FRagmin® and Fast Revascularization during InStablity in Coronary artery disease FRISC II.
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Transcript of FRagmin® and Fast Revascularization during InStablity in Coronary artery disease FRISC II.
FRFRagmin® and Fast Revascularization agmin® and Fast Revascularization during during IInnSStablity in tablity in
CCoronary artery diseaseoronary artery disease
FRISC IIFRISC II
FRISC IIFRISC II
Trial DesignTrial Design
• Assessment of the efficacy of long-term treatment with Fragmin® vs. placebo in patients managed with a non-invasive treatment strategy
– Enrolled 2276 patients with unstable coronary artery disease
– Patients recruited from June, 1996 - August 1998– 58 Scandinavian Centers– Randomized– Double Blind– Placebo Controlled– Intention to Treat Analysis
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Study Design for Primary ObjectiveStudy Design for Primary ObjectiveFragmin vs. Placebo in Non-Invasive ArmsFragmin vs. Placebo in Non-Invasive Arms
* Randomized to Invasive or Non-Invasive Strategy within 72 hours of enrollment† Randomized to receive placebo or Fragmin® for 3 months
1 Endpoint Death or MI at
3 Months:Both Fragmin® arms
compared to Both Placebo Arms
UCAD Patients w/ symptoms < 48 hours eligible for revascularization, but randomized to a Non-Invasive
Strategy arm*
All Patients receive Fragmin® for 5 to 7
days in the open acute phase after enrollment
UCAD Patients w/ symptoms< 48 hours contraindicated to
revascularization
Fragmin® s.c. twice daily for 3 months (n=1049)
Placebo s.c. twice daily for 3 months
(n=1056)
†
†
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Primary ObjectivesPrimary Objectives
In patients treated with a non-invasive strategy (randomized to non-invasive or contraindicated to an early invasive strategy):
– Compare the prolonged treatment (after open Fragmin s.c. 120 IU/kg/12h - maximal dose 10,000 IU/12h - during the acute phase) for three months using either Fragmin® or placebo s.c. twice daily concerning the:
• incidence of death or MI – (1 Endpoint of D/MI at 3 months)
• need for revascularization• bleeding
Fragmin vs. Placebo in Non-Invasive ArmsFragmin vs. Placebo in Non-Invasive Arms
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Randomization for Primary ObjectiveRandomization for Primary Objective
• Open acute treatment phase– Open Fragmin® 120 IU/kg twice daily for 5 to 7 days
(median duration of open-label Fragmin® treatment was 6 days)
• Patients should be randomized within 72 hours of this treatment
• Day 1 is the start of the double blind prolonged Fragmin® or placebo phase
Fragmin vs. Placebo in Non-Invasive ArmsFragmin vs. Placebo in Non-Invasive Arms
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Randomization for Primary Objective (cont.)Randomization for Primary Objective (cont.)
• Placebo controlled double-blind phase– All patients randomized to Fragmin® or Placebo – Fragmin® or Placebo given s.c. twice daily for 90 days.
• Median treatment duration was similar for Fragmin® and placebo (87 and 88 days respectively)• Gender and Weight Dose Stratification
• Men > 70 kg 7500 IU, < 70 kg 5000 IU • Women > 80 kg 7500 IU, < 80 kg 5000 IU
Fragmin vs. Placebo in Non-Invasive ArmsFragmin vs. Placebo in Non-Invasive Arms
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Inclusion CriteriaInclusion Criteria
• Men > 40 years or women postmenopausal > 12 months
• Last episode of pain < 48 hours before open Fragmin®
• Signs of myocardial ischemia or developing non-Q-MI– ST-depression or T-wave inversion– Available biochemical marker above normal range
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Baseline CharacteristicsBaseline Characteristics
Variable Fragmin Placebo(n=1049) (n=1056)
Age median 67 years 67 yearsMen 68% 69%Hypertension 33% 33%Diabetes mellitus 14% 12%Previous MI 30% 27%Chest pain at rest 82% 80%ST-depression at entry 46% 50%Troponin-T > 0.1 ng/ml 57% (n=574) 60% (n=611)
Fragmin vs PlaceboFragmin vs Placebo
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Important Exclusion CriteriaImportant Exclusion Criteria
• Increased risk of bleeding
• Thrombolysis indication or administered within last 24 hours
• PTCA within the last 6 months
• Waiting for coronary angiogram or revascularization
• Other severe illness
• Anticipated problems of cooperation
Fragmin vs PlaceboFragmin vs Placebo
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Contraindication to Early RevascularizationContraindication to Early Revascularization
Only randomized to Fragmin® or Placebo
• Previous open heart surgery
• Advanced age (> 75 years)
• Other concomitant disease or condition that makes early revascularization inappropriate
Fragmin vs PlaceboFragmin vs Placebo
Lancet 1999; 354: 701-07
Primary Endpoint and Components at 90 days Primary Endpoint and Components at 90 days (during Double - Blind Phase)(during Double - Blind Phase)
Fragmin vs PlaceboFragmin vs Placebo
FRISC II- FRISC II- (Preliminary Data)(Preliminary Data)
8.0
1.6 1.5
6.7
1.3 0.9
0.0
2.0
4.0
6.0
8.0
10.0
Death or MI Death Cardiac Death
% o
f Pat
ient
s
Placebo (n=1056) Fragmin (n=1049)
p=0.17
Lancet 1999; 354: 701-07
Death or MI at 30 and 90 daysDeath or MI at 30 and 90 days(during Double - Blind Phase)(during Double - Blind Phase)
Fragmin vs PlaceboFragmin vs Placebo
FRISC II- FRISC II- (Preliminary Data)(Preliminary Data)
5.9
8.0
3.1
6.7
0.0
2.0
4.0
6.0
8.0
10.0
Death or MI (30 days) Death or MI (90 days)
% o
f Pat
ient
s
Placebo (n=1056) Fragmin (n=1049)
p=0.002
p=0.17
47%
Lancet 1999; 354: 701-07
16%
Results during Double-Blind PhaseResults during Double-Blind Phase(Death or MI)(Death or MI)
Fragmin vs PlaceboFragmin vs Placebo
Time Fragmin Placebo RR (95% CI) p90 days 6.7% 8.0% 0.82 (0.60-1.10) 0.1730 days 3.1% 5.9% 0.53 (0.35-0.80) 0.002
There was a 47% reduction in Death or MI at 30 days with Fragmin compared to placebo which was highly significant ( p = 0.002).
However, there was not a significant reduction in events at 90 days (primary endpoint).
FRISC II- FRISC II- (Preliminary Data)(Preliminary Data)
Lancet 1999; 354: 701-07
FRISC IIFRISC II
Time Fragmin Placebo RR (95% CI) p90 days 6.7% 8.0% 0.81 (0.60-1.10) 0.1730 days 3.1% 5.9% 0.53 (0.35-0.80) 0.002
Death or MI at 90 Days (during DB Phase) Death or MI at 90 Days (during DB Phase)
Lancet 1999; 354: 701-07
p=0.002
p=0.17
Death or MI through 1, 3 and 6 Months Death or MI through 1, 3 and 6 Months (including open acute phase)(including open acute phase)
Fragmin vs PlaceboFragmin vs Placebo
FRISC II -FRISC II -
8.411.2
13.1
6.2
10.0
13.3
0.0
5.0
10.0
15.0
20.0
30 Day D/MI 3 Month D/MI 6 Month D/MI
% o
f Pat
ient
s
Placebo Fragmin
p=0.048
Lancet 1999; 354: 701-07
p=0.34 p=0.93
n= 1121 1129 n= 1103 1115n= 1121 1129
D/MI or Revascularization through 1, 3, or D/MI or Revascularization through 1, 3, or 6 Months (including open acute phase)6 Months (including open acute phase)
Fragmin vs PlaceboFragmin vs Placebo
FRISC II -FRISC II -
25.7
33.439.9
19.5
29.1
38.4
0.0
10.0
20.0
30.0
40.0
50.0
30 Day Events 3 Month Events 6 Month Events
% o
f Pat
ient
s
Placebo Fragmin
p=0.001
Lancet 1999; 354: 701-07
p=0.031 p=0.50
n= 1121 1129 n= 1103 1115n= 1121 1129
30 Day Death or MI based on Troponin Status 30 Day Death or MI based on Troponin Status (during Double - Blind Phase)(during Double - Blind Phase)
Fragmin vs PlaceboFragmin vs Placebo
FRISC II -FRISC II -
6.4
9.3
6.1 6.4
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Troponin < 0.1 ng/ml Troponin > 0.1 ng/ml
% o
f Pat
ient
s
Placebo (n=1056) Fragmin (n=1049)
p=NSp=0.07
Lancet 1999; 354: 701-07
30%
n= 574 611 n= 425 404
FRISC IIFRISC II
Adverse EventsAdverse EventsFragmin vs Placebo (Double-Blind Treatment Period)Fragmin vs Placebo (Double-Blind Treatment Period)
Variable Fragmin Placebo n=1049 n=1056
Major 3.3% 1.5%Minor 23.0% 8.4% Stroke total 1.0% 0.8%
Hemmorhagic 0.8% 0.0%Other Stroke 0.2% 0.8%
Thrombocytopenia (<100K) 0.0% 0.5%Allergic Reactions 2.3% 1.8%
Lancet 1999; 354: 701-07
FRISC IIFRISC II
ConclusionsConclusionsIn UCAD patients, treatment with Fragmin® in addition to
aspirin and anti-anginal treatment:
• Significantly reduced cardiac events (D/MI) by 47% (p=0.002) through 30 days. However, the primary endpoint (reduction in 90 day D/MI) was not significant.
• Significantly reduced D/MI/Revascularization at 30 and 90 days.
• Allows time for planning of invasive procedures.
• Shows comparable risk of bleeding to placebo
• Troponin-T positive (> 0.01 ng/ml) patients had a 30% reduction in D/MI at 90 days if they were randomized to Fragmin (p=0.07).
Lancet 1999; 354: 701-07
Fragmin® and Fragmin® and FFast ast RRevascularization evascularization during during IInnSStablity in tablity in
CCoronary artery diseaseoronary artery disease
FRISC IIFRISC II
FRISC IIFRISC II
Trial DesignTrial Design
• Compare an early invasive with a non-invasive treatment strategy in patients with unstable coronary artery disease
– Enrolled 2457 patients with unstable coronary artery disease
– Patients recruited from June, 1996 - May 1998– 58 Scandinavian Centers– Randomized– Double Blind– Placebo Controlled– Intention to Treat Analysis
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Study Design for Secondary ObjectiveStudy Design for Secondary Objective
* Randomized to Invasive or Non-Invasive Strategy within 72 hours of enrollment† Randomized to receive placebo or Fragmin® for 3 months
1 Endpoint of Death or MI
Measured at 6 Months:
Both Invasive arms compared to Both Non-Invasive Arms
UCAD Patients w/ symptoms < 48 hours
eligible for revascularization*
All Patients receive Fragmin® for 5 to 7
days in the open acute phase after enrollment
Invasive StrategyPCI or CABG within 7 days †
(n=1222)
Stepwise Selective (Non-Invasive) Revascularization Strategy † ‡
(n=1235)
Fragmin® or Placebo s.c twice daily
Fragmin® or Placebo s.c twice daily
for 3 months
for 3 months
‡ PCI or CABG only if driven by refractory clinical symptoms
Invasive vs. Non-InvasiveInvasive vs. Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Secondary ObjectivesSecondary Objectives
In patients eligible for an early invasive strategy:– Compare a direct invasive approach with early coronary
angiography and revascularization (invasive) vs. a stepwise selective approach with coronary angiography and revascularization only if driven by refractory clinical symptoms (non-invasive) concerning:• death or MI
– (1 Endpoint for this phase is D/MI at 6 months)• revascularization• bleeding
Invasive vs. Non-InvasiveInvasive vs. Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Baseline CharacteristicsBaseline Characteristics
Variable Invasive Non-invasive (n=1222) (n=1235)
Age median 66 years 65 yearsMen 71% 68%Hypertension 30% 31%Diabetes mellitus 13% 12%Previous MI 23% 22%ST-depression at entry 45% 46%Troponin-T > 0.1 ng/ml 57% 58%LVEF < 45% 14% 12%
Invasive vs Non-InvasiveInvasive vs Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Coronary Procedures by ArmsCoronary Procedures by Arms
Variable Invasive Non-invasive (n=1222) (n=1235)
Coronary Angiography 98% 47% Time to Angiography 4 days 17 daysPCI n (%) 522 (43%) 220 (18%) Time to PCI 4 days 16.5 days
Stents 61% 70%Abciximab 10% 10%
CABG n (%) 430 (35%) 233 (19%) Time to CABG 7 days 28 days
Invasive vs Non-InvasiveInvasive vs Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Important Exclusion CriteriaImportant Exclusion Criteria
• Increased risk of bleeding
• Thrombolysis indication or administered within the last 24 hours
• PTCA within the last 6 months
• Waiting for coronary angiogram/revascularization
• Contraindication to early revascularization– Previous open heart surgery– Advanced age (> 75 years)– Other severe disease
Invasive vs Non-InvasiveInvasive vs Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Randomization for Secondary ObjectiveRandomization for Secondary ObjectiveInvasive vs Non-InvasiveInvasive vs Non-Invasive
• Open acute treatment phase– All patients were administered open Fragmin® 120 IU/kg twice daily for 5 to 7 days
• Patients should be randomized within 72 hours of this treatment• Day 1 is the start of the open acute treatment phase
Lancet 1999; 354: 708-15
FRISC IIFRISC II
Randomization for Secondary Objective (cont.)Randomization for Secondary Objective (cont.)
• Invasive direct strategy– Coronary angiogram/revascularization < 7 days in all patients– PCI/CABG at > 70% stenosis in major coronary arteries:
• PTCA preferred for 1-2 vessel disease• CABG preferred for 3 vessel or left main disease
Invasive vs Non-InvasiveInvasive vs Non-Invasive
• Non-invasive selective strategy– Coronary angiography and revascularization only at :
• recurring or incapacitating symptoms or• severe ischemia at exercise test
Patients without contra-indications to an early invasive strategy are randomized to either an:
Lancet 1999; 354: 708-15
Primary Endpoint: Primary Endpoint: Death or MI at 6 months*Death or MI at 6 months*
Invasive vs. Non-InvasiveInvasive vs. Non-Invasive
FRISC II -FRISC II -
12.1
9.4
0.0
5.0
10.0
15.0
Death or MI
% o
f Pat
ient
s
Non-Invasive (n=1226) Invasive (n=1207)
22 % p=0.031
* Does not include patients contraindicated to revascularizationLancet 1999; 354: 708-15
FRISC IIFRISC II
Death or MI at 6 months (inv vs non-inv)Death or MI at 6 months (inv vs non-inv)Patients Eligible for RevascularizationPatients Eligible for Revascularization
Lancet 1999; 354: 708-15
p=0.031
FRISC IIFRISC II
Death and MI through 6 monthsDeath and MI through 6 monthsPatients Eligible for RevascularizationPatients Eligible for Revascularization
Lancet 1999; 354: 708-15
p=0.045 p=0.10
FRISC IIFRISC II
Death or MI at 6 months*Death or MI at 6 months*
* Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15
6 Months Death or MI by Gender*6 Months Death or MI by Gender*Invasive vs. Non-InvasiveInvasive vs. Non-Invasive
FRISC II- FRISC II- (Preliminary Data)(Preliminary Data)
13.9
8.38.910.5
0.0
5.0
10.0
15.0
20.0
Male Female
% o
f Pat
ient
s
Non-Invasive Invasive
RR 1.26 (0.80-1.97)
21%
RR 0.64 (0.49-0.84)
36%
n= 828 863 n= 398 344
* Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15
FRISC IIFRISC II
Adverse EventsAdverse EventsInvasive vs Non-InvasiveInvasive vs Non-Invasive
Variable Invasive Non-invasive (n=1222) (n=1235)
% (n) % (n)Major Bleeding 1.6% (19) 0.7% (9) Minor Bleeding 7.6% (93) 5.8% (72)Total Stroke 0.2% (2) 0.2% (3)
Thrombocytopenia (<100K) 0.1% (1) 0.1% (1)
* Does not include patients contraindicated to revascularizationLancet 1999; 354: 708-15
FRISC IIFRISC II
ConclusionsConclusions
In unstable angina/non Q wave MI patients, the early invasive strategy:
• Reduces the incidence of 6 month death or MI by 22% (p=0.031)– reduced the incidence of 6 month death or MI in men by
36%; RR 0.53 (0.45-0.65)– increased the incidence of 6 month death or MI in women
by 21%; RR 1.26 (0.80-1.97)
• Reduces symptoms of angina
• Reduces re-admissions and late procedures
Invasive vs Non-InvasiveInvasive vs Non-Invasive
Lancet 1999; 354: 708-15
FRISC IIFRISC II
ConclusionsConclusions
• Early revascularization reduced the incidence of 6 month death or MI by 22% compared with a stepwise selective revascularization strategy:
– Only 10% of all patients received abciximab. “The increasing use of abciximab in association with percutaneous coronary intervention and stenting will lower the rate of events related to percutaneous coronary interventions by 50%”
– The superiority of an early invasive approach in reducing death or MI through 6 months was driven by a 36% reduction in men. Female patients had a non-significant increase in 6 month death or MI with an early invasive approach compared to a non-invasive strategy.
Lancet 1999; 354: 708-15
In unstable angina/non Q wave MI patients
FRISC IIFRISC II
ConclusionsConclusions
• Female patients may benefit from a non-invasive treatment strategy compared to an early invasive strategy.
– In female patients treated with a non-invasive treatment strategy, long-term anti-thrombotic treatment with Fragmin® reduced death or MI by 23% through 90 days.
In unstable angina/non Q wave MI patients receiving a non-invasive treatment strategy:
• Troponin-T + (> 0.1g/ml) patients receiving a non-invasive treatment strategy had a trend in the reduction of death and MI through 90 days when treated with long-term Fragmin® compared to placebo (9.3% vs. 6.6%; p=0.07).
• Long-term anti-thrombotic treatment with Fragmin® reduces death or MI by 47% through 30 days which isuseful if early interventional procedures are inappropriate.