Folate Therapy and In-Stent Restenosis and Coronary Stenting

Source: Lange H, et al. N Engl J Med. 2004;350:2673-2681.

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 micromol/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.


Quinapril Reduces Markers of Oxidative Stress in the Metabolic Syndrome

Source: Khan B, et al. Diabetes Care. 2004;27:1712-1715.

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.


Donepezil in Patients with Alzheimer’s

Source: AD2000 Collaborative Group Lancet. 2004;363:2105-2115.

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.


Effect of the Dietary Approaches to Stop Hypertension Diet and Reduced Sodium Intake on Blood Pressure Control

Source: Svetkey LP, et al. J Clin Hypertens. 2004;6:373-381.

The Dietary Approaches to Stop Hypertension (DASH) diet, which suggests high intake of fruits, vegetables, and low-fat diary products, has been shown to favorably affect blood pressure in Stage 1 Hypertension (140-159/90-99) as well as pre-hypertension (130-39/85-89). A reduced sodium intake diet (RSI) has also been shown to have beneficial BP effects in these groups. Whether the combination would provide additive benefits was the subject of this trial. Subjects (n = 412) were randomly allocated to DASH or control diets with high (142 mmoL/d), intermediate (107 mmoL/d), or low (65 mmoL/d) sodium content. Study subjects ate the DASH (or control) diet for 3 consecutive 30 day intervals, each interval with a different sodium content. To ensure compliance and consistency, all meals were provided by Svetky and colleagues.

Adding sodium restriction to the DASH diet resulted in a 2-2.6 fold greater likelihood of BP being controlled. At the lowest sodium intake, 84% of hypertensive patients achieved BP control (< 140/90). In persons with isolated systolic hypertension, the pattern of responsivity was similar. In persons with high-normal BP, 76% were restored to normotension with DASH+RSI. Application of these dietary modulations has meaningful beneficial effects, and may obviate or reduce the need for pharmacotherapy.


Methylprednisolone, Valacyclovir, or the Combination for Vestibular Neuritis

Source: Strupp M, et al. N Engl J Med. 2004;351:354-361.

Vestibular neuritis (VN) is characterized by acute onset of vertigo, a positive Romberg’s sign, nystagmus, and nausea. It is second only to benign paroxysmal positional vertigo as a cause of peripheral vestibular vertigo. The most popularly favored putative cause of VN is herpes simplex virus, although other etiologic explanations (like vestibular ischemia) are also suggested. Full vestibular recovery from VN occurs in less than half of cases, leaving patients with deficits such as postural imbalance during walking.

Corticosteroids, antiviral agents, or both are sometimes used to treat VN, but little evidence exists to confirm or disprove the efficacy of such interventions. This study compared methylprednisolone (MPD), valacyclovir (VAL), the combination (MPD + VAL) and placebo in subjects (n = 141) with acute VN of less than 3 days duration. MPD was administered orally QAM for 22 days, titrated 100 mg daily down to 10 mg. VAL was dosed 500 mg t.i.d. orally for 7 days.


Improved Plasma Glucose Control, Whole-Body Glucose Utilizations, and Lipid Profile on a Low-Glycemic Index Diet in Type 2 Diabetic Men

Source: Rizkalla SW, et al. Diabetes Care. 2004;27:1866-1872.

At the same level of grams of carbohydrate, different foods vary in their rate of rise of plasma glucose, and in the subsequent amount and timing of insulin response they elicit. In theory, consumption of foods with a favorable (ie, low) glycemic index should favorably affect diabetic control. To date, there have been insufficient data to confirm or refute the role of a dietary choices based upon glycemic index. Supporting the role of a low glycemic index diet (LGI) are data that indicate better A1c levels and reduced fat mass, even in the absence of a measurable effect upon plasma glucose.

Rizkalla et al studied diabetic men (n = 12) who were administered a LGI diet vs a high glycemic index diet for 4 weeks, followed by a 4 week washout and then crossover to the other diet.

Numerous statistically significant favorable changes occurred during the LGI phase, including impact on fasting glucose, A1c, glucose use, LDL, plasma fatty acids, and even fibrinolysis status, as indicated by plasminogen activator inhibitor activity. If these effects are sustainable, they could have important positive long-term effects on diabetes.