring repeat (urgent) intervention. zP = .782 for pooled A arms versus pooled B arms. §Within 48 hours of study-drug initiation. bP = .505 for pooled A arms versus pooled B arms.

substantially, ranging from 34 to 42 among treatment arms. There was some suggestion of a differential effect of combined tenecteplase-tirofiban treatment by infarctrelated artery; combination therapy appeared to exert a greater effect in patients with a culprit LAD versus other coronary arteries.

More patients in the combination-therapy arms showed complete resolution of ST-segment elevation at 60 minutes than did patients given tenecteplase alone (Table VI); the median degree of resolution was 64% versus 47%, respectively ( P = .031). This pattern persisted at 3 hours, except in phase 3, in which the

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Figure 2

100 Monotherapy

Combination

TIMI Grade 3 Flow at 60 Min (%)

80

60

40

20

0

n

TIMI-14 tPa

1

INTEGRITI TNK

235 103

106 105

4

ENTIRE TNK

76 67

5

INTRO-AMI tPA

81 75

3

SPEED rPA

2

98 100

FASTER TNK

85 192

Incidence of TIMI grade 3 flow at 60 minutes, dose-confirmation phases of studies testing fibrinolysis versus fibrinolysis plus GPIIb/IIIa inhibition.

patients given tenecteplase alone had a slightly higher rate of complete resolution. Overall, the median degree of resolution at 3 hours was 90% with combination therapy versus 79% with tenecteplase alone ( P = .003). There were no intracranial hemorrhages in any experimental or control arm of the study. The incidence of most other events, including bleeding and mortality, showed no consistent dose-response pattern (Table VII).

Discussion The findings of the current trial support the concept that inhibition of platelet aggregation is an important aspect of pharmacological reperfusion for STEMI with half-dose fibrinolysis and extend prior observations to include the GPIIb/IIIa inhibitor tirofiban. Although the incidences of TIMI grade 3 flow at 60 minutes with the combination regimens were not superior to that observed in the full-dose tenecteplase control arm, a similar TIMI flow grade was achieved despite a reduction in the tenecteplase dose. ST-segment resolution was more

rapid and complete with combination reperfusion versus full-dose tenecteplase alone, suggesting enhanced microcirculatory perfusion to the infarct zone with combination treatment. Unique to this trial compared with other contemporary phase II angiographic trials in MI was the absence of intracranial hemorrhage among the 409 patients enrolled. Why was the incidence of TIMI grade 3 flow not higher at 60 minutes in the experimental arms in this study? In fact, this observation is consistent with other data when viewed in the context of other phase II angiographic trials of pharmacological reperfusion for STEMI (Figure 2).1-5,10,11 At 60 minutes, the pooled rate of TIMI grade 3 flow in the current study was 58% in the full-dose fibrinolytic group and 57% in the half-dose fibrinolytic plus GPIIb/IIIa inhibitor group—a very small increase in TIMI grade 3 flow that would not be expected to translate into a reduction in mortality. Additional aspects of the biology of GPIIb/IIIa inhibition of activated platelets are worth considering when evaluating the effect of combination reperfusion regimens on early epicardial artery blood flow. The binding

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86 Ohman et al

of fibrinogen to the GPIIb/IIIa receptor is calciumdependent. Therefore, when specimens are drawn in tubes containing calcium-chelating anticoagulants, they may give a falsely high impression of the degree of inhibition of platelet aggregation.12 This has been noted for eptifibatide,13 but similar considerations pertain to tirofiban.14 The range of bolus doses of tirofiban tested in this study (10-15 Ag/kg) was based on its experience in PCI. Reports from several investigators and the findings of the RESTORE15 and TARGET16 suggest that the bolus doses in the current study may have been associated with inadequate early inhibition of platelet aggregation to enhance angiographic reperfusion rates. Coupled with the fact individuals vary considerably in the inhibitory response of GPIIb/IIIa receptors to a given dose of intravenous GPIIb/IIIa inhibitor, alternative bolus doses of tirofiban may be required to achieve z80% inhibition of platelet aggregation in most patients.17 These might include a larger single bolus, such as 20 to 25 Ag/kg, or a double-bolus regimen to provide high levels of platelet inhibition that could then be maintained by a continuous infusion.18 More recently, it has been suggested that a higher dose of tirofiban with a single large bolus can be used for angioplasty.19 However, this was not known at the time of the performance of this trial and may indeed have altered the design of the study. The tendency toward improved ST-segment resolution with combination reperfusion therapy in this study also has been consistently observed across studies of various GPIIb/IIIa inhibitors and fibrinolytic agents.5 The improved myocardial reperfusion signaled by better ST-segment resolution is considered responsible, at least partly, for the lower rate of complications of MI seen in trials of combination reperfusion compared with full-dose fibrinolysis. Of note, however, neither short-term nor long-term mortality has been reduced in large trials of combination reperfusion compared with full-dose fibrinolysis.20-23 The reasons for this are unclear, but possibilities include enrollment of mostly low-risk patients in phase III trials of combination reperfusion, the mortality- and morbidity-reducing effects of contemporary postinfarction drug regimens, and the increasing use of PCI, either rescue or delayed, after pharmacological reperfusion. An important clinical concern when contemplating pharmacological reperfusion for STEMI is the risk of major bleeding, especially intracranial hemorrhage. To date, phase II and III trials of combination reperfusion have not lived up to the hope that reducing the dose of fibrinolytic would translate into lower rates of bleeding. In fact, the opposite has occurred, with combination reperfusion being associated with higher rates of major bleeding overall and unacceptably high rates of intracranial hemorrhage in the elderly.22

In that regard, safety observations in the current study are of interest. There were no intracranial hemorrhages in any treatment arm. The absence of intracranial hemorrhage in the tirofiban arms may reflect b80% inhibition of platelet aggregation while the fibrinolytic effect was maximal. Although not statistically significant, the rate of nonintracranial bleeding tended to increase as the tenecteplase dose increased from 0.27 to 0.36 mg/kg and as the tirofiban bolus dose increased from 10 to 15 Ag/kg. These findings underscore the delicate balance between elements of a pharmacological reperfusion regimen. Although higher doses of a GPIIb/IIIa inhibitor may be needed to approach 80% inhibition of platelet aggregation early after administration of the reperfusion regimen, this may come at the cost of an increased risk of bleeding, especially if the dose of the fibrinolytic is also increased. This balance is of even greater concern in patients with an increased risk of bleeding, such as the elderly, who were excluded from this study and most other phase II angiographic trials. This study has 2 main limitations. First, a proportion of the patients in each arm was not included in the primary angiographic efficacy analysis. However, including the angiography-ineligible patients in the analysis did not quantitatively change the results. Second, the lack of difference in angiographic results may reflect the small sample sizes or inadequate dosing of 1 or both agents, or both. However, the large ASSENT-3 study22,23 produced results similar to those of the current study—increased resolution of ST-segment elevation with half-dose fibrinolysis combined with a different GPIIb/IIIa inhibitor (abciximab), but no translation of these benefits into a reduction in mortality as shown in the GUSTO-V study.21 The results of this trial have several implications for investigation of pharmacological regimens for STEMI. To complete the evaluation of tirofiban, regimens that achieve higher levels of platelet inhibition should be tested. Given the risk-benefit pattern that is emerging for combination reperfusion regimens, alternative strategies are worthy of investigation, including restricting their use to younger patients and/or restricting the dose of GPIIb/IIIa inhibitor in the elderly to only 75% of the dose used in younger patients. Future studies may need to explore the third of the pharmacological components in STEMI, namely, anticoagulation. If a safer and more specific anticoagulant could be used rather than heparin, a more precise balance might be achieved among all 3 components— anticoagulation, fibrinolysis, and platelet inhibition—to enhance safety and efficacy.

References 1. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. Circulation 1999;99:2720 - 32.

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2. The SPEED Study Group. Trial of abciximab with and without lowdose reteplase for acute myocardial infarction. Circulation 2000;101:2788 - 94. 3. Brener SJ, Zeymer U, Adgey AA, et al. Eptifibatide and low-dose tissue plasminogen activator in acute myocardial infarction: the integrilin and low-dose thrombolysis in acute myocardial infarction (INTRO AMI) trial. J Am Coll Cardiol 2002;39:377 - 86. 4. Giugliano RP, Roe MT, Harrington RA, et al. Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the INTEGRIlin and Tenecteplase in acute myocardial Infarction (INTEGRITI) phase II angiographic trial. J Am Coll Cardiol 2003;41:1251 - 60. 5. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE–Thrombolysis In Myocardial Infarction (TIMI) 23 Trial. Circulation 2002;105:1642 - 9. 6. de Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation 2000;101:239 - 43. 7. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis In Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142 - 54. 8. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93:879 - 88. 9. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Ann Intern Med 1991;115:256 - 65. 10. Cannon CP, Gibson CM, McCabe CH, et al. TNK–tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Circulation 1998;98:2805 - 14. 11. Antman EM, Gibson CM, de Lemos JA, et al. Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. Eur Heart J 2000;21:1944 - 53. 12. Schneider DJ, Tracy PB, Mann KG, et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997;96:2877 - 83. 13. Phillips DR, Teng W, Arfsten A, et al. Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96:1488 - 94. 14. Kabbani SS, Aggarwal A, Terrien EF, et al. Suboptimal early inhibition of platelets by treatment with tirofiban and implications for coronary interventions. Am J Cardiol 2002;89:647 - 50. 15. The RESTORE Investigators. The effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445 - 53. 16. Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888 - 94. 17. Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the

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Appendix A. Study participants Angiographic Core Laboratory, Moffitt Hospital, University of California San Francisco: C.M. Gibson, K. Ryan, S. Murphy. Duke Clinical Research Institute: R.M. Califf, T. Demby-Ulmer, L. Harrelson, E. Hawkins, M. Molina, R. Oliverio, K. Stevens. Electrocardiographic Core Laboratory, TIMI Group: J.A. de Lemos Genentech, Inc: H.V. Barron. Leuven Coordinating Center: W. Desmet, K. D’Hollander, M. Moriera, F. van de Werf. Merck & Company: C. Arena, M. Bremer, C. Cavalente, C. Constantin, P. DiBattiste, J. Lappe, S. Lee, L. Resnansky, S. Snappin. TIMI Study Group: E.M. Antman, E. Braunwald, J.A. de Lemos, C.M. Gibson, J. Holub, C. McCabe, R. Pai. Sites (number enrolled): Argentina (20): Sanatorio Mitre, Buenos Aires: A.S. Liprandi; Clinica Bazterrica, Buenos Aires: V. Mauro; Hospital Italiano, Buenos Aires: M. Cohen; Australia (12): St Vincent’s Hospital, Sydney, New South Wales: D. Muller; Ashford Community Hospital, Ashford, South Australia: J. Whitford; Flinders Medical Centre, Bedford Park South Australia: P.E. Aylward; Belgium (42): CHU Sart Tilman service de Cardiologie, Liege: V. Legrand; UZ Gasthuisberg Dienst Cardiologie, Leuven: F. Van de Werf; Dienst Cardiologie, Genk: M. Vrolix; Brazil (14): Hospital Sao Paolo, Sao Paolo: A. Carvalho; Hospital Socor, Belo Horizonte: J. Saad; Canada (31): Centre Hopitalier Universitaire de Montreal, Montreal, Quebec: P. Laramee; Hospital Maisonneuve-Rosemont, Montreal, Quebec: C. Constance; Centre Universite Sante l’estrie Fluerimont,

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Quebec: M. Nguyen; Jewish Community Hospital, Montreal, Quebec: L. Rudski; Chile (9): Hospital Clinico Pintificia Universidad Catolica, Santiago: R. Corbalan; Columbia (30): Clinica Medellin, Calle: R. Botero; Costa Rica (5): Hospital San Juan de Dios, San Juan: A. Brilla; Germany (37): Charite Universitatsklinicum der humbolt Universitat zu Berlin, Berlin: K.J. Osterziel; Universitat Heidelberg, Heidelberg: H. Kucherer; Chefarzt der II Med Abteilung, Munchen: H. Mudra; Med Abteilung III, Trier: K.E. Hauptmann; Medizinische Klinik 1, Aachen: J. Vom Dahl; Klinikum der Universitat Regensburg, Regensburg: H. Schunkert; Arzt fur Innere Medizen-Kardiologie II, Mainz: H.J. Rupprecht; The Netherlands (24): Leyenburg Hospital, Den Haag: R.M. Robles de Medina; R&D Cardiologie, Eindhoven: R. Michels; Israel (11): Heart Institute, Zerifin: Z. Vered; Italy (7): Ospedale S. Maria delle Croci, Ravenna: A. Maresta; Ospedali Riuniti de Bergamo, Bergamo: G. Guagliumi; Mexico (9): Hospital 1 de Octubre ISSSTE, Salinas: M. Mendiolea; New Zealand (15): Christ Church Hospital, Hamilton: H. Ikram, Waikito Hospital, Hamilton: G. Devlin; Green Lane Hospital, Auckland: H.D. White; Spain (18): Hospital Clinico, Madrid: J. Ferrero-Zorita; Hospital Clinic 1 Provincial, Barcelona: G.S. Romero; Hospital Valle de Hebron, Barcelona: J. Figueras-Bellot; Switzerland (14): Cardio Centra Ticino, Lugano: T. Moccetti; United Kingdom (36): Royal Devon and Exeter Hospital, Exeter, Devon: D. Smith; Blackpool Victoria Hospital, Lancashire: M. Brack; Hairmyers Hospital, Glasgow: K. Oldroyd; Royal Victoria Hospital, Belfast: J. Adgey; United States (75): Good Samaritan Hospital, Dayton, Ohio: A. Abdul-Karim; Columbus

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Hospital, Columbus, Ohio: P. Amsterdam; University of Texas at Houston Health Science Center: H.V. Anderson; University of Michigan Health Systems, Ann Arbor: E.R. Bates; Washington Adventist Hospital, Takoma Park, Md: D. Brill; Bergan Mercy Medical Center, Omaha: S. Carollo; Sacred Heart Hospital, The Heart Care Grour, Allentown, Pa: W. Combs; Harborview Medical Center, Seattle: M. Corson; Emory University Hospital, Atlanta: J. Douglas; University of Wisconsin Hospitals & Clinics, Madison: D. Ende; University of Massachusetts Memorial Medical Center, Worcester: M. Furman; Iowa Heart Center, Des Moines: M. Ghali; LSU Health Sciences Center, Shreveport: H. Hanley; University of Maryland School of Medicine, Baltimore: W. Herzog: Mercer Bucks Cardiology, Yardley, Pa: G. Heyrich; Heart and Vascular Center of Florida, Port Charlotte: V. Howard; Florida Cardiovascular Research Rothman Center, Atlantis: J. Kieval; Metropolitan Cardiology Consultants, Coon Rapids, Minn: M. Kraemer; Ben Taub General Hospital, Houston: N. Lakkis, South Orange County Cardiovascular Associates, Laguna Hills, Calif: D. LaMont; Latter-Day Saints Hospital, InterMountain Healthcare, Salt Lake City, Utah: J.B. Muhlestein; The Greater Ft. Lauderdale Heart Group Research: A. Niederman; Alabama Cardiovascular Specialists, Alabaster: T. Paul, Jr; Scripps Mercy Hospital, San Diego: P. Phillips; Austin Cardiovascular Associates, Austin, Tex: M. Pirwitz; Oklahoma Foundation for Cardiovascular Research, Oklahoma City: D. Schmidt, J. Williams; St Petersburg-Suncoast Medical Group, St Petersburg, Fla: V. Singh; Winthrop University Hospital, Mineola, NY: R. Steingart; Cardiology of Oklahoma, Tulsa: W.W. Stoever.