In this issue...

• Chronic Headache: A Potential Risk Factor for Stroke?
• Remission of Depression: A Step Towards Improved Cognitive Function
• Large Artery Disease Linked To Early Recurrent Stroke
• Lowering Blood Pressure In Stroke Patients Reduces The Risk Of Cognitive Decline
• Update On Antiplatelet Therapy For Stroke Prevention
• Conclusion
• Antibiotic Use Linked To Stroke Prevention
• Dual Hormone Replacement Therapy: Preventive Measure or a Risk Factor
• New Approvals Internationally
• TICKLE YOUR BRAIN

Chronic Headache :
A Potential Risk Factor for Stroke?

 

Chronic headache is an independent predictor of stroke among men, as per the results of a study published in the May 12, 2003 issue of Archives of Internal Medicine.

The potential relationship between migraine and increased risk of stroke has become somewhat clearer in recent years. However, there is very scarce data on the possible association between chronic unspecified headache and the risk of stroke. The present prospective study aimed at exploring the link between chronic headache and risk of stroke. In addition, the researchers also wanted to determine whether this association was independent of other cardiovascular risk factors i.e. diabetes, hypertension, smoking and serum cholesterol levels.

A huge cohort of 16992 men and 18064 women was analysed with the help of a self-administered questionnaire. The end point was the incidence of stroke (defined as first nonfatal event or stroke death without a preceding nonfatal event).

The researchers found that chronic headache was more common in females as compared to males. During the first year of follow-up, men with headache had a 4-fold higher risk of stroke as compared with men without headache. Interestingly, this association was markedly attenuated with an increasing duration of follow-up
(Table 1). The headache associated hazard ratios of stroke in women also showed a positive trend, although this association was not statistically significant.

Adjustments for smoking, blood pressure, BMI, diabetes and serum cholesterol led to only a slight decrease in hazard ratios. The increased stroke risk was more robust for ischemic stroke, although hemorrhagic stroke also showed a statistically insignificant but positive association with headache.

Since the association between headache and the risk of stroke was particularly strong during a short follow-up, chronic headache may be a marker of the underlying disease process leading to acute stroke.

Remission of Depression: A Step Towards Improved Cognitive Function

According to a 2-year study published in the June 2003 issue of American Journal of Psychiatry, the initial cognitive impairment caused by depression following stroke is reversible if the depression is successfully treated.

Kenji Narushima, MD, University of Iowa College of Medicine, US and group compared a group of 17 depressed patients with a group of non-depressed patients having similar characteristics with regards to type of stroke, size of lesion, age, race, etc. The comparison between the two groups was based on the scores of mini mental state examination (MMSE).

Mean initial MMSE score for depressed patients was 23.3, compared with 26.3 for the non-depressed patients. The MMSE score increased significantly to 26.6 in the depressed group at 3 months and remained approximately stable for up to 2 years. The mean MMSE score in the non-depressed group showed no significant change in a 12-month follow-up.

The researchers said that the findings indicate “the sustained improvement in cognitive function after depression is lifted.”

After remission of depression, scores for both the groups were almost identical at 6 months, indicating that the effects of brain infarction and depression on cognitive function are additive. The researchers believe that their study demonstrates for the first time that treatment or remission of depression results in improved cognition for more than 2 years. The early detection of post stroke depression would maximize cognitive function, the researchers concluded.

Large Artery Disease Linked To Early Recurrent Stroke

 

The aetiology of a first stroke predicts the likelihood of having an early recurrent event, with large artery disease having the worst odds ratio, as per the results presented at the 12th European Stroke Conference on May 23, 2003 .

As the evidence of aetiological subtype of stroke and its recurrence is very scanty, Joanna Lovett (a research neurologist at Oxford University , UK ) and team decided to look at whether patients with large artery disease were at a higher risk.

In a huge meta-analysis of four studies involving 1,670 stroke patients, the researchers recorded aetiological subtypes of the strokes suffered.

The risk of a recurrent stroke was found to be significantly associated with the subtype of the first stroke (p<0.001) at both, day 7 and day 30.

Patients whose first stroke involved large artery disease had by far the greatest chance of recurrence at both day 7 and 30 [odds ratio (OR)= 3.1]. Although large artery disease was present only in 18% of the patients, it was present in 38% of patients who had recurrences. In contrast, at 30 days, small vessel disease had an OR of only 0.2 only for recurrent stroke.

“People with large artery disease are those who are going to suffer most recurrent strokes. Therefore, we should identify them early and refer them for carotid endarterectomy, which is effective if performed in the first couple of weeks,”
concluded Dr. Lovett.

Lowering Blood Pressure In Stroke Patients Reduces The Risk Of Cognitive Decline

 

High blood pressure and stroke are associated with increased risk of dementia and cognitive decline, as per a study conducted by Dr. John Chalmers ( University of Sydney, Australia ) and colleagues.

In a randomized, double-blind, placebo-controlled trial published in the May 12, 2003 issue of Archives of Internal Medicine, the researchers examined the effect of blood pressure lowering on cognition and dementia in 6105 patients with a history of stroke or TIA. The patients received either perindopril + indapamide combination or placebo and the mean follow-up was 3.9 years.

Dementia was observed in 6.3% patients in the active group as compared to 7.1% in the placebo group. The team reported that 9.1% patients in treatment group versus 11% patients in the placebo group experienced cognitive decline (p=0.10). Active treatment was associated with a 34% lower risk of composite end point of dementia with recurrent stroke and a 45% reduction in risk for cognitive decline (p = 0.001)

 

Update On Antiplatelet Therapy For Stroke Prevention

 

The high rates of mortality and long-term disability associated with ischemic stroke, coupled with its prevalence, necessitates good, long-term preventive strategies. Despite recent advances in immediate stroke treatment, prevention is still, by far, the best method for reducing stroke morbidity.

Options for stroke prevention before/after a first TIA/stroke include drug therapy, life style modification and surgery (carotid endarterectomy) (Table 1).

The list for preventive measures is continually expanding as the understanding for the underlying causes of stroke is becoming clear. This article outlines the current consensus on the role of antiplatelet therapy in stroke prevention.

Role of platelets in ischemic stroke
A potential relationship between platelet activation and cerebral ischemia was first suspected by Denny Brown, Russel and Hollen Horst in the 1960s. Compounds that are potent inhibitors of platelet activation, adhesion and aggregation therefore provide a powerful intervention in cerebral ischemia. However, despite the overwhelming success of this therapy for the treatment of myocardial ischemia in last decade, antiplatelet therapy for stroke has received little attention, until very recently. Advances in stroke trials with an improved understanding of the pathophysiology of stroke have allowed nihilism surrounding stroke therapy in the 1960s to be replaced by the cautious optimism of the 1990s.

Issues concerning antiplatelet therapy
The precise role of antiplatelet therapy in secondary stroke prevention remains a matter of some debate. Although antiplatelet agents have been shown to be active in the prevention of secondary stroke, questions of effective doses and regimen still remain unanswered. In addition, hematological and gastrointestinal side effects of these agents remain a clinical concern for patients and prescribing physicians.

 

Antiplatelet therapy - early trends
During the 1970s and 1980s, three antiplatelet agents aspirin, dipyridamole and ticlopidine were investigated for secondary prevention of stroke. The earliest trials of these agents were often hampered by small sample size and heterogenous populations. As a result, the earlier trials yielded equivocal/ contradictory results. But by the end of the 1980s, a stronger body of evidence in favour of these agents began to emerge due largely to the introduction of meta-analysis. It has been nearly 25 years since aspirin therapy was first demonstrated to be clinically efficacious for secondary stroke prevention. Although it is now well established that antiplatelet therapy with either aspirin or ADP receptor antagonists viz. ticlopidine/clopidogrel is clearly efficacious in reducing neurological sequelae, examination of these agents for treatment of acute cerebral ischemia has received little attention either clinically or experimentally.

 

Aspirin
Several small, early studies of aspirin for prevention of secondary stroke were unable to confirm a beneficial effect. In late 1991, the United Kingdom Transient Ischemic Attack (UK-TIA) trial and Swedish Aspirin Low Dose Trial (SALT) suggested the efficacy of aspirin therapy for preventing secondary stroke in patients with a history of cerebrovascular disease. Also, in 1991, the Dutch TIA trial evaluated the effects of low-dose (30 mg/day) and medium-dose (283 mg/day) among 3131 patients with TIA/stroke. There was no significant difference in efficacy between aspirin doses. More important from a clinical standpoint, however, was the finding that lower-dose aspirin was associated with a reduced incidence of gastric discomfort and gastric bleeding. Another meta-analysis by Algra and Van Gijn restricted to aspirin therapy in stroke patients. There was a risk reduction by 13% in risk of stroke, MI/vascular death at any dose between 50-1500 mg/day. Although there was no significant difference between efficacy, gastrointestinal adverse effects were less prevalent with low-dose aspirin. In response to the preponderance of evidence favouring low-dose aspirin for stroke prevention, the US FDA has indicated the appropriate dose for stroke prevention after TIA or stroke as 50 to 325 mg daily.

 

ADP antagonists
The P2 purinoceptor is activated physiologically by adenosine diphosphate (ADP), which may be released from red blood cells and the endothelium as well as from the platelet-dense granules. The development of adenosine receptor antagonists such as ticlopidine and clopidogrel has allowed for a new mechanistic strategy.

In 1989, the Canadian American Ticlopidine Study (CATS) conducted in 1072 patients, showed a significant 33.5% relative risk reduction for stroke. Also, the Ticlopidine Aspirin Stroke Study (TASS) conducted in 3,069 patients documented a statistically significant 12% risk reduction for ticlopidine over aspirin. But the use of ticlopidine is associated with a number of adverse reactions including diarrhoea, rash, neutropenia, thrombotic thrombocytopenic purpura, etc.

Clopidogrel, another ADP antagonist, has been compared with aspirin in the large CAPRIE trial (Clopidogrel vs Aspirin to Prevent Recurrent Ischemic Events) involving 19185 patients with recent ischemic stroke, myocardial infarction or symptomatic peripheral arterial disease. In this trial, there was a significant 8.7% relative risk reduction in composite outcome of ischemic stroke, myocardial infarction or vascular death in favour of clopidogrel. Clopidogrel was not associated with an occurrence of neutropenia, the side effect of greatest concern with ticlopidine.

Dipyridamole
Early research on the efficacy of dipyridamole in secondary stroke prophylaxis did not provide any beneficial results. Dipyridamole at doses of 400 mg/day and 800 mg/day showed no significant impact on the incidence of TIA, stroke or death.

 

Combination therapy

Dipyridamole plus Aspirin
The first European Stroke Prevention Study (ESPS-1) detected a striking degree of stroke prevention with high-dose aspirin (330 mg tid) plus medium-dose dipyridamole (75 mg tid) in patients with prior stroke, TIA or reversible neurologic deficit. Data from 2500 randomized patients showed that combination therapy was associated with a statistically significant 38.1% reduction in the occurrence of fatal or nonfatal stroke at two years (p<0.001).

The second European Stroke Prevention Study [ESPS-2] confirmed that combination of aspirin plus dipyridamole was significantly more effective than either drug alone. During two years of follow-up, the risk of stroke was significantly reduced by 18.1% with aspirin alone, 16.3% with modified-release dipyridamole alone and by 37% with the combination.

Aspirin Plus ADP Antagonist
Experiments have shown that a combination of ADP antagonist and low-dose aspirin is a potent antiplatelet strategy as compared to aspirin alone or ADP antagonist alone in stroke patients. This strategy of combination may beuseful because, partial failure in stroke prophylaxis is attributable at least, in part, to incomplete inhibition of multiple pathways leading to platelet aggregation.

Also, the ongoing trials like MATCH (Management of Atherothrombosis with Clopidogrel in High risk patients with recent transient ischemic attack) and CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) will throw some light on the use of clopidogrel-aspirin combination in secondary stroke prevention.

 

Bleeding complications: A benefit-risk analysis
Several antiplatelet drugs are available for secondary stroke prevention and each drug has its own spectrum of side effects. Bleeding is one of the most important side effects, which may limit or offset a beneficial effect of the intervention. Table 2 compares the risk of bleeding as well as the risk of vascular events in some of the important trials of antiplatelet agents.

A good safety assessment is essential with medications for stroke prevention, as they must be administered for extended period - potentially many years.

The major side effects of aspirin i.e. gastric discomfort and gastric bleeding are most common reasons for withdrawal from therapy. Data from individual aspirin trials show side effect-related withdrawal rates ranging from 4.8% to 19%. Prevention of stroke and other vascular events by aspirin, although economically favourable has a cost in the way of severe bleeds. Also, aspirin intolerance and resistance is a clinically significant problem. Clopidogrel therefore represents an important alternative to aspirin.

Meta-analyses have confirmed that ticlopidine is a useful alternative in preventing stroke in high-risk patients. But the drug is more expensive than aspirin and it has the burden and expense of the biweekly blood tests during the first 3 months of treatment due to risk of neutropenia.

The pharmacologic effects of clopidogrel are similar to ticlopidine, but the safety profile of the drug appears to be better.

Cost-effectiveness of Antiplatelet Regimens
Many trials have evaluated the benefit of long-term use of aspirin in reducing the risk of thrombotic events. Also other antiplatelet regimens, clopidogrel and dipyridamole plus aspirin combination show a further reduction in events as compared to aspirin in large clinical trials. Despite their increased efficacy, these drug regimens are more expensive than aspirin alone, but the question, which arises, is whether these options are cost-effective.

From an analysis of antiplatelet trials in TIA/stroke patients, it has been observed that aspirin leads to a 3.3% reduction in risk of all strokes i.e. aspirin avoids 80 strokes each year when given to 8000 TIA/ischemic stroke patients in a population of 1 million TIA/ischemic stroke patients. As compared to aspirin, treating all 8000 TIA/ischemic stroke patients with clopidogrel would avoid about 48 more strokes each year than aspirin i.e. risk reduction of 5.3% for all strokes.

Thus, compared with aspirin alone, the additional costs incurred by clopidogrel are offset by the savings afforded through its increased clinical benefit.

Conclusion

 

The available data on antiplatelet therapy has now resolved several issues regarding the appropriate use of antiplatelet therapy in stroke prevention.

• Numerous studies and meta-analyses have shown that low-dose aspirin used to balance the protective benefits against its potential side effect, has a significant, albeit, modest effect on the incidence of secondary stroke prevention.
  
• Ticlopidine, although superior to aspirin in preventing recurrent stroke events, is associated with a broad spectrum of adverse events viz. hematological disorders, gastrointestinal side effects and urticaria etc.
  
• The results of CAPRIE trial suggest that clopidogrel is more effective than aspirin in preventing vascular events. Also, clopidogrel has a superior safety profile as compared to ticlopidine and hence is a preferred choice.
  
• Data from ESPS-2 suggests that the combination of dipyridamole + aspirin is also an effective measure for stroke prevention.
  
• A combination of ADP antagonist (clopidogrel/ticlopidine) and aspirin could also be an effective alternative for recurrent stroke prevention.

References
1. Scot Med J 1999; 44: 57-62
2. Neurology 1998; 51 (Suppl 3): S9-S14
3. Arch Intern Med 2000; 160: 1579-1582
4. J Intern Med. 1999; 246: 239-245
5. Arch Intern Med 2000; 60: 2773-2778
6. Stroke 1989; 20: 1643-1647

Antibiotic Use Linked To Stroke Prevention

 

Use of antibiotics, especially penicillin, is associated with a decreased risk of stroke, as per a study published in the August 8th rapid access issue of Stroke.

The above findings are consistent with an increasing number of reports that have linked infections with atherosclerosis and thrombosis. To study this link, Dr. Paul Brassard ( Royal Victoria Hospital , Montreal ) and colleagues analyzed data from 1888 stroke patients and 9440 matched controls that were drawn from an elderly population being treated for hypertension.

Current antibiotic use or use within the last year was associated with a drop in stroke risk by about 20%. Out of the different antibiotic classes, the only one that showed a significant relationship was the penicillins.

Current penicillin users were 47% less likely to experience a stroke than non-users. Although past penicillin use was beneficial, the risk reduction was not as high as with current use.

“For all time windows, penicillin use was consistently associated with a reduced stroke risk,” said Dr. Brassard. “The only explanation I can offer is that because penicillins are so broad spectrum they may destroy not just C. pneumonia, but other bacteria that can contribute to atherosclerosis,” he added.

Dr. Brassard also pointed out that some benefits may be attributed to macrolides or fluoroquinolones, but because of small patient numbers, the association was not statistically significant.

Dual Hormone Replacement Therapy:
Preventive Measure or a Risk Factor

 

The researchers of Women's Health Initiative Trial have pointed out that oestrogen plus progestin, a combination being tested for primary prevention of cardiovascular disease in postmenopausal women, increases their risk of stroke. The trial was prematurely ended because of this and other adverse events. This abandoned trial was the first randomized trial to assess the effect of combined hormone therapy in reducing risk of cardiovascular disease. The results were presented at the 12th European Stroke Conference on May 24, 2003 .

The trial involved around 40 centres and over 16,000 women who were monitored for a mean of 5.2 years. The women were randomized into two groups: 8506 who received conjugated equine oestrogen 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day (E + P group) and 8102 who received placebo.

The researchers found that 151 women in E + P group and 107 in the placebo group experienced stroke. The E + P group had a hazard ratio for stroke of 1.31 (95% CI = 1.02-1.68). This danger was consistent across all age groups, with the hazard ratio increasing from 1.25 in the oldest women (70-79 years) to 1.66 in the youngest (50-59 years).

“The results clearly show that this hormone therapy increases the risk of stroke. It is also known to increase the risk of invasive breast cancer, venous thromboembolism and even coronary heart disease - the very thing it was meant to prevent. There may be benefits for osteoporosis and colorectal cancer, but the benefits of long-term hormone replacement therapy are now being outweighed by the risks,” said Dr. Baird, Chief of the Stroke Neuroscience Unit, National Institute of Neurological Disorders and Stroke, Maryland.

New Approvals Internationally

 

Carbiodopa + Levodopa + Entacapone

The US FDA has approved in June 2003 the combination of carbiodopa, levodopa and entacapone tablets for the treatment of patients with idiopathic Parkinson's disease, who experience signs and symptoms of end-of-dose “wearing-off.” The effectiveness of levodopa administered with carbiodopa and entacapone in treatment of Parkinson's disease has been established in three 24-week multicentre trials in patients with Parkinson's disease experiencing “wearing off.” In these trials, patients showed improved motor function and daily activities. While carbiodopa reduces the side effects of levodopa, entacapone optimizes its benefits, permitting Parkinson's disease patients to have an improved ability to perform everyday tasks and a reduction in symptoms associated with the disease.

Levetiracetam

The US FDA has approved the oral solution (100 mg/ml) of levetiracetam in July 2003, providing a new option for patients with epilepsy who cannot swallow tablets. Levetiracetam has been approved as an adjunctive treatment for partial onset seizures in adults with epilepsy. It is believed that addition of a liquid form of levetiracetam would further extend its value through greater flexibility in dosing.

TICKLE YOUR BRAIN

 

Across Clues

1. Destruction of myelin on the axons of nerves

4. Part of the brain; means “bridge”

6. Abnormal widening of a blood vessel

7. Continuous contraction of muscles, which may interfere with movement, speech, etc and caused by damage to the portion of brain/spinal cord that controls voluntary movement

12. Mental declination and deterioration

14. Relieving symptoms, but not curing

15. Neurotransmitter released at the ends of some nerve cells

16. Posterior part of the brain

17. Depression or groove in the surface of the cerebral cortex

18. One of the indicative symptoms for definite vertebrobasilar territory ischemia

 

Down Clues

1. Neurotransmitter that is deficient in Parkinson's disease

2. Malignant tumor of the neuroglial cells in the brain

3. The straining maneuver that can increase ICP

5. Chronic encephalopathy found in thiamine-deficient alcoholics, characterized by memory deficit and poor problem solving

6. Peculiar sensation appearing before more definite symptoms

8. Damage to the spinal cord caused by formation of fluid filled cavity

9. Manner of walking

10. Removal of the thymus gland; treatment for myasthenia gravis

11. An uncoordinated gait seen with cerebellar dysfunction

13. Microscopic branching fiber of a nerve cell that is the first part to receive the nervous impulse

Across	Down
1. DEMYELINATION 4. PONS 6. ANEURYSM 7. SPASTICITY 12. DEMENTIA 14. PALLIATIVE 15. ACETYLCHOLINE 16. CEREBELLUM 17. FISSURE 18. TETRAPARESIS	1. DOPAMINE 2. ASTROCYTOMA 3. VALSALVA 5. WERNICKE'S 6. AURA 8. SYRINX 9. GAIT 10. THYMECTOMY 11. ATAXIA 13. DENDRITE