COMBINATION THERAPY FOR MS IS SAFE AND EFFECTIVE

The results of an open-label trial suggest that combination therapy of intramuscular interferon beta-1a and oral doxycycline may be effective, safe, and well tolerated for some patients with relapsing-remitting multiple sclerosis (MS), as reported in the December 10, 2007, online Archives of Neurology. However, larger controlled clinical trials are needed to evaluate the safety and efficacy of this combination, the researchers stated.

Alireza Minagar, MD, an attending neurologist at Louisiana State University Health Sciences Center, Shreveport, and colleagues conducted a seven-month trial of 15 patients with relapsing-remitting MS taking intramuscular interferon beta-1a with breakthrough disease activity; after administering three months of ongoing treatment, the researchers added 100 mg/day of oral doxycycline for four months. The participants underwent monthly neurologic examination, brain MRI using triple-dose gadolinium, and safety blood work.

Results showed that doxycycline and interferon beta-1a combination therapy resulted in significant reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values. In addition, the investigators found a correlation between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. The researchers also reported suppression of transendothelial migration of monocytes incubated with serum from patients with relapsing-remitting MS undergoing combination therapy. There was only one relapse, and there were no reports of adverse synergistic effects caused by combination therapy or unexpected adverse events.

“It has previously been demonstrated that increased levels of matrix metalloproteinase-9 are associated with increases in gadolinium-enhancing lesions in patients with relapsing-remitting MS,” Dr. Minagar and colleagues stated. “Thus, the addition of doxycycline, a matrix metalloproteinase inhibitor, to interferon beta-1a may reduce the number of contrast-enhancing lesions on brain MRIs. This theory is supported by the results in this cohort, in which the effect was more pronounced in patients with lowered serum levels of matrix metalloproteinase-9.”

The investigators suggested that “combination therapy in MS may be particularly useful in patients who have failed treatment with a single immunomodulatory agent.”

Suggested Reading
Minagar A, Alexander JS, Schwendimann RN, et al. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol. 2007 Dec 10; [Epub ahead of print].

POSSIBLE HEMORRHAGIC STROKE RISK FACTORS IDENTIFIED FOR ATORVASTATIN

Among patients treated with atorvastatin, hemorrhagic stroke as an entry event, male gender, increasing age, and the treatment itself were associated with a more frequent incidence of hemorrhagic stroke, according to an exploratory analysis conducted by Larry B. Goldstein, MD, and colleagues. However, atorvastatin did not disproportionately affect the hemorrhagic stroke risk associated with these factors. The researchers’ findings were published in the December 12 online Neurology.

“In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, atorvastatin 80 mg/day reduced the risk of stroke in patients with recent stroke or transient ischemic attack,” the investigators explained. “Post hoc analysis found this overall benefit included an increase in the numbers of treated patients having hemorrhagic stroke.” Fifty-five patients in the treatment group had a hemorrhagic stroke, versus 33 patients in the placebo group.

Of the total 4,731 patients in the SPARCL study, which was a double-blind, randomized clinical trial, 67% had ischemic strokes, 31% had transient ischemic attacks, and 2% had hemorrhagic strokes as entry events. In addition to atorvastatin treatment, hemorrhagic stroke as the entry event, male gender, increasing age, and stage 2 hypertension at the last visit prior to the hemorrhagic stroke were also risk factors for hemorrhagic stroke. There were no statistical interactions between these factors and atorvastatin treatment.

“Anticoagulants and some antiplatelet regimens may be associated with increased risk of poststroke brain hemorrhage,” Dr. Goldstein, of Duke University Medical Center in Durham, North Carolina, and colleagues noted. “We, however, found no overall effect of antiplatelet drugs or anticoagulants on the risk of brain hemorrhage in SPARCL. Despite statins having antithrombotic properties, we also found no statistical interaction between treatment and the use of any individual or combination of antithrombotic drugs.”

Dr. Goldstein and colleagues pointed out that although epidemiologic studies have reported an association between low cholesterol levels and an increased risk of hemorrhagic stroke, more recent clinical trials involving statins for coronary heart disease have not found such an association. “Consistent with these observations, we found no relationships between the baseline levels of either total or LDL cholesterol and the risk of hemorrhagic stroke, no disproportionate increase in the risk of bleeding associated with treatment based on baseline cholesterol levels, and no independent effect of LDL-cholesterol levels at the last measurement prior to a hemorrhagic stroke in those treated with atorvastatin,” the investigators stated.

“In making therapeutic decisions, the increase in the risk of hemorrhagic stroke found in SPARCL, if not due to chance, must be balanced against the benefit of treatment with atorvastatin 80 mg per day in reducing the overall risk of stroke, as well as other cardiovascular events found in the study’s prespecified, intention-to-treat analysis,” Dr. Goldstein’s research team stressed. They also pointed out that “it remains uncertain whether there is a difference in the risk of bleeding in statin-treated patients with prior stroke compared to those with coronary heart disease, given the small numbers of patients with hemorrhagic stroke in these trials and the post hoc nature of the analyses.”

Suggested Reading
Goldstein LB, Amarenco P, Szarek M, et al. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2007 Dec 12; [Epub ahead of print].

PHYSICAL FUNCTIONAL HEALTH MAY PREDICT STROKE RISK

Poor physical functional health as assessed by the Short Form (SF)-36 may indicate an increased risk of stroke among adults older than 40, as reported in the December 11, 2007, Neurology. Although the relationship between physical functional health–related quality of life and stroke risk needs further study, investigators stated that “the physical function score may identify men and women in the apparently healthy general population at increased risk of stroke independent of classic risk factors who may benefit most from preventive interventions.”

Phyo Kyaw Myint, MRCP, and colleagues examined the relationship between SF-36 physical functional health–related quality of life and incident stroke in 13,615 men and women ages 40 to 79 participating in the European Prospective Investigation into Cancer–Norfolk. These adults had not had a stroke, myocardial infarction, or cancer at baseline. Data were derived from a health and lifestyle questionnaire, a health examination, self-reported physical functional health, and death certification and hospital record linkage in cases of stroke incidence.

There were 244 incident strokes, and participants who reported better physical functional health had a significantly lower risk of incident stroke. Compared with participants in the bottom quartile of SF-36 physical component summary scores (5.2 to 43.6), adults who were in the top quartile (55.2 to 72.1) had 50% less risk of stroke; they were also younger; had lower BMI, systolic blood pressure, and cholesterol levels; had higher forced expiratory volume in one second; and had lower prevalence of diabetes, current smoking, and physical inactivity. In addition, the average consumption of alcohol among participants in the top quartile was within recommended limits (8.5 units per week).

The association between better physical functioning and lower stroke risk was independent of age, gender, BMI, systolic blood pressure, cholesterol levels, smoking status, physical activity, prevalent illness, social class, alcohol consumption, and forced expiratory volume in one second. This association persisted after excluding strokes that occurred within the first two years of follow-up.

Suggested Reading
Myint PK, Surtees PG, Wainwright NWJ, et al. Physical health-related quality of life predicts stroke in the EPIC-Norfolk. Neurology. 2007;69(24):2243-2248.

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