Background-Patients with acute ischemic syndromes (AIS) suffer high ra
tes of recurrent ischemic events despite aspirin treatment. Long-term
therapy with oral anticoagulants in addition to aspirin may reduce thi
s risk. We studied the effects of long-term warfarin at 2 intensities
in patients with AIS without ST elevation in 2 consecutive randomized
controlled studies. Methods and Results-In phase 1, after the cessatio
n of 3 days of intravenous antithrombotic therapy, 309 patients were r
andomized to receive fixed low-dose (3 mg/d) warfarin for 6 months tha
t produced a mean international normalized ratio (INR) of 1.5+/-0.6 or
to standard therapy. Eighty-seven percent of patients received aspiri
n in both groups. The rates of cardiovascular (CV) death, new myocardi
al infarction (MI), and refractory angina at 6 months were 6.5% in the
warfarin group and 3.9% in the standard therapy group (relative risk
[RR], 1.66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI,
and stroke were 6.5% in the warfarin group and 2.6% in the standard t
herapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rat
e of rehospitalization for unstable angina was 21% and did not differ
significantly between the groups. Four patients in the warfarin group
(2.6%) and none in the control group experienced a major bleed (RR, 2.
48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor
bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.
93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 p
atients were randomized <48 hours from the onset of symptoms to receiv
e warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 o
r standard therapy for 3 months. Eighty-five percent received aspirin
in both groups. The rates of CV death, new MI, and refractory angina a
t 3 months were 5.1% in the warfarin group and 12.1% in the standard g
roup (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death,
new MT, and stroke were 5.1% in the warfarin group and 13.1% in the s
tandard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Signif
icantly fewer patients were rehospitalized for unstable angina in the
warfarin group than in the control group (7.1% and 17.2%, respectively
; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfari
n group and 1 in the control group experienced a major bleed, and ther
e was a significant excess of minor bleeds in the warfarin group (28.6
% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.001). Conclusions-
Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5)
plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin a
ppears to reduce the rate of recurrent ischemic events in patients wit
h AIS without ST elevation.