Risk of bolus thrombolytics

1
Risk of bolus thrombolytics
Shamir Mehta, MD Director, Coronary Care
Unit McMaster University Medical Center Hamilton,
Ontario Paul Armstrong, MD Professor of
Medicine University of Alberta Hospital Edmonton,
Alberta
2
Background
Risk of bolus lytics

• Despite promising phase II studies, no bolus
  thrombolytic agent has demonstrated superior
  efficacy (reduced death/MI) compared with either
  TPA or SK
• These agents have been aggressively marketed as
  being more convenient, despite no data showing
  that this impacts on clinical outcomes
• In the absence of efficacy, safety becomes
  critically important because there is no
  risk/benefit ratio to consider

-Mehta
3
Intracranial hemorrhage
Risk of bolus lytics

• Most feared complication of thrombolytic therapy
• A complication of treatment rather than of the
  underlying disease process
• Usually a risk-benefit tradeoff
• (TPA vs SK in GUSTO 1)
• No single bolus thrombolytic trial was adequately
  powered to detect a 30 excess in ICH.

-Mehta
4
Risk of bolus lytics
Power to detect ICH

• To detect a 30 excess in ICH
• Assume ICH rate of 1
• 2 groups, 11 randomization, 90 power

More than 50,000 patients would be required in a
single trial to reliably detect a 30 excess in
ICH
-Mehta
5
Increased peak blood levels of bolus agents
Risk of bolus lytics
Plasma concentration (ng/ml)
Time (Minutes)
Cannon et al. Circulation 1998982805-14
6
Risk of bolus lytics
Trials of bolus vs infusion thrombolytics
Mehta et al. Lancet 2000356449-54
7
Bolus vs infusion overall results
Risk of bolus lytics
Mehta et al. Lancet 2000356449-54
8
ICH bolus vs infusion
Risk of bolus lytics
N103,972
Study
OR
95 CI
ISIS-3
1.25
0.93
-
1.68
INJECT
2.03
1.04
-
3.99
COBALT
1.38
0.86
-
2.22
GUSTO-III
1.04
0.72
-
1.49
BIRD
1.01
0.50
-
3.23
ASSENT-2
0.99
0.72
-
1.35
InTIME-II
1.72
1.22
-
2.44
1.25
1.08
-
1.45
Total
0.0
1.0
2.0
3.0
4.0
Odds Ratio
Bolus better
Infusion better
Mehta et al. Lancet 2000356449-54
9
Conclusions Mehta
Risk of bolus lytics

• Bolus thrombolytic agents are not associated
  with an efficacy advantage in terms of reduced
  death or reinfarction, but are associated with an
  increase in intracranial hemorrhage
• Physicians and policy makers should be informed
  about this excess risk when making therapeutic
  decisions regarding choice of thrombolytic agent

10
False alarm
Risk of bolus lytics

• Dr Mehta and his colleagues... have raised a
  false alarm about the use of bolus fibrinolysis
  based on what appears to be a statistical collage
  that obscures some facts.
• Paul Armstrong
• Professor of Medicine
• University of Alberta Hospital
• Edmonton, Alberta

11
Questions for debate
Risk of bolus lytics
Why would one move to bolus thrombolysis? Are the
properties of the fibrinolytics relevant? Is the
dose relevant? Is the adjunctive therapy relevant?
-Armstrong
12
ISIS 3 APSAC comparison revisited
Risk of bolus lytics
-Armstrong
13
rPA and TNK vs t-PA
Risk of bolus lytics
OR (95 CI)
GUSTO III ASSENT II Combined
1.039 (0.722-1.495) 0.991 (0.725-1.354) 1.011
(0.796-1.285)
.25
1
4
odds ratio for ICH relative to tPA
-Armstrong
14
Risk of bolus lytics
Conclusions Armstrong
rPA and TNK vs TPA Frequency or likelihood of an
ICH is essentially identical rPA and TNK, which
are in general use, are safe, effective, and
provide important advantages
15
ICH in bolus vs infusion therapy
Risk of bolus lytics
Excluding ISIS-3
Bolus better
Infusion better
1.25
2
-0.5
1.5
1
Log Odds Ratio
Mehta et al. Lancet 20003561850
16
ICH in bolus vs infusion therapy
Risk of bolus lytics
Versus alteplase
Bolus better
Infusion better
1.22
2
-0.5
1.5
1
Log Odds Ratio
Mehta et al. Lancet 20003561850
17
ICH in bolus vs infusion therapy
Risk of bolus lytics
Versus streptokinase
Bolus better
Infusion better
2.19
3
2
-0.5
1.5
1
Log Odds Ratio
Mehta et al. Lancet 20003561850
18
ICH in bolus vs infusion therapy
Risk of bolus lytics
Bolus better
Infusion better
1.75
Same/similar agent
P0.0001
1.25
Newer thrombolytic agent
P0.02
2
-0.5
1.5
1
Log Odds Ratio
Mehta et al. Lancet 2000356449-54
19
Heparin dosing
Risk of bolus lytics

• The same doses of UFH were included in the 2
  groups in all 7 trials in the meta-analysis
• Any reduction in ICH would be observed in both
  groups, and the relative difference is likely to
  be maintained
• There is little randomized data confirming that
  efficacy is maintained with lower heparin dosing
• Clinical implications of medication errors have
  not been adequately addressed

-Mehta
20
InTIME-II
Risk of bolus lytics

• The study was overdosed (120 KU.kg-1)
• There is a drug-drug interaction with a clear and
  excess partial thromboplastin time for 6 hrs
  after therapy
• Lowering heparin lowered ICH rate in both arms

-Armstrong
21
Effect of heparin
Risk of bolus lytics

• ICH Rate
• InTIME II
• infusion alteplase 0.62
• bolus lanoteplase 1.12
• ASSENT II
• infusion alteplase 0.94
• bolus tenecteplase 0.93

InTIME II investigators, Eur Heart J 2000212005
22
Perseveration on statistics
Risk of bolus lytics

• The perseveration around the statistics without
  consideration of the unique aspects of the
  components of dose and adjunctive therapy and how
  modifications in that therapy modify the result
  fails to take into account the realities.
• Paul Armstrong
• Professor of Medicine
• University of Alberta Hospital
• Edmonton, Alberta

23
Fibrin specificity
Risk of bolus lytics

• In GUSTO I, ISIS-3, and INJECT the agent with the
  greater higher specificity was associated with
  higher intracranial hemorrhage
• No reason to believe different in InTIME-II

-Mehta
24
Recommendations for practice
Risk of bolus lytics

• The meta-analysis was designed to inform
  clinicians, not to dictate clinical practice
• Physicians must know the data in order to weigh
  risk/benefits and make reasonable clinical
  decisions that benefit patients

-Mehta
25
Final comments Armstrong
Risk of bolus lytics

• Must look on both sides of the confidence limits
• Bolus agents are different and influenced by
  adjunctive therapy.
• Bolus agents have helped move to earlier therapy
  and improved time to treatment
• Awaiting results from studies of bolus therapy in
  conjunction with GP IIb/IIIa inhibitors

26
Final comments Mehta
Risk of bolus lytics

• Looking forward to the results of pre-hospital
  treatment of AMI
• Also awaiting GP IIb/IIIa inhibitors plus reduced
  dose bolus thrombolytics
• Despite the money and effort, bolus thrombolytics
  have not yet shown a clear superiority