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


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


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


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


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)


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)



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


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)


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).


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)


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)



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)



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


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


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


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


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


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


• 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*



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


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


% (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


Lancet 1999; 354: 708-15

FRISC IIFRISC II


• 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


• 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.

Documents

FRagmin® and Fast Revascularization during InStablity in Coronary artery disease FRISC II