FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease LONGTERM

1
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease -
LONG-TERM HEPARIN -

• Purpose
• To assess efficacy of long-term treatment with
  the low molecular mass heparin dalteparin, in
  non-invasive treatment strategy for unstable
  coronary artery disease
• Reference
• FRISC II Investigators. Long-term
  low-molecular-mass heparin in unstable
  coronary-artery disease FRISC II prospective
  randomised multicentre study. Lancet
  19993547017.

2
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease -
LONG-TERM HEPARIN TRIAL DESIGN -

• Design
• Randomized, multicenter, double-blind,
  placebo-controlled non-invasive arm of trial
  also investigating invasive treatment
• Patient selection
• Hospitalized with ischemia symptoms for lt48 h
  before start of heparin/dalteparin increasing or
  at rest (chest pain with ST depression, T
  inversion or raised biochemical markers)
• Pre-randomization therapy
• Aspirin 300600 mg b-blockade unless
  contraindicated organic nitrates, Ca
  antagonists as required statins, ACE inhibitors,
  aggressive antidiabetic treatment according to
  guidelines
• Dalteparin 120 U/kg every 12 h or infusion of
  standard heparin

3
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease -
LONG-TERM HEPARIN TRIAL DESIGN cont. -

• Randomization
• Up to 72h after start of open-label dalteparin,
  patients randomized to
• early invasive or non-invasive treatment (in
  absence of contraindications for invasive
  treatment) or
• dalteparin or placebo for 90 days (all patients)
• All patients received open-label dalteparin 120
  U/kg every 12h for at least 5 days until
• non-invasive double-blind dalteparin/placebo
  treatment started or
• revascularization and double-blind
  dalteparin/placebo started

4
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease -
LONG-TERM HEPARIN TRIAL DESIGN cont. -

• Patients
• 2267 (median age 67 years) entered long-term
  heparin vs. placebo arm
• Follow up and primary endpoint
• Primary endpoint death or MI at 30 days
• Treatment
• Dalteparin 5000 (women lt80 kg, men lt70 kg) or
  7000 U SC twice daily or placebo for 90 days

5
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease-
LONG-TERM HEPARIN RESULTS -

• For double-blind period
• Decrease in death or MI significant at 30 days
  but not at 3 months
• For total treatment period
• Significant decrease at 3 months in triple
  endpoint of MI, death or revascularization for
  total cohort but this benefit not carried over to
  end of 6 months
• Subgroups
• Patients with raised troponin-T at entry showed
  30 relative (2.7 absolute) decrease in MI or
  death at 3 months (P0.07) this effect not seen
  in patients with normal troponin T

6
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease-
LONG-TERM HEPARIN RESULTS cont. -
Death or MI during double-blind and total
treatment period
0.14
Probability of death, MI or revascularization
Placebo
0.12
Total
Dalteparin
treatment
0.10
period
0.08
Double-blind
period
0.06
0.04
0.02
0
0
10
20
40
50
60
70
30
90
80
Days after start of treatment
FRISC II Investigators.
Lancet
1999
354
701

7.
7
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease -
LONG-TERM HEPARIN RESULTS cont. -
Triple outcome death, MI or revascularization
0.40
Probability of death, MI or revascularization
Placebo
Dalteparin
0.30
0.20
0.10
0
0
10
20
30
50
60
70
90
40
80
Days after start of open-label dalteparin
FRISC II Investigators.
Lancet
1999
354
701

7.
8
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease-
LONG-TERM HEPARIN RESULTS cont. -
9
FRISC II Fragmin and fast Revascularization
during InStability in Coronary artery disease-
LONG-TERM HEPARIN SUMMARY -

• Dalteparin lowers risk of death, MI and the need
  for revascularization during the first month
• Initial benefits not sustained during longer term
  follow up within non-invasive treatment strategy