By Louis Kuritzky, MD
Folate Therapy and In-Stent Restenosis and Coronary Stenting
Observational data have supported the role of homocysteine (HCS) as a cause of or contributor atherosclerosis. Randomized trials of interventions to reduce HCS have provided conflicting results, although some of the most positive results in favor of interventions to lower HCS (specifically, folate-based treatment) have been in the realm of coronary stent restenosis. Lange and colleagues provide a randomized trial of HCS lowering after coronary stent placement.
After successful coronary stenting, subjects (n = 636) were randomly assigned to folate therapy for 6 months (folate, vitamin B-6, and vitamin B-12 given initially IV, then orally) or placebo. Study outcomes included luminal diameter and rate of restenosis.
In the study group as a whole, in contrast to some prior data, folate-based treatment was associated with a higher restenosis rate and a higher percentage of patients requiring repeated revascularization. On the other hand, there was a trend (confidence interval crosses unit risk) towards restenosis benefits in some important subgroups: diabetics, women, and persons with baseline marked elevations of HCS (> 15 micro-mol/L). These data do not support the routine employment of HCS modulating treatments such as folate based therapy in an effort to reduce rates of restenosis.
Lange H, et al. N Engl J Med. 2004; 350:2673-2681.
Quinapril Reduces Markers of Oxidative Stress in the Metabolic Syndrome
The metabolic syndrome (MBS) may be defined as 3 or more of: increased waist circumference (men > 40 inches, women > 35 inches), triglycerides > 150, reduced HDL (men < 40, women < 50), BP > 130/85, and fasting blood sugar > 100. MBS is highly prevalent and is associated with meaningful increases in risk of stroke and myocardial infarction; since markers of an abnormal pro-oxidative state in MBS may be indicative of pathways to development of atherosclerosis, studies of agents which affect inflammatory or oxidative states are of interest.
The renin-angiotensin-aldosterone system (RAS) appears to modulate vasculopathic changes through inflammation and oxidation, amongst other paths. Quinapril (Q-pril), an ACE inhibitor, has shown efficacy in management of hypertension, but has not been heretofore specifically studied for oxidative effects in a MBS population.
MBS subjects (n = 40) were randomized to Q-pril 20 mg/d or placebo. Markers of oxidation included 8-isoprostane, erythrocyte superoxide dismutase activity, and LDL oxidation lag time. After 4 weeks, favorable effects on all markers were seen. Because a normotensive population was chosen, and blood pressure change over time was not significantly different from placebo, the changes on oxidative state markers appear to be independent of blood pressure. Whether modulation of such surrogate markers will translate into clinically meaningful end points remains to be determined.
Khan B, et al. Diabetes Care. 2004 Jul;27:1712-1715.
Donepezil in Patients with Alzheimer’s
Because use of cholinesterase inhibitors is neither inexpensive nor without significant potential adverse effects, their long-term impact on patients with dementing disorders like Alzheimer’s Disease (ALZ) is important to define.
Although measurable positive impact upon cognitive tests and global measures of change over the short term are encouraging, long-term results may provide a better vantage point from which to discern the risk-benefit balance of such treatment.
The AD2000 Collaborative Group carried out this study. Subjects (n = 566) were enrolled defined by DSM IV ALZ criteria, although a small minority also suffered concomitant vascular, parkinsonian, or psychotic disorders. All patients were naïve to anticholinergic CNS agents at the outset of the trial.
Study subjects were randomized to placebo or donepezil, beginning at 5 mg/d; long-term treatment was maintained for 3 years at 5-10 mg/d. Outcomes included cognition (by the mini-mental state examination), functionality (by the Bristol activities of daily living scale), requirement for institutional care, and progression of disability.
Although cognition and activities of daily living were statistically significantly improved in the active treatment group, this did not translate into meaningful changes in the most important outcomes: institutionalization, progression of disability, behavioral symptoms, costs, and psychological well-being of the primary caregiver, none of which was favorably impacted by treatment. The study concludes that donepezil is neither clinically effective, nor cost effective.
AD2000 Collaborative Group Lancet. 2004;363:2105-2115.
Folate Therapy and In-Stent Restenosis and Coronary Stenting; Quinapril Reduces Markers of Oxidative Stress in the Metabolic Syndrome; Donepezil in Patients with Alzheimers
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