VIENNA — Potent cholesterol-lowering therapy appears to reverse neurocognitive decline in normolipidemic elderly patients with atrial fibrillation, Dr. Elke Wezenberg said at the annual congress of the European Society of Cardiology.
If this new finding from the small pilot SPACE (Silent Brain Infarction and Cognitive Decline Prevention in Atrial Fibrillation by Cholesterol Lowering in the Elderly) trial is confirmed in a planned larger, more definitive study, then the use of lipid-lowering medications would be warranted in all patients with atrial fibrillation (AF), regardless of their cholesterol level, added Dr. Wezenberg, a psychiatrist at Radboud University, Nijmegen (the Netherlands).
She attributed the positive cognitive effects of the SPACE regimen of 40 mg of atorvastatin/10 mg of ezetimibe daily to the drugs' anti-inflammatory action. Participants had relatively high baseline C-reactive protein (CRP) levels indicative of extensive systemic inflammation. Their CRP levels decreased significantly during 1 year of lipid lowering, and the decline correlated inversely with the observed improvement in cognitive function.
SPACE was a double-blind, placebo-controlled prospective study involving 31 patients, mean age 74, with an average 14-year history of AF. All were on warfarin and adequately anticoagulated, with an international normalized ratio of 2.0–3.0. At baseline and again after 1 year, participants were evaluated for depression using the Montgomery-Asberg Depression Rating Scale (MADRS), by MRI for white matter lesions, as well as by an extensive neuropsychologic test battery for memory, language, executive function, and speed of information processing.
At baseline, participants were free of clinically significant depressive symptoms, showed no indication of impairment on the Mini-Mental State Examination, and were asymptomatic in terms of activities of daily living. However, nearly all patients showed baseline mild neurocognitive impairment, with greater than expected difficulties on specific neurocognitive tests, especially those concerned with speed of information processing, memory, executive function, and psychomotor speed.
At 1 year of follow-up, the placebo group showed continued decline in these neurocognitive domains. In contrast, the AF patients on lipid-lowering therapy demonstrated significant improvement over baseline in speed of information processing, memory, and executive function as assessed by switching tests. The active treatment arm also showed a nonsignificant trend for a reduction in white matter lesions, believed to be of vascular origin.
An estimated 2.2 million Americans have AF, making it the most common cardiac arrhythmia by far. Its prevalence climbs with age, reaching roughly 8% in patients age 80 or older.
It is well established that AF is a risk factor for ischemic strokes, silent brain infarcts, and dementia, even when patients are adequately anticoagulated. The rationale for SPACE comes from prior studies showing that inflammatory markers are increased in patients who have AF, white matter lesions, and/or cognitive impairment—and lipid-lowering drugs are known to decrease inflammation.
The SPACE findings are at odds with the 5,804-patient randomized Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study, in which 3 years of pravastatin didn't slow cognitive decline (Lancet 2002;360:1623–30).
In an interview, Dr. Wezenberg explained that in her view the main explanation for the disparate results is that PROSPER involved a heterogeneous population with a far lower average risk for stroke and microinfarcts than a population comprised purely of individuals with AF. Moreover, the degree of lipid-lowering achieved with 40 mg/day of pravastatin in PROSPER was considerably less than with the SPACE regimen.
And as the PROSPER investigators noted, pravastatin is a hydrophilic statin that doesn't efficiently cross the blood-brain barrier.
The SPACE study was funded by the departments of psychiatry and cardiology at Radboud University.