the assessment of the safety and efficacy of a new treatment strategy for acute myocardial...

The Assessment of the Safety and Efficacy of a New The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction Treatment Strategy for Acute Myocardial Infarction

(ASSENT-4 PCI) Trial(ASSENT-4 PCI) Trial

The Assessment of the Safety and Efficacy of a New The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction Treatment Strategy for Acute Myocardial Infarction

(ASSENT-4 PCI) Trial(ASSENT-4 PCI) Trial

ASSENT- 4 PCI TrialASSENT- 4 PCI TrialASSENT- 4 PCI TrialASSENT- 4 PCI Trial

Presented atPresented atThe European Society of CardiologyThe European Society of Cardiology

Hot Line Session 2005Hot Line Session 2005

Presented by Dr. Frans Van de WerfPresented by Dr. Frans Van de Werf

www. Clinical trial results.org

Full-dose TNK + Primary PCI60 IU/kg, maximum 4000 IU

n=829GP IIb/IIIa inhibitors allowed only for bail

out use

Full-dose TNK + Primary PCI60 IU/kg, maximum 4000 IU

n=829GP IIb/IIIa inhibitors allowed only for bail

out use

ASSENT- 4 PCI TrialASSENT- 4 PCI TrialASSENT- 4 PCI TrialASSENT- 4 PCI Trial

1667 patients age > 18 years with ST elevation myocardial infarction (summed ST deviation > 6 mm); time from symptom onset within 6 hrs; intent to perform primary PCI

RandomizedMean follow-up: 6 mos (30 days reported to date)

63% of patients received clopidogrel/ticlopidine during PCI Additional UFH was given to 67.4% in the TNK + PCI group and 70.1% in the PCI alone group

1667 patients age > 18 years with ST elevation myocardial infarction (summed ST deviation > 6 mm); time from symptom onset within 6 hrs; intent to perform primary PCI

RandomizedMean follow-up: 6 mos (30 days reported to date)

63% of patients received clopidogrel/ticlopidine during PCI Additional UFH was given to 67.4% in the TNK + PCI group and 70.1% in the PCI alone group

Presented at ESC 2005Presented at ESC 2005

Primary PCI70 IU/kg, no maximum dose

n=838GP IIb/IIIa inhibitors allowed at physician

discretion

Primary PCI70 IU/kg, no maximum dose

n=838GP IIb/IIIa inhibitors allowed at physician

discretion

Primary Endpoint: Composite of death, shock, or congestive heart failure at 90 days. Secondary Endpoint: Composite of death, shock, or congestive heart failure at 30

days; shock or CHF at 90 days; single components of the composite endpoint.

Primary Endpoint: Composite of death, shock, or congestive heart failure at 90 days. Secondary Endpoint: Composite of death, shock, or congestive heart failure at 30

days; shock or CHF at 90 days; single components of the composite endpoint.


ASSENT- 4 PCI Trial: PCIASSENT- 4 PCI Trial: PCIASSENT- 4 PCI Trial: PCIASSENT- 4 PCI Trial: PCI

87.1% 91.1%

0%

20%

40%

60%

80%

100%

TNK + PCI PCI alone

87.1% 91.1%

0%

20%

40%

60%

80%

100%

TNK + PCI PCI alone

Patients undergoing PCIamong two treatment groups (%)

p=0.01

81.3%

19.1%

85.7%

19.7%

0%

20%

40%

60%

80%

100%

With stent DES

TNK + PCI PCI alone

81.3%

19.1%

85.7%

19.7%

0%

20%

40%

60%

80%

100%

With stent DES

TNK + PCI PCI alone

Patients undergoing PCI with stent (%)


p=0.02p=0.02

p=0.97p=0.97

• PCI was performed at a median of 104 minutes following TNK bolus administrationPCI was performed at a median of 104 minutes following TNK bolus administration• Median time from symptom onset to randomization was 140 minutes in the combined Median time from symptom onset to randomization was 140 minutes in the combined therapy group and 135 minutes in the PCI alone grouptherapy group and 135 minutes in the PCI alone group• 19% of patients were randomized in the ambulance19% of patients were randomized in the ambulance


0.2%

9.6%3.0%

50.5%

0%

20%

40%

60%

GP IIb/IIIa inhibitorsprior to PCI

GP IIb/IIIa inhibitorsduring PCI

TNK + PCI PCI alone

0.2%

9.6%3.0%

50.5%

0%

20%

40%

60%

GP IIb/IIIa inhibitorsprior to PCI

GP IIb/IIIa inhibitorsduring PCI

TNK + PCI PCI alone

GP IIb/IIIa inhibitor administration prior to and during PCI (%)

p<0.001p<0.001

p<0.001p<0.001

•GP IIb/IIIa inhibitors were given GP IIb/IIIa inhibitors were given more often prior to PCI in the more often prior to PCI in the PCI alone treatment groupPCI alone treatment group

•GP IIb/IIIa inhibitors were given GP IIb/IIIa inhibitors were given more often during PCI in the more often during PCI in the PCI alone treatment groupPCI alone treatment group

ASSENT- 4 PCI Trial: GP IIb/IIIa InhibitorsASSENT- 4 PCI Trial: GP IIb/IIIa InhibitorsASSENT- 4 PCI Trial: GP IIb/IIIa InhibitorsASSENT- 4 PCI Trial: GP IIb/IIIa Inhibitors

www. Clinical trial results.org Presented at ESC 2005Presented at ESC 2005

ASSENT- 4 PCI Trial: TIMI Flow GradeASSENT- 4 PCI Trial: TIMI Flow GradeASSENT- 4 PCI Trial: TIMI Flow GradeASSENT- 4 PCI Trial: TIMI Flow Grade

43.6%

95.3%

15.0%

97.6%

0%

20%

40%

60%

80%

100%

TFG 3 prior to PCI TFG 2/3 post-PCI

TNK + PCI PCI alone

43.6%

95.3%

15.0%

97.6%

0%

20%

40%

60%

80%

100%

TFG 3 prior to PCI TFG 2/3 post-PCI

TNK + PCI PCI alone

TIMI grade 3 flow prior to PCI and TIMI grade TIMI grade 3 flow prior to PCI and TIMI grade 2/3 flow post-PCI (%)2/3 flow post-PCI (%)

p<0.001p<0.001

•TIMI grade 3 flow prior to PCI TIMI grade 3 flow prior to PCI was present more frequently in was present more frequently in the TNK + PCI arm (43.6% vs the TNK + PCI arm (43.6% vs 15.0%)15.0%)

•TIMI grade 2/3 post-PCI was TIMI grade 2/3 post-PCI was slightly higher in the PCI alone slightly higher in the PCI alone group (95.3% vs 97.6%)group (95.3% vs 97.6%)

p=0.03p=0.03

www. Clinical trial results.org Presented at ESC 2005Presented at ESC 2005

ASSENT- 4 PCI Trial: Abrupt Closure, Re-infarction, ASSENT- 4 PCI Trial: Abrupt Closure, Re-infarction, and Repeat TVRand Repeat TVR

ASSENT- 4 PCI Trial: Abrupt Closure, Re-infarction, ASSENT- 4 PCI Trial: Abrupt Closure, Re-infarction, and Repeat TVRand Repeat TVR

1.9%

4.1% 4.4%

0.1%

1.9%

1.0%

0%

2%

4%

Abruptclosure

Re-infarction Repeat TVR

TNK + PCI PCI alone

1.9%

4.1% 4.4%

0.1%

1.9%

1.0%

0%

2%

4%

Abruptclosure

Re-infarction Repeat TVR

TNK + PCI PCI alone

Analysis of in-hospital abrupt closure, re-Analysis of in-hospital abrupt closure, re-infarction, and repeat TVR (%)infarction, and repeat TVR (%)

p<0.001p<0.001

• In-hospital abrupt closure In-hospital abrupt closure occurred more often in the TNK occurred more often in the TNK + PCI treatment group (1.9% vs + PCI treatment group (1.9% vs 0.1%)0.1%)

• Re-infarction occurred more Re-infarction occurred more often in the TNK + PCI often in the TNK + PCI treatment group (4.1% vs 1.9%)treatment group (4.1% vs 1.9%)

•Repeat TVR occurred more Repeat TVR occurred more often in the TNK + PCR often in the TNK + PCR treatment group (4.4% vs 1.0%)treatment group (4.4% vs 1.0%)

p<0.001p<0.001p=0.01p=0.01

www. Clinical trial results.org Presented at ESC 2005Presented at ESC 2005Presented at ESC 2005Presented at ESC 2005

ASSENT- 4 PCI Trial: Pericarditis, Tamponade, ASSENT- 4 PCI Trial: Pericarditis, Tamponade, and Cardiac Ruptureand Cardiac Rupture

ASSENT- 4 PCI Trial: Pericarditis, Tamponade, ASSENT- 4 PCI Trial: Pericarditis, Tamponade, and Cardiac Ruptureand Cardiac Rupture

0.7%0.6%

0.9%

0.1%

0.4%

0.2%

0.0%

0.5%

1.0%

Pericarditis Tamponade CardiacRupture

TNK + PCI PCI alone

0.7%0.6%

0.9%

0.1%

0.4%

0.2%

0.0%

0.5%

1.0%

Pericarditis Tamponade CardiacRupture

TNK + PCI PCI alone

Analysis of in-hospital pericarditis, tamponade, Analysis of in-hospital pericarditis, tamponade, and cardiac rupture (%)and cardiac rupture (%)

p=0.07p=0.07

• Pericarditis occurred more Pericarditis occurred more often in the TNK + PCI often in the TNK + PCI treatment group (0.7% vs 0.1%)treatment group (0.7% vs 0.1%)

• Presence of tamponade did Presence of tamponade did not differ significantly between not differ significantly between the two treatment groupsthe two treatment groups

•Cardiac rupture occurred more Cardiac rupture occurred more often in the TNK + PCR often in the TNK + PCR treatment group (0.9% vs 0.2%)treatment group (0.9% vs 0.2%)

p=0.11p=0.11

p=0.50p=0.50

www. Clinical trial results.org Presented at ESC 2005Presented at ESC 2005Presented at ESC 2005Presented at ESC 2005

ASSENT- 4 PCI Trial: EM Dissociation, Pulmonary ASSENT- 4 PCI Trial: EM Dissociation, Pulmonary Edema, and VFEdema, and VF

ASSENT- 4 PCI Trial: EM Dissociation, Pulmonary ASSENT- 4 PCI Trial: EM Dissociation, Pulmonary Edema, and VFEdema, and VF

1.7%

3.4%

5.6%

1.0%

3.1%3.7%

0.0%

2.0%

4.0%

6.0%

EMdissociation

Pulmonaryedema

VF

TNK + PCI PCI alone

1.7%

3.4%

5.6%

1.0%

3.1%3.7%

0.0%

2.0%

4.0%

6.0%

EMdissociation

Pulmonaryedema

VF

TNK + PCI PCI alone

Analysis of in-hospital EM dissociation, Analysis of in-hospital EM dissociation, pulmonary edema, and VF (%)pulmonary edema, and VF (%)

p=0.20p=0.20

• Presence of EM dissociation Presence of EM dissociation did not differ significantly did not differ significantly between the two treatment between the two treatment groupsgroups

• Presence of pulmonary edema Presence of pulmonary edema did not differ significantly did not differ significantly between the two treatment between the two treatment groupsgroups

•VF occurred more often in the VF occurred more often in the TNK + PCR treatment group TNK + PCR treatment group (5.6% vs 3.7%)(5.6% vs 3.7%)

p=0.08p=0.08

p=0.78p=0.78


ASSENT- 4 PCI Trial: Mortality at 30 daysASSENT- 4 PCI Trial: Mortality at 30 daysASSENT- 4 PCI Trial: Mortality at 30 daysASSENT- 4 PCI Trial: Mortality at 30 days

6.0%

3.8%

0%

2%

4%

6%

8%

TNK + PCI PCI alone

6.0%

3.8%

0%

2%

4%

6%

8%

TNK + PCI PCI alone

•The primary endpoint of mortality was higher in the TNK + PCI treatment group compared with the PCI alone group (6.0% vs 3.8%, p=0.04) at 30 days

Analysis of mortality at 30 days (%)p = 0.04


n=50n=50 n=32n=32


ASSENT- 4 PCI Trial: Mortality Subgroup AnalysisASSENT- 4 PCI Trial: Mortality Subgroup AnalysisASSENT- 4 PCI Trial: Mortality Subgroup AnalysisASSENT- 4 PCI Trial: Mortality Subgroup Analysis

7.3%

6.0%

3.1%3.8% 4.0% 3.7%

0%

2%

4%

6%

8%

Hospitalswith on-site

PCI

Communityhospitals

Ambulance

TNK + PCI PCI alone

7.3%

6.0%

3.1%3.8% 4.0% 3.7%

0%

2%

4%

6%

8%

Hospitalswith on-site

PCI

Communityhospitals

Ambulance

TNK + PCI PCI alone

•The greatest mortality difference by treatment group was seen in hospitals with on-site PCI (7.3% vs 3.8%), with less difference in community hospitals (6.0% vs 4.0%), and a shift in direction for patients enrolled in the ambulance (3.1% vs 3.7%)

Subgroup analysis of mortality based on site of randomization (%)


n=754n=754 n=588n=588 n=325n=325


ASSENT- 4 PCI Trial: Total Stroke and ICH at 30 daysASSENT- 4 PCI Trial: Total Stroke and ICH at 30 daysASSENT- 4 PCI Trial: Total Stroke and ICH at 30 daysASSENT- 4 PCI Trial: Total Stroke and ICH at 30 days

•Total stroke occurred more often in the TNK + PCI group (1.81% vs 0%), as did ICH (0.97% vs 0%) at 30 days

Analysis of total stroke and ICH at 30 days (%)


1.81%

0.97%

0 00.0%

0.5%

1.0%

1.5%

2.0%

Total stroke ICH

TNK + PCI PCI alone

1.81%

0.97%

0 00.0%

0.5%

1.0%

1.5%

2.0%

Total stroke ICH

TNK + PCI PCI alone

p<0.001p<0.001

p=0.004p=0.004


ASSENT- 4 PCI Trial: Ischemic Stroke, Haemorrhagic ASSENT- 4 PCI Trial: Ischemic Stroke, Haemorrhagic Conversion, and Unclassified Stroke Rates at 30 daysConversion, and Unclassified Stroke Rates at 30 daysASSENT- 4 PCI Trial: Ischemic Stroke, Haemorrhagic ASSENT- 4 PCI Trial: Ischemic Stroke, Haemorrhagic Conversion, and Unclassified Stroke Rates at 30 daysConversion, and Unclassified Stroke Rates at 30 days

•Ischemic stroke occurred more often in the TNK + PCI group (0.60% vs 0%), as did haemorrhagic conversion (0.12% vs 0%) at 30 days

Analysis of ischemic stroke, haemorrhagic conversion, and unclassified stroke rates at 30 days (%)


0.60%

0.12%0.24%

0 0 00.0%

0.5%

1.0%

Ischemic stroke Haemorrhagicconversion

Unclassified

TNK + PCI PCI alone

0.60%

0.12%0.24%

0 0 00.0%

0.5%

1.0%

Ischemic stroke Haemorrhagicconversion

Unclassified

TNK + PCI PCI alone

p=0.03p=0.03

p=0.50p=0.50

p=0.25p=0.25


ASSENT- 4 PCI Trial: Bleeding Events at 30 daysASSENT- 4 PCI Trial: Bleeding Events at 30 daysASSENT- 4 PCI Trial: Bleeding Events at 30 daysASSENT- 4 PCI Trial: Bleeding Events at 30 days

• No difference in the frequency of major bleed existed between the two treatment groups (5.7% vs 4.4%) at 30 days

•The presence of any bleeding event (major + minor bleeding) was more common in the TNK+ PCI treatment group (31.3% vs 23.4%) at 30 days (p<0.001)

Analysis of bleeding events at 30 days (%)


5.7%

31.3%

4.4%

23.4%

0%

10%

20%

30%

Major bleed Any bleeding event

TNK + PCI PCI alone

5.7%

31.3%

4.4%

23.4%

0%

10%

20%

30%

Major bleed Any bleeding event

TNK + PCI PCI alone

p=0.26p=0.26

p<0.001p<0.001


ASSENT- 4 PCI Trial: Transfusions at 30 daysASSENT- 4 PCI Trial: Transfusions at 30 daysASSENT- 4 PCI Trial: Transfusions at 30 daysASSENT- 4 PCI Trial: Transfusions at 30 days

•The percentage of transfusions administered was greater in the TNK + PCI treatment group

•93.8% received no transfusion in the TNK + PCI treatment group; 95.8% received no transfusion in the PCI alone treatment group (p=0.21)

Analysis of transfusions at 30 days (%)


3.8%

2.5%2.7%

1.5%

0%

2%

4%

1-2 units >2 units

TNK + PCI PCI alone

3.8%

2.5%2.7%

1.5%

0%

2%

4%

1-2 units >2 units

TNK + PCI PCI alone


ASSENT- 4 PCI Trial: Comparison with Previous ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients)ASSENT Trials (TNK in MI patients)


• Outcomes in the TNK + PCI treatment group did not differ from previous ASSENT trials

•Outcomes in the PCI alone treatment group showed a significant decrease in percentage of deaths at 30 days

Analysis of 30-day death among other ASSENT trials (%)


6.2% 6.0% 6.0% 6.0%

3.8%

0%

2%

4%

6%

8%

30-day deathASSENT-2 ASSENT-3

ASSENT 3+ ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone

6.2% 6.0% 6.0% 6.0%

3.8%

0%

2%

4%

6%

8%

30-day deathASSENT-2 ASSENT-3


ASSENT-4 PCI Alone




• Outcomes in the TNK + PCI treatment group did not differ from previous ASSENT trials

•Outcomes in the PCI alone treatment group showed a significant decrease in percentage of ICH cases

Analysis of ICH across all ASSENT trials (%)


0.93% 0.93% 0.97% 0.97%

0%0.0%

0.5%

1.0%

1.5%

ICHASSENT-2 ASSENT-3


ASSENT-4 PCI Alone

0.93% 0.93% 0.97% 0.97%

0%0.0%

0.5%

1.0%

1.5%

ICHASSENT-2 ASSENT-3


ASSENT-4 PCI Alone




• Outcomes in the TNK + PCI treatment group did not differ significantly from previous ASSENT trials

•Outcomes in the PCI alone treatment group showed a significant decrease in percentage of total stroke

Analysis of total stroke across all ASSENT trials (%)


1.8% 1.7%1.5%

1.8%

0%0.0%

0.5%

1.0%

1.5%

2.0%

Total strokeASSENT-2 ASSENT-3


ASSENT-4 PCI Alone

1.8% 1.7%1.5%

1.8%

0%0.0%

0.5%

1.0%

1.5%

2.0%

Total strokeASSENT-2 ASSENT-3


ASSENT-4 PCI Alone




• Outcomes in the TNK + PCI treatment group did not differ significantly from previous ASSENT trials

•Outcomes in the PCI alone treatment group showed a significant decrease in percentage of re-infarction cases

Analysis of re-infarction among other ASSENT trials (%)


4.1% 4.2%5.8% 5.2%

2.7%

0%

2%

4%

6%

Re-infarctionASSENT-2 ASSENT-3


ASSENT-4 PCI Alone

4.1% 4.2%5.8% 5.2%

2.7%

0%

2%

4%

6%

Re-infarctionASSENT-2 ASSENT-3


ASSENT-4 PCI Alone




• Outcomes in the TNK + PCI treatment group differed significantly from the ASSENT-3 and ASSENT 3+ Trials results

•Outcomes in the PCI alone treatment group did not differ from the ASSENT-2 Trial, but were more significant in comparison to the ASSENT-3 and ASSENT 3+ Trials

Analysis of major bleed among other ASSENT trials (%)


4.7%

2.2%2.8%

5.7%4.4%

0%

2%

4%

6%

Major bleedASSENT-2 ASSENT-3


ASSENT-4 PCI Alone

4.7%

2.2%2.8%

5.7%4.4%

0%

2%

4%

6%

Major bleedASSENT-2 ASSENT-3


ASSENT-4 PCI Alone


ASSENT- 4 PCI Trial: Comparison with Those in ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI OverviewPrimary-PCI Overview


• Outcomes in the TNK + PCI treatment group did not differ significantly compared with the primary-PCI overview

•Outcomes in the PCI alone treatment group were significantly lower than those in the primary-PCI overview

Analysis of 30-day death among ASSENT-4 and those in the primary-PCI overview (%)


6.0%

3.8%

7.0%

0%

2%

4%

6%

8%

30-day death

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone

Primary-PCI overview

6.0%

3.8%

7.0%

0%

2%

4%

6%

8%

30-day death

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone





• Outcomes in the TNK + PCI treatment group were significantly higher compared with the primary-PCI overview

•Outcomes in the PCI alone treatment group did not differ from the primary-PCI overview

Analysis of ICH among ASSENT-4 and those in the primary-PCI overview (%)


0.97%

0% 0.05%

0.0%

0.5%

1.0%

ICH

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone


0.97%

0% 0.05%

0.0%

0.5%

1.0%

ICH

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone





• Outcomes in the TNK + PCI treatment group were higher compared with the primary-PCI overview

•Outcomes in the PCI alone treatment group were significantly lower compared with the primary-PCI overview

Analysis of total stroke among ASSENT-4 and those in the primary-PCI overview (%)


1.8%

0%

1.1%

0%

1%

2%

Total stroke

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone


1.8%

0%

1.1%

0%

1%

2%

Total stroke

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone





• Outcomes in the TNK + PCI treatment group were higher compared with the primary-PCI overview

•Outcomes in the PCI alone treatment group did not differ with the primary-PCI overview

Analysis of re-infarction among ASSENT-4 and those in the primary-PCI overview (%)


5.2%

2.7% 2.5%

0%

2%

4%

6%

8%

Re-infarction

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone


5.2%

2.7% 2.5%

0%

2%

4%

6%

8%

Re-infarction

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone





• Outcomes in the TNK + PCI treatment group were lower compared with the primary-PCI overview

•Outcomes in the PCI alone treatment group were significantly lower compared with the primary-PCI overview

Analysis of major bleed among ASSENT-4 and those in the primary-PCI overview (%)


5.7%

4.4%

7.0%

0%

2%

4%

6%

8%

Major bleed

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone


5.7%

4.4%

7.0%

0%

2%

4%

6%

8%

Major bleed

ASSENT-4 TNK + PCI

ASSENT-4 PCI Alone



ASSENT- 4 PCI Trial: SummaryASSENT- 4 PCI Trial: SummaryASSENT- 4 PCI Trial: SummaryASSENT- 4 PCI Trial: Summary

• The trial intended to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients.

• Among patients with ST elevation MI intended for primary PCI, administration of full-dose fibrinolytic (TNK) immediately prior to PCI was associated with increased mortality and stroke at 30 days compared with primary PCI alone.

• Primary endpoint data are not yet available.

• Further evaluation of the clinical benefit of fibrinolytics among patients undergoing early PCI for STEMI appears warranted (FINESSE).

• The trial intended to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients.

• Among patients with ST elevation MI intended for primary PCI, administration of full-dose fibrinolytic (TNK) immediately prior to PCI was associated with increased mortality and stroke at 30 days compared with primary PCI alone.

• Primary endpoint data are not yet available.

• Further evaluation of the clinical benefit of fibrinolytics among patients undergoing early PCI for STEMI appears warranted (FINESSE).


the assessment of the safety and efficacy of a new treatment strategy for acute myocardial...

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