ACTIVE-A: Cardiovascular End Points by Treatment Group

End pointClopidogrel, n (%/y)Placebo, n (%/y)Relative risk (95% CI)p
Major vascular events 832 (6.8) 924 (7.6) 0.89 (0.81-0.98) .01
Stroke 296 (2.4) 408 (3.3) 0.72 (0.62-0.83) <.001
MI 90 (0.7) 115 (0.9) 0.78 (0.59-1.03) .08

Strokes of ischemic or unknown origin were reduced significantly, and hemorrhagic stroke was increased, although not significantly.

ACTIVE-A: Strokes by Treatment Group

End pointClopidogrel, n (%/y)Placebo, n (%/y)Relative risk (95% CI)p
All strokes 296 (2.4) 408 (3.3) 0.72 (0.62-0.84) <.001
Ischemic stroke 235 (1.9) 343 (2.8) 0.68 (0.57-0.80) <.001
Hemorrhagic stroke 30 (0.2) 22 (0.2) 1.37 (0.79-2.37) NS

ACTIVE-A: Major Bleeding by Treatment Group

End pointClopidogrel, n (%/y)Placebo, n (%/y)Relative risk (95% CI)p
Major bleeding 251 (2.0) 162 (1.3) 1.57 (1.29-1.92) <.001
Fatal hemorrhage 42 (0.3) 27 (0.2) 1.56 (0.96-2.53) .07

1.The ACTIVE trial is the largest trial performed to date of an antithrombotic therapy in AF, with more than 3 times as many strokes as in any previous trial.

2.In the ACTIVE trial, patients with AF and 1 or more additional risk factors for stroke who were suitable candidates for warfarin therapy were enrolled in ACTIVE-W, a comparison of warfarin vs the combination of clopidogrel and aspirin.

3.Patients with AF and 1 or more additional risk factors for stroke who were deemed unsuitable for warfarin therapy (specific risk factor for bleeding in 23%, physician assessment in 50%, and patient preference in 26%) were enrolled in ACTIVE-A.

4.All participants in ACTIVE-A received aspirin, and they were randomized to also receive clopidogrel (75 mg/day) or placebo.

5.The main study endpoint was a composite of major vascular events (stroke, MI, CNS systemic embolism, or death from vascular causes).

6.There were 7554 participants from 580 centers in 33 countries.

7.Median follow-up was 3.6 years.

8.Use of the combination of clopidogrel and aspirin was linked with an 11% reduction in the primary outcome (P = .01), largely due to a 28% reduction in stroke (P < .001).

9.There was a significant reduction in strokes of ischemic or unknown origin.

10.Clopidogrel had a similar effect on both disabling and fatal vs nondisabling strokes. About 65% of all strokes in ACTIVE-A were disabling.

11.There was a nonsignificant trend to reduction in MI with clopidogrel plus aspirin.

12.The combination of clopidogrel and aspirin was not associated with any reduction in vascular death or in non-CNS systemic embolism vs placebo.

13.The number of hemorrhagic strokes was increased with clopidogrel and aspirin, but this was not significant.

14.With clopidogrel, there were 26 fewer fatal ischemic strokes, and 3 more fatal hemorrhagic strokes, for a net reduction of 23 fatal strokes.

15.With clopidogrel, the rate of major bleeding was significantly increased from 1.3% to 2.0% per year, and there were significant increases in intracranial and extracranial bleeding.

16.There was also a trend to increased fatal bleeding that did not reach statistical significance.

 

Pearls for Practice

 

  • In patients with AF who cannot take warfarin, the combination of clopidogrel and aspirin was associated with a reduction in major vascular events, particularly stroke, vs placebo. A risk benefit analysis indicates that among 1000 of AF patients treated for 3 years, 28 strokes, of which 17 would be fatal or disabling, and 6 MIs would be prevented.

 

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