COUMADIN (Page 7 of 9)

14.2 Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
Patients Treated With
Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin
Event
py=patient years

Thromboembolism

2.2/100 py

8.6/100 py

7.9/100 py

Major Bleeding

2.5/100 py

0.0/100 py

0.9/100 py

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
Event Moderate Warfarin TherapyINR 2.65 High Intensity Warfarin TherapyINR 9.0
py=patient years

Thromboembolism

4.0/100 py

3.7/100 py

Major Bleeding

0.95/100 py

2.1/100 py

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

14.3 Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7.

Table 7: WARIS – Endpoint Analysis of Separate Events
Event Warfarin(N=607) Placebo(N=607) RR(95% CI) % RiskReduction(p -value)
RR=Relative risk; Risk reduction=(1 — RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years

Total Patient Years of Follow-up

2018

1944

Total Mortality

94 (4.7/100 py)

123 (6.3/100 py)

0.76 (0.60, 0.97)

24 (p=0.030)

Vascular Death

82 (4.1/100 py)

105 (5.4/100 py)

0.78 (0.60, 1.02)

22 (p=0.068)

Recurrent MI

82 (4.1/100 py)

124 (6.4/100 py)

0.66 (0.51, 0.85)

34 (p=0.001)

Cerebrovascular Event

20 (1.0/100 py)

44 (2.3/100 py)

0.46 (0.28, 0.75)

54 (p=0.002)

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group
Event Aspirin(N=1206) Warfarin(N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p -value
a Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.b The rate ratio is for aspirin plus warfarin as compared with aspirin.c The rate ratio is for warfarin as compared with aspirin.d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.e Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.CI=confidence intervalND=not determined

No. of Events

Major Bleedinga

8

33

28

3.35b (ND) 4.00c (ND)

NDND

Minor Bleedingd

39

103

133

3.21b (ND)2.55c (ND)

NDND

Composite Endpointse

241

203

181

0.81 (0.69-0.95)b 0.71 (0.60-0.83)c

0.030.001

Reinfarction

117

90

69

0.56 (0.41-0.78)b 0.74 (0.55-0.98)c

<0.0010.03

Thromboembolic Stroke

32

17

17

0.52 (0.28-0.98)b 0.52 (0.28-0.97)c

0.030.03

Death

92

96

95

0.82

There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

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