Anticoagulation Increases Risk of Stroke, Death in the Absence of Atrial Fibrillation
Source: Stroke prevention in reversible ischemia trial (SPIRIT) study group. Randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857-865.
It has been a fairly common practice among physicians, particularly internists or general practitioners, to use anticoagulants as a preventor of secondary stroke, especially following minor attacks or TIAs. This Dutch study examines the value of this practice compared to aspirin alone. The investigators projected their statistical positive end point as a 24% benefit in a target of 3000 affected patients to be followed for an average 2.9 years. Pre-analysis was to be conducted in five successive cohorts with 1500 patient-year participation. Patients were excluded if they had histories of severe carotid stenosis, atrial fibrillation, cardiac valve disease, recent myocardial infarction (MI), or hematologic problems. Outcome concentrated on death from any vascular cause and any recurrent stroke, MI, or bleeding complication. Randomized patients were given either sufficient anticoagulants to attain an INR between 3.0 and 4.5 or an aspirin dose equivalent to 30 mg daily.
The trial was prematurely stopped at the first outcome analysis of 1316 patients who were followed for a mean of 14 months between April 1993 and May 1996. Overall, by the time of that first evaluation, 54 anticoagulated patients had suffered serious complications vs. 26 taking aspirin. The table summarizes these results.
Table
Anticoagulants vs. Aspirin After Cerebral Ischemia
Anticoagulants Aspirin
All cited complications12.4%5.4%
Death5.4%2.2%
All vascular deaths3.7%1.7%
All non-fatal strokes3.7%2.7%
Major bleeding 8.0%0.09%
All non-hemorrhagic death and non-fatal stroke or MI4.1% 4.0%
These distressing end points became apparent after only 17% of the anticipated total numbers were treated, a phenomenon vividly apparent on the Kaplan-Meier survival curve. Obviously, the project stopped as soon as the data became apparent. Nevertheless, certain aspects came to light. Two-thirds of the studied population included males with a mean age of 63 ± 10.5 years. Age greater than 65 years and a high incidence of leucoaraiosis on CT scans each increased risk of complications. Finally, a risk of hemorrhage with an INR of 3 was about 4% and was about the same at an INR of 3.5. An INR of 4, however, doubled the risk of hemorrhage to about 8%, and at 4.5, the risk rose to about 19%.
Comment by Fred Plum, MD
The message is clear: Anticoagulant therapy producing INR values of 3-4.5 at least doubles the risk of severe brain hemorrhage as a secondary prevention measure against arterially related stroke. Whether lowering INR levels to a ceiling of 3 carries any benefit remains to be seen. Until such evidence makes itself known, however, the editors recommend using anticoagulants only for chronic atrial fibrillation, deep vein thrombosis, and special hematologic problems. Even in these circumstances, we administer neurologically asymptomatic patients with atrial fibrillations, adjusting warfarin dosage so as to range at the 1.8-2.5 INR levels. Whether this level will protect against secondary stroke remains to be evaluated scientifically.
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