WARFARIN MAY BE MORE EFFECTIVE THAN ASPIRIN IN ELDERLY STROKE PATIENTS WITH ATRIAL FIBRILLATION

Anticoagulation therapy may be beneficial for stroke patients 75 and older who have atrial fibrillation, according to results from the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study reported in the August 11 Lancet. Jonathan Mant, MD, Senior Lecturer in Public Health at the University of Birmingham in the UK, and colleagues randomized 973 patients (mean age, 85) with atrial fibrillation to receive warfarin (target international normalized ratio 2-3) or aspirin (75 mg/day); mean follow-up period was 2.7 years. There were 21 strokes, two other intracranial hemorrhages, and one systemic embolus among those who received warfarin and 44 strokes, one other intracranial hemorrhage, and three systemic emboli among those who received aspirin.

Stroke risk was higher in patients receiving warfarin before study entry than in those new to warfarin; the treatment was as effective in patients age 85 and older as it was in younger participants. The yearly risk of stroke was 1.8% in the warfarin group compared with 3.8% in the aspirin group. In addition, the yearly risk of extracranial hemorrhage was 1.4% and 1.6% in the warfarin and aspirin groups, respectively, and the yearly risk of all major hemorrhages, including intracranial and hemorrhagic stroke, was 1.9% and 2.0% in the warfarin and aspirin groups, respectively. The yearly risk of a composite outcome of major vascular events (stroke, myocardial infarction, pulmonary embolus, or vascular mortality) was 5.9% in the warfarin group and 8.1% in the aspirin group, and the yearly risk of nonstroke vascular events was 6.1% in the warfarin group and 6.3% in the aspirin group.

Furthermore, two years after randomization, 96 patients (25%) assigned to warfarin and 86 patients (23%) assigned to aspirin were using a lipid-lowering agent; there was also no difference in blood pressure between the two groups after randomization. Mean systolic blood pressure two years after randomization was 137 mm Hg for patients receiving warfarin or aspirin, while the mean diastolic blood pressure was 75 mm Hg for patients receiving warfarin and 76 mm Hg for patients receiving aspirin.

“We have shown that warfarin is more effective than aspirin in prevention of stroke in people with atrial fibrillation who are aged 75 or over,” Dr. Mant and colleagues stated. However, the researchers noted that “the similarity in risk of major hemorrhage between patients on warfarin and those on aspirin in this study is surprising.” They pointed out that due to wide confidence intervals, it may be possible that warfarin does increase hemorrhage risk compared to aspirin. Another possible explanation could be the fact that 40% of patients were on warfarin before study entry, as warfarin hazards appear to be greater to those who are new to the treatment.

Moreover, the dilution of differences in effect between aspirin and warfarin caused by treatment crossover may also explain the similarity in hemorrhage risk, as one-third of the participants receiving warfarin did not start treatment or started it but later stopped, and 17% of the participants receiving aspirin also took warfarin by the end of the study. However, the possible effect of underestimation of bleeding risk among patients taking warfarin due to crossover “is likely to be small, because no differences were reported in either the intent-to-treat or the on-treatment analyses,” Dr. Mant and colleagues pointed out. Also, “only 20% of the patients excluded from the study because the treatments were not judged to have equal potential benefit were excluded because warfarin was felt to be inappropriate” due to high risk of hemorrhage, the researchers stated.

In an accompanying editorial, David Garcia, MD, Assistant Professor of Internal Medicine at the University of New Mexico, and Elaine Hylek, MD, MPH, Associate Professor of Medicine at Boston University, stated that “the fact that BAFTA showed that warfarin is more effective than aspirin, even in this relatively low-risk group of patients, adds to other evidence that, in patients with atrial fibrillation, anticoagulation protects patients against stroke more effectively than antiplatelet therapy.” Although “BAFTA firmly establishes the superior efficacy of warfarin” in these patients, the editorialists noted that “in the future, our greatest challenge will be to identify those patients (elderly or not) who are truly at the highest risk of major bleeding, particularly intracranial hemorrhage.”

Suggested Reading
Mant J, Hobbs R, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370(9586):493-503.
Garcia D, Hylek E. Stroke prevention in elderly patients with atrial fibrillation. Lancet. 2007;370(9586):460-461.

WOMEN MAY EXPERIENCE A MORE MILD FORM OF PARKINSON'S DISEASE

Findings from a prospective study of patients with Parkinson’s disease suggest a more benign phenotype of the disease in women. Researchers from the Netherlands longitudinally observed 253 consecutive patients who visited a movement disorders outpatient clinic between 1988 and 2003. They published their results in the August Journal of Neurology, Neurosurgery, and Psychiatry.

Charlotte A. Haaxma, MD, a resident within the Department of Neurology at Radboud University Nijmegen Medical Centre, and colleagues included only patient data from the first 10 years after symptom onset for patients who had not yet initiated levodopa or dopamine agonist treatment “to compare the natural course of Parkinson’s disease between men and women.” The participants were assessed using a selection of seven items of the Unified Parkinson’s Disease Rating Scale III (sUPDRS-III) at onset and every three to six months thereafter.

Sixty-two percent of the participants were men; although fewer than 25% of the participants used anti-Parkinson’s disease drugs, the medication had a  modest effect on motor function, and the use and doses were similar between the sexes, reported the researchers. At symptom onset, women were 2.1 years older than men (mean age, 53.4 vs 51.3), and presented more often with tremor (67% vs 48%). However, mean sUPDRS-III scores did not differ between sexes at onset or during disease progression, with an increase of 0.09 points per year. Single photon emission CT (SPECT) imaging was conducted anywhere from 0.7 to 9.9 years after symptom onset; the authors reported that women had 16% higher [123I]FP-CIT binding than men did at onset. However, the rate of decline in tracer binding (3.1% per year) did not differ between the sexes.

Women were also requested to complete a questionnaire regarding estrogen status throughout their lives. The researchers reported, “The more children a woman had before Parkinson’s disease onset, the higher the age at onset,” with 2.7 years later onset per child; the pattern did not hold true for women without children, however. “These women may have a different basal estrogen status than women with children,” they suggested. In women whose Parkinson’s disease onset was after menopause, the duration of the fertile life span was associated with a 0.5-year later onset per year, while age at menarche did not correlate with age at onset.

Suggested Reading
Haaxma CA, Bloem BR, Borm GF, et al. Gender differences in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78(8):819-824.

STATINS LINKED TO REDUCED NEUROFIBRILLARY TANGLE BURDEN IN ALZHEIMER'S DISEASE

Use of statins for patients with Alzheimer’s disease may be significantly associated with reduced neurofibrillary tangle burden, as reported in the August 28 Neurology. Gail Li, MD, PhD, of the University of Washington Alzheimer’s Disease Research Center in Seattle, and colleagues analyzed brain autopsies of 110 subjects (age range, 65 to 79) who were cognitively healthy at enrollment. Thirty-six (33%) had received at least three prescriptions for statins.

A majority of participants who used statins were male, had a higher incidence of cardiovascular disease or diabetes mellitus, had higher pretreatment total cholesterol levels and lower pretreatment HDL levels, and were more often smokers, compared with nonusers. On average, participants received their first statin prescription at age 76; the average number of statin prescriptions filled was 30. The mean time of first statin prescription was two years after enrollment and five years before death. Among statin users, 21 patients (58%) received simvastatin for at least half of their statin prescriptions. Lovastatin was used by 12 patients (33%) and was the second most commonly used agent.

Based on pharmacy dispensing records, the researchers compared neuropathologic findings between statin users (with three or more prescriptions of 15 or more pills of simvastatin, pravastatin, lovastatin, or atorvastatin) and nonusers. Patients receiving statins showed trends toward having more severe vascular pathology, they were more likely to have cystic infarcts and microvascular lesions, and they had higher rates of moderate to severe versus mild or no atherosclerosis compared with nonusers; however, these trends did not reach significance. There was a higher Braak stage associated with a greater number of microvascular lesions. However, there was not a higher score on the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging. Braak staging showed a lower burden of neurofibrillary tangles, and CERAD grading showed a lower burden of neuritic plaque among statin users compared with nonusers. After controlling for age at death, gender, Cognitive Abilities Screening Instrument score at study entry, brain weight, and presence of microvascular lesions, the investigators found a significantly reduced risk for typical Alzheimer’s disease pathology among statin users compared with nonusers.

“There is increasing epidemiologic evidence of association between cardiovascular risk factors (such as high blood pressure and high cholesterol) and risk of Alzheimer’s disease,” Dr. Li and colleagues stated. “To our knowledge, [ours] is the first study demonstrating an association between statin exposure and neuropathologic changes associated with Alzheimer’s disease.”

However, the researchers pointed out that patients with vascular factors, such as cardiovascular disease, diabetes, and lower pretreatment HDL cholesterol have an increased likelihood of being prescribed statins. “Whether vascular disease causes, exacerbates, or just coexists with Alzheimer’s disease pathology is not clear and is beyond [the] scope of this study,” they noted. “Regardless of the mechanism, however, we did find that vascular disease (specifically, microvascular lesions) was associated with both statin use (exposure) and neurofibrillary tangles (outcome), this suggesting a potentially confounded relationship between statin use and Alzheimer’s disease pathology.”

This confounding effect could increase Alzheimer’s disease pathology burden on patients, due to the fact that presence of microvascular lesions was linked to an increased neurofibrillary tangles burden in the study’s statin users. “To control for the effect of such confounding by indication, we included cerebral microvascular lesions as an adjustment in our logistic regression models,” Dr. Li and colleagues stated. “Although such adjustment rarely accomplishes full control on confounding effects, its use here was sufficient to reveal a significant association between statin use and Braak stage or Alzheimer’s disease–type pathology where this association had been inconclusive in unadjusted models.”

The researchers concluded that “the association between statin therapy and reduced neurofibrillary tangles in the current study and our previous observation of statin-induced reductions in CSF p-tau181 levels provide converging evidence that statins might reduce pathologic phosphorylation of tau in humans.” They added that “additional observational studies and controlled trials will be required to determine if there is a causal link between statin treatment and the development of neurofibrillary tangles or other Alzheimer’s disease–related neuropathologies.”           

Suggested Reading
Li G, Larson EB, Sonnen JA, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007;69(9):878-885.

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