Clinical Briefs in Primary Care

Migraine and Subclinical Brain Lesions

Source: Kruit MC, et al. JAMA. 2004;291:427-434.

The data on the relationship between migraine and other vascular events such as stroke have been conflicting, although in some populations (such as young women smokers who suffer migraine with aura) the adverse association is more clear-cut. Because such a high proportion of women, and a not-insubstantial population of men suffer migraine, any important association with other major morbidities becomes epidemiologically compelling.

Using MRI scans in a population of migraine sufferers without history of prior stroke or TIA, infarcts and white matter lesions were defined, all by the same neuroradiologist who was blinded to the clinical data about the patients (n = 435, inclusive of 140 controls). Most patients (71%) were female, the mean age was 48 years, and patients were equally divided between migraine with and without aura.

Although the absolute number of infarcts demonstrated only a trend towards being more frequent in migraneurs, it was the posterior circulation infarcts which were markedly more common (7-fold increase in migraine population vs controls), an effect which was even more exaggerated in the migraine with aura category (odds ratio = 13.7). In the total unselected population, no difference in white matter lesions between migraine sufferers and controls was discerned; however women migraneurs had an increased odds ratio (OR = 2.1) for white matter lesions compared to controls.

None of these patients had any prior evidence of cerebral ischemic events. The relationship between migraine and increased risk of cerebral ischemia prompts consideration of whether more vigorous prevention of migraine might reduce risk of subsequent tissue damage.

Memantine Treatment in Alzheimer Disease

Source: Tariot PN, et al. JAMA. 2004;291:317-324.

Memantine (MEM) is the first clinically available NMDA receptor antagonist with demonstrated clinical efficacy and an acceptable adverse event profile for persons with Alzheimer disease (ALZ). Cholinesterase inhibitors like donepezil (DON) might work in a complementary fashion, hence this MEM + DON trial.

Subjects with ALZ (n = 404) who had been on a stable dose of DON for at least 6 months, and were free of known secondary etiologies for dementia, were randomized in a double-blind fashion to MEM titrated from 5 mg/d up to 20 mg/d (administered as 10 mg b.i.d.) for 6 months, vs placebo. DON was continued in both the placebo and the MEM treatment arm.

Changes in cognitive function, functional capacity, and global outcome were measured throughout the trial, the primary outcome being based upon scores on the Severe Impairment Battery and Activities of Daily Living Inventory.

There was a statistically significant positive effect of MEM when added to DON, complemented with a very favorable adverse effect profile: more patients in the placebo group withdrew due to adverse events than in the MEM group. Only headache and confusion were more common in the MEM group, both of which occurred in less than 10% of recipients. In addition to being useful as ALZ monotherapy, there may be additional clinical benefits from combining MEM with DON in ALZ therapy.

Casual Postprandial Glucose Levels in Type 2 Diabetes Management

Source: El-Kebbi IM, et al. Diabetes Care. 2004;27:335-339.

Tight control of type 2 diabetes (DM2) has been proven to reduce microvascular complications. Use of the hemoglobin A1c to assess long-term control is standard, but for modulation of treatment, timed specimens (eg, fasting, 1-2 hours postprandial) obtained by patient self-monitoring of blood glucose are often the information clinicians use to make choices about therapy modification.

Unless instructed otherwise, most DM2 patients are 1-4 hours postprandial at the time of an office visit. El-Kebbi, et al, investigated whether casual glucose levels obtained at the office visit might function as an adequate barometer of glucose control to help modify treatment.

Established DM2 patients (n = 1827) at the Grady Diabetes Clinic (Atlanta) underwent simultaneous A1c and casual glucose measurement during their regular visit. The correlation between casual glucose measurement and A1c was strong (correlation coefficient = 0.63). The presence of a casual glucose > 150 predicted an A1c > 7.0 with a sensitivity of 78% (positive predictive value = 80%).

El-Kebbi and colleagues suggest that a casual plasma glucose greater than 150 mg/dL may serve as a surrogate for A1c; results above this level should prompt an intensification of therapy.

Exemestane after Tamoxifen Therapy in Breast Cancer

Source: Coombes RC, et al. N Engl J Med. 2004;350(11):1081-1092.

Tamoxifen (TAM) is well established to reduce, over 5 years, both risk of breast cancer (BCA) recurrence (47%) and mortality (26%) among women who have undergone surgery for BCA and who have estrogen-receptor positive tumors. Exemestane (EXE) is classified as an irreversible steroidal inactivator, and works by blocking the enzyme (aromatase) which is responsible for converting androgens to estrogens, ultimately inhibiting aromatization by about 98%. Although TAM is of remarkable positive benefit, it is not without risks, including increased likelihood of endometrial cancer attributed to endometrial stimulation. EXE is not known to induce endometrial proliferation, or increase proclivity for endometrial cancer.

The Intergroup Exemestane Study (IES) investigated whether substituting EXE for TAM after 2-3 years would provide better outcomes than simply treating with TAM continuously for 5 years. Study subjects were postmenopausal women (n = 4742) who remained free of recurrence during sustained TAM treatment. EXE (25 mg p.o. q.d.) was substituted for TAM in one half of the subjects.

After a median followup of 30.6 months, the risk of recurrence, contralateral BCA, or death was reduced by 32% in the EXE group compared with TAM. The adverse effects seen more frequently with EXE than TAM included diarrhea and arthralgia, but thromboembolisms was almost twice as common in the TAM group. Coombes and colleagues suggest that switching women from TAM to EXE at the 2-3 year point in treatment may provide more favorable outcomes.

An Analysis of How Long Patients Remain on Various Antihypertensive Therapies

Source: Esposti LD, et al. J Clin Hypertens. 2004;6:76-84.

The term "drug efficacy" is technically intended to reflect impact of an agent on a designated end point in a study population participating in a clinical trial. "Drug effectiveness," on the other hand, refers to the "real life" effects drug treatment produces as seen separately from a clinical trial; ie, what impact might be seen when "typical patients" use a medication in, for instance, the community setting.

As many as half of patients who begin antihypertensive drug therapy (HTN-Rx) discontinue treatment within a few months of initiation. Study subjects from the area in and around Ravenna, Italy comprised this hypertensive patient population (n = 14,062). All were first-time recipients of a new HTN-Rx. "Persistent patients" were defined as either maintaining, combining with, or switching from their initial HTN-Rx to another HTN-Rx, for a duration of > 273 days from the day of enrollment.

Discouragingly, 48% of patients discontinued treatment after a single prescription! Medication choices were similar to those commonly used in the United States (ACE/ARB/HCTZ/CCB/Beta Blocker). Angiotensin Receptor Blockers demonstrated the highest continuation rate, followed by ACE inhibitors, CCBs, and Diuretics.

Cost of treatment decreased as age increased, and increased for persons who switched or combined agents. Angiotensin receptor blockers were the most expensive single agents. Overall, specific individual drug cost and pattern of drug persistence correlated best with total cost for hypertension treatment. These data suggest that although drug cost is important, aspects of the drug treatment which affect persistence patterns ultimately have a substantial effect on overall cost.

Association of Endothelial Dysfunction with Insulin Resistance and Carotid Wall Thickening in Hypertension

Source: Suzuki M, et al. Am J Hypertens. 2004;17:228-232.

Endothelial dysfunction (END) is a fundamental defect in essential hypertension (HTN) and is closely associated with carotid wall thickening (CWT), a consistent marker for early atherosclerotic change. Insulin resistance (IR) is also associated with both HTN and CWT, suggesting a potential relationship between IR and END.

HTN subjects (n = 41) were studied if they met inclusion criteria including HTN, no diabetes, no suggestion of secondary HTN, no major cardiovascular, renal, hepatic, or other endocrine disease, no smoking, and no medications which modulate carbohydrate or lipid metabolism (eg, statin, steroids) for at least 12 months. All subjects underwent measurement of endothelial function, carotid interomedial thickness by ultrasound, and insulin sensitivity as defined by insulin/glucose infusion.

END was found to be associated both with IR and CWT. The changes in CWT and END were strongly associated, suggesting a close correlation between functional (END) and structural (CWT) atherosclerotic changes. The confirmed association between END, CWT, and IR may prompt consideration of investigation to seek causality between, eg, IR and CWT