Study flaws hinder review of TCM for stroke

Medical Tribune September 2009 P3

The poor quality of published data prevents a proper assessment of the efficacy of traditional Chinese medicine (TCM) remedies for stroke, a study suggests.

Despite finding 11,234 journal articles on TCM post-stroke therapies, the researchers from Italy and China were unable to conduct a meta-analysis as intended. Thirty four randomized controlled trials (RCTs) were found, but wide variation in the studies prevented them from being pooled. Moreover, all but one RCT reported results in favor of TCM, prompting the authors to suggest a “strong publication bias.”

“The key to lead to evidence-based practices is establishing a consensus on standardized relevant outcome measures and then designing and conducting appropriate RCTs that adopt those standards,” they wrote.

[Stroke 2009 Aug;40(8):2797-804]

Cognitive rehab shows promise for stroke patients

Medical Tribune September 2009 SFI
David Brill

A cognitive rehabilitation program used after traumatic brain injuries could also help stroke patients to overcome lingering attention deficits, a new study shows.

Stroke survivors who received Attention Process Training (APT) within 4 weeks were better able to concentrate on visual and auditory tasks 6 months later, New Zealand researchers reported in the journal Stroke.

It is the first study to test APT in an important but neglected area of stroke rehabilitation, the researchers say. Concentration problems are very common in stroke patients – affecting quality of life and contributing to poor functional outcomes – yet specific interventions remain largely unstudied.

Singapore stroke expert Dr. Nagaendran Kandiah, a consultant neurologist at the National Neuroscience Institute (NNI), said that APT could be a useful tool for local patients but that equivalent programs would need to be tailored to the language and culture. Researchers at the NNI are already “actively working on this”, he said.

Further research is also needed to better establish the local prevalence of post-stroke attention deficits, he added. Preliminary data from NNI suggest that about 15 to 20 percent of patients have cognitive difficulties, including poor attention, following a stroke.

“There is a significant amount of literature that shows that cognitive training is useful for post-stroke patients. The awareness that attention deficits and other cognitive deficits are common and can be potentially treated needs to be emphasized both to the public and medical community,” said Nagaendran.

The Stroke study researchers randomized 78 stroke patients to receive standard care alone or standard care plus up to 30 hours of APT (mean 13.5 hours). [2009 Jul 23; Epub ahead of print]

APT patients scored significantly better on the Integrated Visual Auditory Continuous Performance Test (IVA-CPT) Full-Scale Attention Quotient (FSAQ), at 5 weeks and 6 months after randomization. The test measures reaction times to auditory and visual stimuli, and can distinguish between genuine attention to the task and impulsive responding.

There were however no significant differences between the groups in other cognitive performance indicators, or broader outcome measures such as the Physical Component Score.

Lead author Dr. Suzanne Barker-Collo, a clinical psychologist and senior lecturer at the University of Auckland, said that she was disappointed that the intervention did not show benefit across other domains but was pleasantly surprised at the magnitude of effect on the primary outcome.

“We were expecting maybe half a standard deviation difference between the groups, and the effect we found was about four times that,” she said.

There are several cognitive rehabilitation packages available but very little evidence on how best to use them in stroke patients, added Barker-Collo, whose ongoing research seeks to better delineate the profile and time course of cognitive deficits after stroke. She is also reviewing the data from the present study to identify factors that could predict which patients will respond best to APT.

“I think cognition after stroke in general has been ignored to some degree,” she said. “A lot of rehabilitation time is spent on more physical tasks like walking, bathing and dressing – it’s very practical but very often the time spent on that means that not as much time is spent on other things like attention and memory, which are a bit less obvious but can still impact on other functional outcomes. Attention deficit in particular is a very, very common problem.”

Stockings ineffective for DVT prevention after stroke

Medical Tribune July 2009 SFIV

David Brill

Compression stockings do not reduce the risk of deep vein thrombosis (DVT) in stroke patients, despite their widespread usage for this purpose, a major international study shows.

The multicenter CLOTS* 1 trial, involving 2,518 patients, found that stockings were not only ineffective, but increased the risk of ulcers, blisters and skin necrosis.

The results have prompted calls for revision of guidelines, as experts point to substantial cost and time savings from abandoning the practice. Some hospitals in Asia are already reviewing the findings, and may stop using stockings for stroke patients in the near future.

The trial was carried out across 64 centers in the UK, Australia and Italy. DVT occurred in 10 percent of patients who were randomized to thigh-length stockings, and 10.5 percent who were randomized to no stockings. [Lancet 2009 Jun 6;373(9679):1958-65]

All patients were immobile and had been admitted to hospital within a week of acute stroke. They were assessed for DVT at 7 to 10 days, and again at 25 to 30 days.

“In this study, we have shown conclusively that compression stockings do not work for stroke patients,” said study author Professor Martin Dennis of the University of Edinburgh, UK. “National guidelines need to be revised and we need further research to establish effective treatments in this important group of patients.

“Given that most national guidelines recommend stockings in at least some patients, the results of our study will affect the treatment of millions of patients each year. Abandoning this ineffective and sometimes uncomfortable treatment will free up significant health resources – both funding and nurse time – which might be better used to help stroke patients,” he said.

DVT is thought to be less common among Asians than Western populations, but compression stockings are nonetheless commonly used for prophylaxis in stroke patients with lower limb weakness. [Ann Acad Med Singapore 2007 Oct;36(10):815-20]

Dr. Lee Sze Haur, senior neurology consultant at the National Neuroscience Institute (NNI), Singapore, said, however, that this practice “will likely change” in light of the new data.

“Based on the CLOTS trial, there is good reason to consider discontinuing the use of graded compression stockings for prevention of DVT in patients with acute stroke, as this will save cost and time as well as reduce the incidence of skin complications,” said Lee.

National University Hospital, meanwhile, is currently reviewing the evidence before changing its use of compression stockings, according to senior neurology consultant Dr. Bernard Chan. He noted that stockings remain effective for DVT prevention in post-surgical patients, but said that the usage for stroke has been “a long-standing practice without good clinical evidence.”

Two other studies are in progress to establish alternatives for post-stroke DVT prevention. CLOTS 2 compares thigh-length and below-knee stockings, but is now expected to finish early in light of CLOTS 1. The third trial is testing the effects of intermittent pneumatic compression, and is scheduled for completion in 2013.

Blisters, ulcers, skin breaks and necrosis were reported in 64 of the 1,256 patients given stockings in CLOTS 1 (5 percent), compared to just 16 of 1,262 control patients (1 percent; odds ratio 4.18; 95 percent CI 2.40 – 7.27).

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*CLOTS: Clots In Legs Or Stockings After Stroke

Stroke prevention under-used in the elderly

Medical Tribune June 2009 P1&6
David Brill

Elderly patients are missing out on life-saving stroke prevention drugs in primary care, according to a report in the British Medical Journal.

Stroke patients aged 80 to 89 were almost half as likely to be receiving secondary prevention treatments as those aged 50 to 59, the researchers found.

This discrepancy in treatment was not justified by outcomes, however – receipt of the drugs halved mortality risk, regardless of age.

The study of 12,380 patients took place in England but carries an important message for Singapore, according to stroke expert Associate Professor Lee Kim En, senior consultant and head of the department of neurology at the National Neuroscience Institute, Singapore.

“We do not have local figures, but similar findings are expected in Singapore. This is a timely article serving as a reminder that social support must include ensuring the elderly receive their medications,” he said.

“As doctors, we have a responsibility to motivate our elderly patients to continue with treatment regardless of challenges, constraints and limitations. All primary care physicians must share this responsibility.”

The researchers reviewed data from 113 general practices to identify over-50s who had a stroke between 1995 and 2005 and survived the first 30 days. Therapy had to be initiated within 90 days of the stroke to be included in the study as secondary prevention. [BMJ 2009 Apr 16;338:b1279]

Overall treatment rates were low: 25.6 percent of men and 20.8 percent of women were receiving secondary prevention. Mortality within one year of stroke was 5.7 percent for patients receiving treatment, compared to 11.1 percent among those receiving no such therapy.

Treatment rates did not vary by socioeconomic status but dropped markedly with age – from 26.4 percent of patients aged 50 to 59, to 15.6 percent of those aged 80 to 89. Just 4.2 percent of over-90s were receiving treatment.

Lipid lowering drugs were particularly under-used in the elderly – the odds ratio for receipt of these therapies was 0.44 for 80 to 89 year-olds, compared with 50 to 59 year-olds (95 percent CI, 0.33 to 0.59; P<0.001).

The study did not explore the reasons for the observed age bias, but lead researcher Professor Rosalind Raine speculated that responsibility could lie with both patients and prescribers.

“We can’t leave an attack of clinical bias on the doors of the clinicians until we’ve really excluded all of the other explanations,” said Raine, professor of health care evaluation at University College London. “Patients are increasingly more informed, and so there is also a balance about what they’re asking for.”

Some experts have suggested that GPs may be unsure about the efficacy of secondary prevention drugs in the elderly since they are often excluded from clinical trials, she said. She noted, however, that there is a growing body of evidence – particularly from meta-analyses – to support the benefits of this practice. The mortality findings from the present study further underscore this point in a real-world, general practice population, she added.

Raine also ruled out the possibility that prescribers may be worried about adherence in the elderly, since the discrepancy was only evident for lipid lowering drugs and not for cheaper therapies such as antihypertensive and antithrombotic drugs. She expressed her concern that it could be the relative cost of the drugs which is driving this particular effect.

“It does make you wonder if lay beliefs about values of people in society are actually being transposed into the clinical situation. But I do not have evidence on which to base that – it’s only by exclusion of some of the other likely explanations,” she said.

Orbit of JUPITER extends to stroke prevention

Medical Tribune April 2009 P12
David Brill

The benefits of rosuvastatin for patients with elevated high sensitivity C-reactive protein (hsCRP) could include a reduction in the risk of stroke, according to new data from the JUPITER* trial.

The relative risk of any stroke was reduced by 48 percent among patients taking the drug, the study’s investigators reported recently at the International Stroke Conference in San Diego, US.

This finding appears to have been driven largely by a reduction in ischemic stroke rates – just 23 of the 8,901 patients in the treatment group experienced this outcome compared to 47 in the equally-sized placebo group (hazard ratio 0.49; P=0.004). Rates of hemorrhagic stroke, conversely, were not significantly different – six events occurred in the intervention group and nine in the placebo group (hazard ratio 0.67; P=0.44).

The new stroke data bring fresh fuel to the debate about the role of hsCRP in risk stratification and the use of statins for primary prevention – questions that have risen to prominence since the presentation of the original JUPITER study at the American Heart Association’s annual Scientific Sessions in November last year. [N Engl J Med 2008 Nov 20;359(21):2195-207]

“The bottom line is that we now have conclusive evidence for the efficacy of statins specifically for primary prevention of stroke,” said Dr. Robert Glynn of Brigham and Women’s Hospital in Boston, US, one of the JUPITER investigators who presented the latest findings.

LDL cholesterol is not typically considered as a risk factor for stroke in patients without established vascular disease, said Glynn, noting that CRP, however, has been shown to be a valid predictor of stroke risk. Statin therapy, which lowers levels of both biomarkers, could therefore be particularly beneficial for stroke prevention in patients with elevated CRP, he added.

The ARIC** study implicated hsCRP as a risk marker for stroke. The study, which involved 12,762 middle-aged men and women followed up for around 6 years, showed that those with an hsCRP level above 3 mg/L had an adjusted hazard ratio for ischemic stroke of 2.7 when compared to those with an hsCRP level below 1 mg/L. [Arch Intern Med 2005 Nov 28;165(21):2479-84]

The SPARCL*** study, meanwhile, demonstrated the benefits of atorvastatin (80 mg daily) for secondary stroke prevention in a population of 4,731 patients with a recent history of stroke or transient ischemic attack. After a median follow up of 4.9 years, overall stroke risk was reduced by 16 percent in the statin group compared to placebo (adjusted hazard ratio 0.84; P=0.03) with comparable mortality between the two groups. There was, however, an increase in the number of hemorrhagic strokes: 55 events occurred in the atorvastatin group and 33 in the placebo group. [N Engl J Med 2006 Aug 10;355(6):549-59]

The original JUPITER trial found that after a median of 1.9 years of follow up rosuvastatin (20 mg daily), as compared to placebo, reduced the relative risk of major cardiovascular events by 44 percent in a cohort of 17,802 overtly healthy subjects with baseline hsCRP levels above 2 mg/L and LDL cholesterol levels below 130 mg/dL (hazard ratio 0.56; P<0.00001). Over the course of the study hsCRP levels were reduced by 37 percent and LDL cholesterol levels by 50 percent. *JUPITER: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin **ARIC: Atherosclerosis Risk in Communities *** SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels

Study brings new hope for acute ischemic stroke treatment

Medical Tribune December 2008 P6
David Brill

The window of opportunity for treating acute ischemic stroke (AIS) is set to widen, bringing hope to previously untreatable patients, a stroke expert said recently.

The recently published European Cooperative Acute Stroke Study (ECASS) III, showed that thrombolysis with alteplase can reduce the long-term disability risk, when given up to 4.5 hours after symptom onset.

Present guidelines limit the use of alteplase to a window of 3 hours post-stroke, but less than 2 percent of patients currently receive the treatment.

Dr. Lee Kim En, head of the department of neurology at the National Neuroscience Institute in Singapore, said at a recent press conference that the ECASS III data are convincing and it is "just a matter of time" until international approval is gained and guidelines adjusted accordingly.

"More patients will benefit from this extension of the window," he said, noting that treatment within 3 hours is typically very difficult to achieve since patients rarely arrive at hospital within this timeframe.

"Alteplase is the only proven therapy for AIS, which is why we are working very hard to extend the benefits to the other 98 percent of patients."

ECASS III randomized 821 AIS patients who presented during the extended post-stroke window to receive either alteplase or placebo. [N Engl J Med 2008 Sep 25;359(13):1317-29]
A favorable outcome at 90 days, as defined by a score of 0 or 1 on the modified Rankin scale for stroke disability, was reported for 52.4 percent of patients in the treatment group compared to 45.2 percent in the placebo group (odds ratio 1.34; P=0.04).

Alteplase increased the risk of intracranial hemorrhage, which affected 27 percent of patients in the treatment group compared with 17.6 percent in the placebo group (P=0.001). Mortality, however, was not significantly different between the groups, suggesting that the increased risk was outweighed by the overall benefits of treatment, according to Lee.

He added that it remains important to treat stroke as quickly as possible, and that the study findings should not be seen as an excuse to delay this process.

"Time is brain – every minute counts here. Having more time does not mean you can take more time… if you can give treatment within a minute of coming through the door that’s the best thing to do."

The new protocol is already being introduced at Tan Tock Seng Hospital, Singapore, which treats around 2,000 AIS patients each year. At present just 20 to 25 of these receive alteplase, Lee said.

While the hospital is working hard to accelerate its internal processing of AIS patients, increasing public awareness of stroke symptoms will also be an important step towards improving outcomes, he said.

In the event that a stroke patient presents to their GP, the physician can also help by documenting the time of symptom onset and sending them straight to hospital, he added.

ECASS III was conducted between July 2003 and February 2008 at 30 sites across 19 European countries. Alteplase was given intravenously at a dosage of 0.9 mg per kg. The trial was sponsored by Boehringer- Ingelheim, which manufactures the drug.

Aspirin alternative could benefit Chinese stroke patients

Medical Tribune July 2008 P9
David Brill

Cilostazol is as effective as aspirin at preventing stroke recurrence but carries a lower risk of brain bleeding events, according to the results of a pilot study published in The Lancet Neurology.

These findings suggest that the drug could be a safer alternative to aspirin for secondary stroke prevention, particularly in Chinese populations, which have high rates of hemorrhagic stroke and other bleeding events.

Lead author Dr. Yining Huang of the Peking University First Hospital in Beijing, said that cilostazol could be used routinely in future, but should only be given to patients at high risk of hemorrhage. He added that aspirin is more cost effective and should remain first-line treatment for the majority of patients.

The study also found that mild side effects such as headache, dizziness and palpitations were more common among patients taking cilostazol.

The researchers conducted a randomized double-blind trial comprised of 720 patients who had experienced an ischemic stroke within the past 6 months. Participants took aspirin (100 mg per day) or cilostazol (100 mg twice per day) for between 12 and 18 months. [Lancet Neurol 2008 Jun;7(6):494-499]

Over the study period seven brain bleeding events occurred in the aspirin group, compared to just one in the cilostazol group (P=.034).

Cilostazol also reduced the overall risk of stroke recurrence by 38.1 percent but this comparison was not statistically significant. The authors suggest that the small sample size and short follow-up duration meant that the study was underpowered to assess the relative efficacies of the two drugs.

Dr. Charles Siow, a consultant neurologist at the Siow Neurology Headache and Pain Centre in Singapore said: “If the study can be replicated and the efficacy confirmed in a larger study, cilostazol may be an option for stroke prevention.” Siow added that cilostazol, a phosphodiesterase 3 inhibitor, could replace aspirin in routine practice only if the issues of side effects and cost were resolved.

Stroke is a leading cause of death in China, and there is a high proportion of hemorrhagic
stroke. Research has demonstrated that stroke rates vary across different regions but are typically higher than in Western countries. [Stroke 2006 Jan;37(1):63-8]

A larger-scale multicenter trial comparing cilostazol with aspirin is already underway in Japan. Two thousand six hundred patients have been enrolled and are due to be followed up for between 1 and 5 years. Huang said that the interim results were “very positive.”

The trial is expected to finish in December this year and will be published in 2010.