Clinical Health Updates

Warfarin > aspirin in preventing strokes in pts older than 75 with A fib (BAFTA)

Clinical Question:
In patients older than 75 years with atrial fibrillation, is warfarin more effective than aspirin at preventing strokes?

Bottom Line:
This study confirms that warfarin titrated to a target international normalized ratio (INR) of 2.0 to 3.0 is more effective than 75 mg aspirin in preventing strokes without significantly increasing the risk of bleeding complications.

Reference:
Mant J, Hobbs FD, Fletcher K, et al, for the BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.

Study Design:
Randomized controlled trial (single-blinded)

Synopsis:
Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. The investigators assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients. 973 patients aged 75 years or over (mean age 81.5 years, SD 4.2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2-3) or aspirin (75 mg per day). Follow-up was for a mean of 2.7 years (SD 1.2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269. There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8%vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43-1.73; absolute risk reduction 0.2%, -0.7 to 1.2).

Coenzyme Q10 ineffective in Parkinson’s disease

Clinical Question:
Does coenzyme Q10 improve symptoms in patients with midstage Parkinson’s disease?

Bottom Line:
Coenzyme Q10, when added to stable drug regimens, is no better than placebo in improving symptoms of midstage Parkinson’s disease.

Reference:
Storch A, Jost WH, Vieregge P, et al., for the German Coenzyme Q10 Study Group. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Arch Neurol 2007;64:938-944.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q(10) (CoQ(10)) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons. Given the background above the authors then determined whether nanoparticular CoQ(10) is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations. They did a multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial. The participating clinics are academic and nonacademic movement disorder clinics. One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment were included. Intervention Random assignment to placebo or nanoparticular CoQ(10) (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment. The subjects underwent evaluation with the Unified Parkinson’s Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits. One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were -3.69 for the placebo group and -3.33 for the CoQ(10) group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ(10) group. The frequency and quality of adverse events were similar in both treatment groups.

Folate prevents stroke

Clinical Question:
Does folic acid supplementation prevent stroke?

Bottom Line:
If these authors identified all the relevant clinical trials, folic acid supplementation for at least 36 months prevents stroke, especially in patients with no prior history of stroke.

Reference:
Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876-1882.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Up to now the efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease remains controversial. So the investigators did a meta-analysis of relevant randomised trials to assess the efficacy of folic acid supplementation in the prevention of stroke. They collected data from eight randomised trials of folic acid that had stroke reported as one of the endpoints. Relative risk (RR) was used as a measure of the effect of folic acid supplementation on the risk of stroke with a random effect model. The analysis was further stratified by factors that could affect the treatment effects. Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0.82, 95% CI 0.68-1.00; p=0.045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0.71, 0.57-0.87; p=0.001), a decrease in the concentration of homocysteine of more than 20% (0.77, 0.63-0.94; p=0.012), no fortification or partly fortified grain (0.75, 0.62-0.91; p=0.003), and no history of stroke (0.75, 0.62-0.90; p=0.002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant.

Brief evaluation aids diagnosis of dementia

Clinical Question:
Can simple interviews of caregivers coupled with recall testing aid the diagnosis of dementia?

Bottom Line:
The combination of an 8-item test administered to caregivers coupled with a 10-word recall list is very good at ruling out dementia and is relatively good at diagnosing it in elderly patients with cognitive, behavioral, and mood disorders.

Reference:
Galvin JE, Roe CM, Morris JC. The evaluation of cognitive impairment in older adults: combining brief informant and performance Measures. Arch Neurol 2007;64:718-724.

Study Design:
Cross-sectional

Synopsis:
To combine the AD8, a brief informant interview, with performance measures to develop a brief screening tool to improve detection of cognitive impairment and dementia in general practice. The AD8 was administered to informants. Clinicians conducted independent patient evaluations and administered the Clinical Dementia Rating Scale and a 30-minute neuropsychological battery. Logistic regression was used to determine the best combination of brief tests to correctly classify patients as having no dementia, uncertain dementia, or dementia. The area under the receiver operator characteristic curve (AUC) evaluated the discriminative ability of the combined tests. Patients (n = 255) were consecutive referrals to a dementia clinic. Patients had a mean +/- SD age of 73.3 +/- 11.3 years, with 13.7 +/- 3.0 (mean +/- SD) years of education. The sample was 56% women; 77% of patients were white. Main Outcome Measure Dementia classification. RESULTS: A model combining the AD8 interview (odds ratio, 1.91; 95% confidence interval, 1.6-2.3) and the Consortium to Establish a Registry for Alzheimer Disease 10-item Word List Recall (odds ratio, 1.43; 95% confidence interval, 1.2-1.7) predicted dementia with 91.5% correct classification (AUC = 0.968; 95% confidence interval, 0.93-0.99). A cutoff of 2 or greater on the AD8 and less than 5 items remembered on the Word List Recall was sensitive (94%) and specific (82%). For cognitive impairments not meeting dementia criteria, combining AD8 (odds ratio, 2.31; 95% confidence interval, 1.3-4.0) and Word List Recall (odds ratio, 1.42; 95% confidence interval, 1.1-1.8) was most predictive (AUC = 0.91; 95% confidence interval, 0.8-1.0). Using the same cutoffs as those used for dementia gave the best combination of sensitivity (85%) and specificity (84%).

*A copy of the AD8 table with scoring rules may be found at

http://alzheimer.wustl.edu/About_Us/PDFs/AD8form2005.pdf.

Sustained-release ropinirole improves advanced Parkinson’s (EASE-PD)

Clinical Question:
Does sustained-release ropinirole, as adjunctive therapy to levodopa, improve symptoms in patient with advanced Parkinson’s disease?

Bottom Line:
Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.

Reference:
Pahwa R, Stacy MA, Factor SA, et al, for the EASE-PD Adjunct Study Investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007;68:1108-1115.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors evaluated the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations. In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily “off” time. At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily “off” time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily “on” time and “on” time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups.

Combo sumatriptan-naproxen slightly better than either alone for acute migraine

Clinical Question:
Is a single tablet containing sumatriptan and naproxen superior to either agent alone in the treatment of acute migraine in adults?

Bottom Line:
Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.

Reference:
Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for the acute treatment of migraine: A randomized trial. JAMA 2007;297:1443-1454.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy. The authors evaluated the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine. Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack. Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain. Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan-naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan-naproxen sodium and each monotherapy. Sumatriptan-naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan-naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan-naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan-naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan-naproxen sodium and sumatriptan monotherapy.

Surgery better than no surgery for spinal stenosis

Clinical Question:
In adults with spinal stenosis, is surgical treatment more effective than nonsurgical treatment?

Bottom Line:
Although patients improved over the 2-year follow-up regardless of initial treatment, those undergoing decompressive surgery reported greater improvement regarding leg pain, back pain, and overall disability. The relative benefit of initial surgical treatment diminished over time, but outcomes of surgery remained favorable at 2 years. Longer follow-up is needed to determine if these differences persist.

Reference:
Malmivaara A, Slatis P, Heliovaara M, et al, for the Finnish Lumbar Spinal Research Group. Surgical or nonoperative treatment for lumbar spinal stenosis? a randomized controlled trial. Spine 2007;32:1-8.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
No previous randomized trial has assessed the effectiveness of surgery in comparison with conservative treatment for spinal stenosis. So authors from Finland assessed the effectiveness of decompressive surgery as compared with nonoperative measures in the treatment of patients with lumbar spinal stenosis. They did a randomized trial in four university hospitals agreed on the classification of the disease, inclusion and exclusion criteria, radiographic routines, surgical principles, nonoperative treatment options, and follow-up protocols. A total of 94 patients were randomized into a surgical or nonoperative treatment group: 50 and 44 patients, respectively. Surgery comprised undercutting laminectomy of the stenotic segments in 10 patients augmented with transpedicular fusion. The primary outcome was based on assessment of functional disability using the Oswestry Disability Index (scale, 0-100). Data on the intensity of leg and back pain (scales, 0-10), as well as self-reported and measured walking ability were compiled at randomization and at follow-up examinations at 6, 12, and 24 months. Both treatment groups showed improvement during follow-up. At 1 year, the mean difference in favor of surgery was 11.3 in disability (95% confidence interval [CI], 4.3-18.4), 1.7 in leg pain (95% CI, 0.4-3.0), and 2.3(95% CI, 1.1-3.6) in back pain. At the 2-year follow-up, the mean differences were slightly less: 7.8 in disability (95% CI, 0.8-14.9) 1.5 in leg pain (95% CI, 0.3-2.8), and 2.1 in back pain (95% CI, 1.0-3.3). Walking ability, either reported or measured, did not differ between the two treatment groups.

Midodrine prevents recurrent vasovagal syncope in kids

Clinical Question:
Does midodrine reduce the frequency of syncopal episodes in children with recurrent vasovagal syncope?

Bottom Line:
In this flawed study, midodrine (ProAmatine) was more effective than usual care in reducing the frequency of syncope in children with recurrent vasovagal syncope.

Reference:
Qingyou Z, Junbao D, Chaoshu T. The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope. J Pediatr 2006;149:777-780.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
In this Chinese study, the authors determine whether midodrine hydrochloride therapy can prevent vasovagal syncope (VVS) in pediatric patients. They included children with recurrent syncope (n = 26) randomly assigned into 2 groups. Group I comprised children given midodrine hydrochloride as first-line therapy in addition to conventional therapy, and group II comprised patients receiving conventional therapy only. Repeat head-up tilt (HUT) testing and follow-up of least 6 months were conducted to evaluate the therapeutic effectiveness and side effects of midodrine in treating VVS in children. The HUT-based effective rate was significantly higher in group I than in group II (75% vs 20%; P < .05). During the follow-up period, the recurrence of syncope was significantly lower in group I than in group II (P < .05).

ABCD rule predicts 7- and 30-day stroke risk in pts with TIA

Clinical Question:
Do clinical factors reliably predict which patients with transient ischemic attacks will experience a stroke in the next 30 days?

Bottom Line:
The findings validate the predictive value of the ABCD score in identifying hospitalized TIA patients with a high risk of early stroke and provide further evidence for its potential applicability in clinical practice.

Reference:
Tsivgoulis G, Spengos K, Manta P, et al. Validation of the ABCD score in identifying individuals at high early risk of stroke after a transient ischemic attack: a hospital-based case series study. Stroke 2006;37:2892-2897.

Study Design:
Decision rule (validation)

Synopsis:
A simple score derived in the Oxfordshire Community Stroke Project (ABCD score) was able to identify individuals at high early risk of stroke after a transient ischemic attack (TIA) both in a population-based and a hospital-referred clinic cohort. The authors aimed to further validate the former score in a cohort of hospitalized TIA patients. They retrospectively reviewed the emergency room and hospital records of consecutive patients hospitalized in our neurological department with a definite TIA according to the World Health Organization (WHO) criteria during a 5-year period. The 6-point ABCD score (age [<60 years=”0,”> or =60 years=1]; blood pressure [systolic < or =”140″ or =”90″ hg=”0,”>140 mm Hg and/or diastolic >90 mm Hg=1]; clinical features [unilateral weakness=2, speech disturbance without weakness=1, other symptom=0]; duration of symptoms [<10 minutes=”0,” minutes=”1,”> or =60 minutes=2]) was used to stratify the 30-day stroke risk.
ABCD score 7-day stroke risk (95% CI) 30-day stroke risk (95% CI)
2 or less 0 0
3 1.7% (0%-5.1%) 3.5% (0%-8.2%)
4 7.6% (1.2%-14%) 7.6% (1.2%-14%)
5 19.1% (7.8%-30.4%) 21.3% (10.4%-33%)
6 18.8% (0%-37.9%) 31.3% (8.6%-54%)

There is one limitation to this generally well-done study: The ABCD model was developed in an outpatient setting to predict risk for all TIA patients. This study only addresses its application to hospitalized patients.

Synthetic cannabinoid effective for chronic neuropathic pain

Clinical Question:
Are synthetic cannabinoids effective in the treatment of chronic neuropathic pain?

Bottom Line:
Synthetic cannabinoids may be effective in the treatment of chronic neuropathic pain. In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed

Reference:
Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290:1757-762.

Study Design:
Cross-over trial (randomized)

Synopsis:
1′,1’dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain. The authors examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans. They did a randomized, placebo-controlled, double-blind crossover trial conducted in Germany from May-September 2002. Twenty-one patients (8 women and 13 men) aged 29 to 65 years (mean, 51 years) who had a clinical presentation and examination consistent with chronic neuropathic pain (for at least 6 months) with hyperalgesia (n = 21) and allodynia (n = 7). Patients were randomized to two 7-day treatment orders in a crossover design. Two daily doses of CT-3 (four 10-mg capsules per day) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days. After a washout and baseline period of 1 week each, patients crossed over to the second 7-day treatment period. Visual analog scale (VAS) and verbal rating scale scores for pain; vital sign, hematologic and blood chemistry, and electrocardiogram measurements; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale; and adverse effects. The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 9.86 [21.43]; P =.02). Eight hours after intake of the drug, the pain scale differences between groups were less marked. No dose response was observed. Adverse effects, mainly transient dry mouth and tiredness, were reported significantly more often during CT-3 treatment (mean [SD] difference, -0.67 [0.50] for CT-3-placebo sequence vs 0.10 [0.74] for placebo-CT-3 sequence; P =.02). There were no significant differences with respect to vital signs, blood tests, electrocardiogram, Trail-Making Test, and Addiction Research Center Inventory-Marijuana scale. No carryover or period effects were observed except on the Trail-Making Test.