In this issue...

• EXTENSION OF THERAPEUTIC WINDOW FOR RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR
• USE OF STATINS MAY CUT STROKE RISK BY A THIRD
• SYNERGY OF ULTRASOUND MONITORING AND TISSUE PLASMINOGEN ACTIVATOR
• AN UPDATE ON ANTICOAGULATION THERAPY FOR STROKE PREVENTION
• TRANSIENT ISCHEMIC ATTACKS INDUCE TOLERANCE TO STROKE
• OBSTRUCTIVE SLEEP APNEA: A RISK FACTOR FOR STROKE
• IMPACT OF METABOLIC SYNDROME ON STROKE
• NEW APPROVALS INTERNATIONALLY
• TICKLE YOUR BRAIN

EXTENSION OF THERAPEUTIC WINDOW FOR RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR

 

The findings of a meta-analysis of 6 trials suggest a potential benefit when rt-PA is administered beyond 3 hours after symptom onset. Investigators pooled data from two National Institute of Neurological Disorders and Stroke (NINDS) trials, two European Cooperative Acute Stroke Study (ECASS) trials, and two Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials analyzing the use of rt-PA within 1 to 6 hours after stroke symptom onset. "Our findings suggest that the beneficial effect of rt-PA might extend beyond 3 hours," writes corresponding author Dr. John R. Marier, NINDS, Rockville , Maryland , United States , for The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators.

The intention to treat analysis included 2,775 patients, median age of 68 years, median NIHSS score of 11, and median onset to start of treatment of 243 minutes. The likelihood of a favourable outcome, defined as modified Rankin Scale of 0 or 1, Barthel Index of 95 or 100, and NIHSS of 0 or 1 at 3 months, increased as the onset to time of treatment decreased.

Intracerebral hemorrhage occurred in 5.9% of the rt-PA treated patients compared with 1.1% of placebo patients.

 

USE OF STATINS MAY CUT STROKE RISK BY A THIRD

“Cholesterol lowering statin therapy rapidly produces a definite and substantial reduction in ischemic strokes, irrespective of the patient's age, sex or blood lipid concentrations, when treatment is initiated,” as per the researchers of the Heart Protection Study (HPS), Oxford, U.K.

In this study, 20,536 individuals with non-fasting total blood cholesterol concentrations of at least 3.5 mmol/L and a history of cerebrovascular disease, coronary disease, other occlusive arterial disease, diabetes mellitus or treated hypertension were randomly allocated to either simvastatin 40 mg or placebo and were followed up for a 5-year period.

Among the 10,269 simvastatin-treated participants, 4.3% had a first stroke as compared to 5.7% of the placebo participants, resulting in a 25% reduction in first event rate for stroke with simvastatin (Fig).

The non-significant trend of simvastatin, towards fewer strokes during the first year of follow-up, shifted to a highly significant 30% reduction by the end of the second year. “During each separate subsequent year of follow-up, there were further reductions of about one-quarter in the stroke rates,” the authors noted.

The incidence of TIA (2.0%) and carotid endarterectomy or angioplasty (0.4%) was also less in simvastatin group as compared to placebo (2.4% and 0.8% respectively). Patients with pre-existing cerebrovascular disease had a 20% reduction in the rate of any major vascular event.

During the HPS, an average of about a sixth of the participants allocated to simvastatin had stopped taking statin and about a sixth of those allocated to placebo had started taking a statin. Hence, the average difference in the LDL-cholesterol of about 1 mmol/L (39 mg/dl) that was observed between all those allocated to statin and placebo represents only two-thirds of the LDL cholesterol differences produced by actual use of 40 mg simvastatin daily. Similarly, the reduction of about a quarter in the incidence of strokes in the intention-to-treat comparisons is likely to represent only about two-thirds of the risk reduction produced by actual compliance with this statin regimen. Hence, actual use of 40 mg simvastatin daily would lower LDL cholesterol by about 1.5 mmol/L and would probably reduce the rates of stroke and of other major vascular events by about a third.

“Given that stroke is one of the major causes of mortality and major morbidity worldwide, these findings indicate that statin therapy should now be considered routinely for all patients at high risk of stroke, irrespective of their initial cholesterol concentrations or the presence of coronary disease”, the authors concluded. The study also provides definite evidence that statin therapy is beneficial for patients with a history of stroke or other cerebrovascular disease.

Lancet 2004; 363: 757-67

Patients who received rt-PA within each interval up to 270 minutes had a 1.0 hazard ratio for death, after adjustment for baseline NIHSS, but the hazard ratio for death was 1.45 among patients treated from 271 to 360 minutes (Table). “Our results confirm the strong association between rapid treatment and favourable outcome,” and “a potential benefit from treatment after 3 hours,” the author concludes, suggesting that the next step is “to identify patients who are likely to respond to treatment when they present at the later end of the suggested therapeutic interval.”

Lancet 2004; 363: 768-74

SYNERGY OF ULTRASOUND MONITORING AND TISSUE PLASMINOGEN ACTIVATOR

 

As per late-breaking research presented at the 29th International Stroke Conference, addition of continuous targeted ultrasound monitoring to standard dose (0.9 mg/kg) intravenous tissue plasminogen activator (tPA) exposes more thrombus to tPA.

The ultrasound device produces a narrow beam, which targets just the vessel and the continuous ultrasound induces small motions in the thrombus, tenderizing the clot to make it more vulnerable to tPA.

One hundred twenty six patients with middle cerebral artery occlusion were evenly randomized to target ultrasound or control (standard tPA) group. All patients received tPA within 3 hours of symptom onset. Complete recanalization occurred in 49% of the target ultrasound patients as compared with 29% of the controls (Fig). Both the groups had a 4.8% symptomatic cerebral hemorrhage.

The median prebolus National Institute of Health Stroke Scale (NIHSS) Score was 16 and 17 in target group and control group, respectively. Thirty two percent of patients in target group reached the prespecified NIHSS endpoint of 3 or less at 24 hours as compared to only 24% patients in control group.

“Patients who underwent low-frequency ultrasound monitoring (2MHz) were 2.5 times more likely to have vessels opened than control patients,” said Andrei V. Alexandro (Assistant Prof. Neurology and Radiology and Director of Cerebrovascular Ultrasound at the University of Texas in Houston), the lead investigator.

“The targeted ultrasound used here is a modification of diagnostic ultrasound, that is found in every hospital. However, success of continuous ultrasound monitoring of cranial occlusion with the focused beam is likely to be operator dependent and it can take up to 6 months of daily practice to achieve proficiency,” added Dr. Alexander.

29th International Stroke Conference: February 7, 2004

AN UPDATE ON ANTICOAGULATION THERAPY FOR STROKE PREVENTION

 

Stroke is the most common life-threatening neurological disease and a major health problem.

Ischemic stroke causes substantial mortality and morbidity. The optimal use of antithrombotic therapies for stroke treatment or prevention is guided by the specific pathogenesis. The risk of stroke recurrence must be individually assessed and weighed against the risk of hemorrhagic complications. Patients with high-risk lesions may benefit from anticoagulation, while antiplatelet therapy appears to be more appropriate in patients at low risk for recurrent strokes. This article focuses on the role of anticoagulants for prevention of stroke.

Anticoagulation in acute ischemic stroke

The anticoagulant therapy for management of acute ischemic stroke aims at:

• Prevention of thrombus extension or recurrent cerebral thromboembolism
• Prevention of venous thromboembolic (VTE) complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE)

For acute cerebral infarction patients who are not eligible for intravenous (IV) recombinant tissue plasminogen activator (rt-PA), a variety of antithrombotic agents can be considered. Several anticoagulants have been evaluated in clinical trials viz:

• Heparin
• Low molecular weight heparins (LMWHs)
• Heparinoids
• Warfarin
• Acenocoumarol

The therapeutic approach to the acute stroke patients should consider the distinct pathophysiologic mechanisms. Data from various studies indicate that the 30-day risk of recurrence is 8% for patients with extracranial atherosclerosis and 7.1% for those with intracranial atherosclerosis. Causes of worsening and recurrence in patients with large artery atherosclerotic stroke include propagation or progression of the thrombosis, distal embolism, or failure of collateral vessels to compensate for the reduced cerebral perfusion. For these reasons, anticoagulation has been advocated as a rational approach on the basis of pathophysiologic considerations despite the absence of supportive evidence.

Anticoagulation in non-cardioembolic strokes

Progressing stroke has frequently been considered as an indication for anticoagulation, although supportive randomized clinical trial data are scant.

Studies performed in the 1950s and 1960s suggest that IV heparin therapy may be beneficial for patients with unstable ischemic stroke with as much as 50% reduction in the likelihood of further worsening.

Since 1986, only a single randomized trial has evaluated IV heparin compared with placebo treatment for patients with acute stable stroke. No significant difference in stroke progression or neurologic outcome was detected in this relatively small study (n=225). A probable reason for this would be a broad treatment window of 48 hrs from stroke onset and exclusion of patients with progressing stroke. In addition, due to small sample size, the study had adequate power to detect only a relatively large difference in efficacy between heparin and placebo treatment. Subcutaneous(SC)heparin administration has been evaluated in the 'International Stroke Trial' (IST). In this trial, 19,435 patients with suspected acute ischemic stroke were followed up primarily to evaluate the death rate within 14 days and death or dependency at six months. Secondary outcomes included recurrent ischemic stroke, hemorrhagic stroke, PE or transfused or fatal extracranial hemorrhage within 14 days. There was no significant difference between heparin and non-heparin group in the primary endpoint, but at 14 days, incidence of recurrent ischemic stroke was significantly reduced in the heparin group. But unfortunately, an increased risk in hemorrhagic stroke neutralized these potential benefits. Recent reviews however, strongly discourage the indiscriminant use of IV heparin for the treatment of acute stroke.

Nadroparin was tested in the setting of acute ischemic stroke to yield mixed results. Three hundred and eight patients were randomized to either nadroparin (high or low dose) or placebo. Although no significant effect was noted at 3 months, there was a significant dose-dependent effect on risk of death or dependency at six months.

Anticoagulation in cardioembolic stroke

Studies suggest a recurrence risk of 1% in the first 14 days for cardioembolic strokes. The cause of an early recurrence in patients with cardioembolic stroke is usually another thrombus becoming dislodged from the intracardiac source and the risk of early stroke recurrence is likely related to the underlying cardiac lesion.

Anticoagulants substantially reduce the risk of cardiac embolism, although the evidence supporting the use of anticoagulation in patients with acute cardioembolic stroke is limited. A small randomized trial compared immediate and delayed anticoagulation in patients with cardioembolic stroke. There were no major complications associated with immediate anticoagulation, but a trend towards reduction of early recurrent embolism was apparent. However, the results of the "Heparin in Acute Embolic Stroke Study" showed that there was no difference in the frequency of early recurrent ischemic stroke or cerebral hemorrhage when treated with either aspirin (160 mg/d) or high dose LMWH, dalteparin (100 IV/kg sc bid).

Antithrombotic therapy for prevention of DVT and PE

Immobilized stroke patients with paralyzed limbs are at high risk of developing venous thromboembolism. It has been suggested that without prophylaxis, DVT may develop in 28-75% of stroke patients and as many as 20% may subsequently suffer from PE.

An overview analysis in 1993 reviewed the results of 10 trials that evaluated heparin in 1,047 patients with acute ischemic stroke; an 80% reduction in DVT and a 58% reduction in PE were found. LMWHs have been found to be equivalent to or better than unfractionated heparin in preventing DVT. Treatment with LMWHs for 5-14 days provides good prophylaxis for VTE in patients suffering from acute stroke. It is recommended that clinicians use prophylactic low-dose SC heparin or LMWHs, as long as there are no contraindications to anticoagulation in these patients.

DVT/PE prophylaxis in patients with intracerebral hemorrhage (ICH)

Only one small study is available to address the risk of early prophylactic therapy with anticoagulants in patients with ICH. In this study, 22 patients with spontaneous ICH were treated with SC heparin beginning on the second day after the ICH. When compared with historical control subjects, early low-dose heparin therapy (day 2) (5,000 U heparin sodium t.i.d. subcutaneously) significantly lowered the incidence of PE compared with delayed (day 4 or day 10) heparin therapy. No increase in the number of patients with rebleeding in the brain was observed. These results suggest that the early use of low-dose heparin may be safe and effective in ICH patients. In patients with an intracerebral hematoma, use of low-dose SC heparin as early as the second day after the onset of the hemorrhage is recommended for the prevention of thromboembolic complications.

Secondary prevention of stroke

Strokes associated with atrial fibrillation (AF) are large and disabling and account for 20% of ischemic strokes due to cardiogenic embolism. In addition to this, a number of surveys using computerized tomography have shown significant numbers of silent cerebral infarcts in the AF population. It is important to know that rhythm control does not seem to reduce stroke and antithrombotic therapy is the mainstay for stroke prevention in such patients. Oral anticoagulation (OAC) is highly effective for prevention of stroke in patients with AF.

Combination of antiplatelet and anticoagulant therapy

Recent surveys suggest that around 10% of high-risk patients with AF receive a combination of aspirin and warfarin. However, there is insufficient data regarding the effectiveness of this approach in AF patients.

Recent studies have evaluated the combination of low-intensity, fixed-dose warfarin and aspirin, in hopes of obtaining synergistic effects for prevention of thromboembolism, without an increase in bleeding complications. Results of these studies show that the addition of aspirin to low-dose warfarin regimen does not provide any significant benefits.

Warfarin underused

Despite the increasing value of warfarin therapy in the prevention of cardioembolic events in patients with AF, the use of warfarin in these patients lags considerably behind proved benefit-versus-risk data. This underuse of warfarin has been observed even in patients free of absolute or relative contraindications. Although aspirin is less effective than warfarin for stroke prevention in these patients, it continues to be commonly prescribed. Hence ongoing encouragement from the medical community to intensify anticoagulation treatment with warfarin in patients with atrial fibrillation is required.

Anticoagulation and intracranial hemorrhage: Facts and hypothesis

Intracranial hemorrhage is the most serious and lethal complication of OACs and is often a major clinical concern for stroke prevention. Intracranial hemorrhage can be divided into intracerebral hemorrhage (ICH) [more accurately intraparenchymal], subdural, epidural and subarachnoid hemorrhage. Out of these, ICH constitutes approximately 70% of the hemorrhages.

The mechanism(s) by which the OACs accentuate the rate of ICH is unclear. Pathological evidence suggests that bleeds from smaller or lower pressure vessels than those leading to massive spontaneous hemorrhages are successfully stanched by normal hemostatic mechanisms.

However, studies have also shown that OAC-associated ICH is also proportional to the intensity of anticoagulation. There is no absolutely “safe” INR, as many patients experience ICH even when their INR is well within the conventional therapeutic range. Predictors of anticoagulant-related ICH are advanced patient age, prior ischemic stroke, hypertension and intensity of anticoagulation.

Subdural hematomas are less frequently reported than ICH, but are crucial to recognize as they are life-threatening and amenable to surgical therapy.

Balancing stroke risk and bleeding risk

In a study, 74 AF patients who had experienced an ischemic stroke while taking warfarin were studied along with control group (AF patients treated in outpatient department) in order to find out the optimal INR for such patients. INR was measured for these patients. The results showed that the risk of stroke rose steeply at INR below 2.0. In contrast, the stroke risk was low and did not appear to fall any further if the INR was pushed above 2.0. Instead, there was an increase in risk of bleeding with any further increase in INR. The risk of hemorrhage rose rapidly at INRs greater than 4.0 to 5.0 [Fig. 1 (a), 1 (b)].

In the past decade, definitive evidence has emerged from multiple randomized clinical trials that establish adjusted-dose oral anticoagulants (INR approximately 2.0-3.0) as highly effective and safe therapy for prevention of stroke in patients with AF.

New Agents

Ximelagatran, an investigative oral direct thrombin inhibitor, appears to be a promising oral anticoagulant. The drug appears to be safe as compared to warfarin and is characterized by prompt onset and offset of anticoagulation, a wider therapeutic margin, predictable pharmacokinetics and a low potential for food and drug interactions as well as absence of a need for dose adjustment. The Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III trial has recently compared warfarin with ximelagatran, in AF patients for prevention of all strokes and systemic embolic events. The results indicate that ximelagatran was not inferior to warfarin in terms of primary endpoint (event rate was 1.6% per year in the ximelagatran group as compared to 2.3% in the warfarin group), but ximelagatran was better tolerated in terms of major and minor bleeding events. Elevation of liver enzymes, however, represents a major concern with ximelagatran.

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TRANSIENT ISCHEMIC ATTACKS INDUCE TOLERANCE TO STROKE

 

Infarct size is smaller and outcomes are better when ischemic strokes are preceded by transient ischemic attacks (TIAs), report German researchers. Results of MRI suggest that these beneficial effects are due to endogenous neuroprotection.

Previous reports have suggested that TIA may offer neuroprotection by promoting ischemic tolerance. However, objective measures were lacking and the mechanism of protection was unclear.

Dr. Susanne Wegener, at the University Hospital Charite in Berlin , and her associates therefore assessed the perfusion and tissue damage in stroke patients. Among the 65 patients with stroke, 10 patients had experienced a TIA within the previous 4 weeks, 6 had experienced one more than 4 weeks ago, and 49 had never had a TIA.

The stroke scale scores were significantly lower at the 12-hour mark and at discharge in the group who had experienced a TIA (Table).

“Although a TIA is an alarming sign, further delineation and exploration of natural ischemic tolerance may offer a new perspective in future neuroprotection and acute stroke therapy,” the researchers concluded.

Stroke 2004; 35 : 616-21

OBSTRUCTIVE SLEEP APNEA: A RISK FACTOR FOR STROKE

 

People with sleep apnea are at a greater risk of developing stroke, just as the stroke survivors are more likely to have sleep apnea, as per the findings presented at the 29th International Stroke Conference of the American Stroke Association by H. Klar Yaggi (Prof. Pulmonary and Critical Care Medicine, Yale University School of Medicine & Yale Center for Sleep Medicine, New Haven).

Dr. Yaggi and colleagues quantified the relationship between obstructive sleep apnea and TIA, stroke or death, by assessing 3,365 patients who were referred to the Yale Center for Sleep Medicine for evaluation of sleep disordered breathing. The researchers analyzed the composite end point of TIA, stroke or death and the rate of obstructive sleep apnea. Seventy five percent of patients with obstructive sleep apnea survived event-free for 5 years as compared to 88% of those without the disorder (p = 0.04). Patients with sleep apnea were more than twice as likely to develop TIA or stroke or to die as compared to their non-affected counterparts [hazard ratio = 2.18; p = 0.04]. A positive relationship was observed between the increase in sleep apnea and risk of TIA or stroke or death.

“Obstructive sleep apnea is an independent predictor of TIA, stroke or death even after adjusting for gender, body mass index, hypertension and diabetes,” the researchers concluded.

29th International Stroke Conference; American Stroke Association: February 9, 2004

IMPACT OF METABOLIC SYNDROME ON STROKE

 

Patients of metabolic syndrome face nearly double the risk of developing stroke as compared to healthy persons, as per the analysis of data from the Framingham Offspring study.

These findings presented at the 29th International Stroke Conference of the American Stroke Association suggest that interventions aimed at preventing or treating the metabolic syndrome may have a major impact on stroke prevention.

Diabetes-free subjects (n = 1,881) with an average age of 59 years were periodically evaluated for diabetes and metabolic syndrome.

Metabolic syndrome was defined as co-existence of at least 3 of the 5 metabolic abnormalities: abdominal circumference of greater than 88.9 cm for women and greater than 101.6 cm for men, triglyceride levels >150 mg/dL, high-density lipoprotein cholesterol levels < 40 mg/dL for men or < 50 mg/dL for women, blood pressure >130/85 mm Hg, or use of antihypertensive medication, and fasting glucose of 110-126 mg/dL.

The criteria of metabolic syndrome was met by 27.6% of men and 21.5% of women. During a maximum follow-up period of 14 years, 5.6% of the men and 4.3% of the women had a stroke or TIA.

After subsequent adjustments for other stroke risk factors including age, systolic blood pressure, antihypertensive therapy, other cardiac conditions and smoking, men with metabolic syndrome had a risk ratio of 1.78 for stroke or TIA (p = 0.06) and women had a risk ratio of 2.21 (p = 0.02) as compared to those who did not have metabolic syndrome.

“What we're seeing in patients with metabolic syndrome is more than just hypertension. It's a conglomeration of factors that put these patients at risk,” said Dr. Robert M. Najarian, while presenting his findings. “By preventing metabolic syndrome, we can prevent stroke and other cardiovascular disease.”

29th International Stroke Conference; American Stroke

NEW APPROVALS INTERNATIONALLY

 

Quetiapine

The US FDA has approved quetiapine fumarate for treating acute mania associated with life impacting disease of bipolar disorder, in January 2004. The drug is well tolerated and effective in treatment of manic episodes, as per the registration trials.

Lamotrigine

FDA approved lamotrigine as monotherapy for adults with partial seizures. This approval for lamotrigine supports the overall trend towards monotherapy as a goal of therapy that may help both seizure control and tolerability for many epilepsy patients.

TICKLE YOUR BRAIN