SHOULD GUIDELINES FOR INITIATION OF STATIN THERAPY BE EXPANDED?

Rigid application of current national and international guidelines for the initiation of statin therapy may deprive up to one half of patients with stroke and transient ischemic attack of the advantages of such therapy, according to an article in the January Archives of Neurology. Bruce Ovbiagele, MD, and colleagues found that most clinically encountered patients with stroke or transient ischemic attack actually met clinical trial–validated criteria for initiation of statin therapy.

The researchers evaluated 100 consecutive patients with stroke or transient ischemic attack admitted to a university hospital stroke service to “assess the impact on clinical practice of broadening indications for statins in patients with stroke.” Algorithms for initiating statin therapy were abstracted from national and international guidelines—the National Cholesterol Education Program Adult Treatment Panel III (NCEP III) and the European Joint Task Force II (EJTF II)—as well as the Heart Protection Study entry criteria and the FDA labeling.

Dr. Ovbiagele and his colleagues found that 20% of patients were taking statins on admission. However, they found that criteria for initiation of statin therapy were met by 48% of patients for the NCEP III and 38% of patients for the EJTF II. The number of patients who met criteria for initiation of statin therapy rose even further with the application of guidelines from the more recent Heart Protection Study and FDA labeling. Criteria were met by 92% of patients for entry to the Heart Protection Study and by 100% of patients for the FDA labeling, indicating that nearly one half of patients with stroke and transient ischemic attack are deprived of statin therapy when national and international guidelines are followed.

In an accompanying editorial, Dilip K. Pandey, MD, PhD, and Philip B. Gorelick, MD, MPH, question whether the liberal use of statins according to FDA guidelines is justified. “Are we rendering treatment that may not be indicated?” they asked.

Drs. Pandey and Gorelick commented, “The current evidence of benefits of statins in secondary prevention of stroke is unclear. The important question of whether national and international guidelines should be revised … remains unanswered.”

They suggested that once the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial has been completed, further evidence of the benefit of statins in patients with stroke will be available.

Ovbiagele B, Kidwell CS, Saver JL. Expanding indications for statins in cerebral ischemia: a quantitative study. Arch Neurol. 2005;62:67-72.
Pandey DK, Gorelick PB. Should statin agents be administered to all patients with ischemic stroke? Arch Neurol. 2005;62:23-24.

VITAMIN E FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Vitamin E may have a neuroprotective effect in cancer patients, according to research in the January 11 Neurology. Because recent studies have shown vitamin E deficiency in cancer patients after two to four courses of chemotherapy, and because vitamin E deficiency results in sensory neuropathy, Andreas A. Argyriou, MD, and colleagues decided to examine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral neuropathy.

The researchers randomized 31 patients with cancer who were treated with six courses of cisplatin, paclitaxel, or a combination of both to either vitamin E (600 mg/day) during chemotherapy and for three months after its cessation, or no supplementation (control group). Eighteen patients were male and 13 were female, with a mean age of 59.2.

Dr. Argyriou and his colleagues found that vitamin E supplementation decreased the incidence of neurotoxicity; four of 16 (25%) patients assigned to vitamin E had neurotoxicity, compared with 11 of 15 (73.3%) patients assigned to the control group. Furthermore, the severity of neurotoxicity was higher in controls.

The researchers identified several limitations to their study. First, because it was a pilot study, the sample size was small; second, it lacked a placebo; and third, “multiple tumor types and chemotherapy regimens make it difficult to generalize” the results.

Despite the study’s limitations, however, Dr. Argyriou and his colleagues said the results indicate that vitamin E is effective in providing neuroprotection in cancer patients treated with cisplatin, paclitaxel, or a combination of both and that a larger, double-blind, placebo-controlled, randomized trial is warranted.

Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. 2005;64:26-31.

ISCHEMIC STROKE MAY BE ASSOCIATED WITH MIGRAINE HEADACHES

Migraine headaches may increase the risk of ischemic stroke, according to a study in the January 8 BMJ. Mahyar Etminan, PharmD, and colleagues reviewed 11 case-control studies and three cohort studies that examined the association between migraine and risk of ischemic stroke in persons ages 15 to 84. They found that among people with any type of migraine, risk of stroke was 2.16 times higher.

Dr. Etminan and colleagues also found that people with migraine with aura were 2.27 times more likely to have a stroke. In addition, persons with migraine without aura were 1.83 times more likely to have a stroke. The researchers pointed out that risk of stroke was even higher among women with migraine who were taking oral contraceptives; this population was 8.72 times more likely to have a stroke.

Dr. Etminan and his colleagues noted that because “use of oral contraceptives is prevalent among young women, the potential risk of stroke among women with migraine who are also users of oral contraceptives must be further investigated.”

The researchers said that the results of the study suggest that migraine may be an independent risk factor for stroke. They commented that “possible mechanisms for this association include irregularities in blood flow, cardiac abnormalities, and abnormal production of prostaglandins as well as noradrenergic or cholinergic transmitters and receptors.” However, they recommended that further studies be conducted to examine these mechanisms.

Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systemic review and meta-analysis of observational studies. BMJ. 2005;330:63-66.

HIGH CONCENTRATIONS OF HOMOCYSTEINE ASSOCIATED WITH INCREASED RISK OF STROKE

Individuals with the MTHFR-TT genotype seem to be at an increased risk of stroke, according to an article in the January 15 Lancet. Researchers said these individuals have, on average, higher concentrations of homocysteine and a slight increased risk of stroke, implicating an association between homocysteine and stroke.

Juan P. Casas, MD, and colleagues reviewed 81 studies that examined the relationship between ischemic or hemorrhagic stroke and the presence of the MTHFR-TT or MTHFR-CC genotypes—people with the MTHFR-CC genotype generally have lower concentrations of homocysteine. The studies involved a total of 31,355 people with and without cardiovascular disease.

The researchers found that “among 15,635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 μmol/L.” They also found that among people with cardiovascular disease, the mean homocysteine concentration was 4.35 μmol/L higher in people with the MTHFR-TT genotype than in people with the MTHFR-CC genotype.

Meta-analysis revealed that people with the MTHFR-TT genotype were 1.26 times more likely to have a stroke than were people with the MTHFR-CC genotype. Findings were similar when analyses were adjusted for age, ethnic background, and geographical location.

Although they seem to have established a role for homocysteine in stroke pathogenesis, Dr. Casas and his colleagues pointed out that further research—focused on supplementation with folic acid, with or without vitamin B—is needed to determine if lowering homocysteine concentrations is beneficial and safe in preventing stroke.

In an accompanying editorial, Graeme J. Hankey, MD, and John W. Eikelboom, MBBS, MSc, stated that a causal association between homocysteine and stroke has yet to be established. They noted that factors that increase both total homocysteine and stroke risk—such as smoking, lower socioeconomic level, existing atherosclerosis, and renal impairment—“could have been confounding factors if they were not recorded in the observational studies or adjusted for in the analyses.”

Dr. Hankey and Mr. Eikelboom emphasized the importance of testing therapeutic approaches for lowering homocysteine concentrations, as Dr. Casas’ research team noted as well. “Even if it is established that total homocysteine increases the risk of stroke, it may not be wise for physicians to prescribe long-term B-vitamin therapy to a broad group,” they said. Once randomized controlled trials have been completed, “physicians should know if it is safe and effective to prescribe long-term B-vitamin therapy to lower total homocysteine and stroke risk,” they added.

Suggested Reading
Casas JP, Bautista LE, Smeeth L, et al. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;365:224-232.
Hankey GJ, Eikelboom JW. Homocysteine and stroke. Lancet. 2005;365:194-196.

COGNITIVE AND NEUROLOGIC IMPAIRMENT AFTER EXTREMELY PRETERM BIRTH

Cognitive and neurologic impairment is common among school-age children who were born at 25 or fewer weeks of gestation, according to Neil Marlow, DM, Professor of Neonatal Medicine at the University of Nottingham, United Kingdom, and colleagues. According to the study, which was published in the January 6 New England Journal of Medicine, impairment was even more pronounced when children born preterm were compared with classroom peers born at full term.

Professor Marlow and his colleagues examined 241 children who had been born preterm when they reached 30 months and 6 years. Of these children, 34 attended schools for children with special needs, 204 attended mainstream schools, and three were in special-needs classes in mainstream schools. A total of 160 classmates born at full term were chosen as a comparison group. Seven developmental pediatricians and eight psychologists performed the assessments.

Children were categorized as having severe, moderate, mild, or no disability. Disability was defined as severe if a child was highly dependent on caregivers and had nonambulant cerebral palsy, an IQ score more than 3 standard deviations below the mean, hearing loss, or blindness. Disability was defined as moderate if a child was reasonably independent and had ambulant cerebral palsy, an IQ score 2 to 3 standard deviations below the mean, hearing loss corrected with a hearing aid, or impaired vision. Disability was defined as mild if a child had “neurologic signs with minimal functional consequences or other impairments such as squints or refractive errors.”

Researchers found that 21% of children born preterm had cognitive impairment—defined as test scores more than 2 standard deviations below the mean. When compared to children born at full term, 41% of children born preterm showed cognitive impairment. Researchers also found that 22%, 24%, and 34% of children born preterm had severe, moderate, and mild disability, respectively. Twelve percent of children born preterm had cerebral palsy. Furthermore, boys were more likely to have cerebral palsy and to score lower on cognitive tests than girls were.

Professor Marlow and his colleagues also examined cognitive and neurologic impairment at 30 months as a predictor for impairment in later life. They found that among children identified as having severe disability at 30 months, 86% had moderate to severe disability at 6 years. In addition, 38% of those with other disabilities and 24% of those with no disability at 30 months had moderate or severe disability at 6 years.

“Further analysis will be needed to determine whether the cognitive impairments may explain the educational difficulties that have been reported for extremely-low-birth-weight children and whether specific learning difficulties, such as in language or behavioral and social areas, are important additional predictors of academic achievement,” said the researchers.

Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med. 2005;352:9-19.

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