PRACTICE Matters 1

Matters PRACTICE PRACTICE Matters

• Stroke is the nation's third leading cause of death, and the

leading cause of serious, long-term disability.

• There are about 13,500 strokes each year in VA.

• Stroke and related diseases consume 5% of VHA

resources.

• Certain veteran populations such as POWs and those with

PTSD, have an increased risk of stroke.

• 85% of strokes are ischemic, resulting from insufficient

blood flow to the brain; 15% are hemorrhagic, resulting

from bleeding into the brain.

• Stroke can be viewed as a “brain attack”. Time is brain.

Fast treatment helps stop tissue damage, save brain

function, and reduce patient dependency.

• Antiplatelet drugs and some thrombolytics show new

promise in reducing death and disability from stroke.

• Treatments must be chosen carefully because they have

important trade-offs in benefits and harms.

• VA sponsored research has led to important advances in

stroke prevention and recovery.

ACUTE

STROKE

TREATMENT

A publication of the Management Decision and Research Center

A program within the Department of Veteran’s Affairs Health Services Research and Development Service

DECEMBER, 1997 VOL. 2 ISSUE 1
2 PRACTICE Matters

TREATMENT GOALS

Brain damage after an ischemic stroke occursquickly and progressively over a period of hours.

A rapid CT scan or MRI is necessary to determine if

a patient is a candidate for thrombolytic therapy, which

must be given within 3 hours of symptom onset.

The goals of treatment are to improve survival and

reduce disability, which occurs in as many as 50% of

stroke patients. Paralysis and loss of vision or speech

are most common.

Treatment decisions are based on many factors,

including:

• cause, location and extent of brain injury;

• availability of CT scan equipment; and

• availability of appropriate medications within a tight

time frame.

THERAPIES

Thrombolytic Therapy

I

ntravenous thrombolytic therapy appears to improve outcomes when administered to carefully selected patients within 3 hours of symptom onset, based

on evidence from about 3,000 patients.

When given immediately, there is no increased

mortality overall but the risk of intracranial hemorrhage increases about five-fold. rt-PA is currently the

only agent licensed by the FDA for the treatment of

acute ischemic stroke.

Given per 1,000 patients. Most data relevant to 3-hour timing

are from single large trial evaluating rt-PA.

Thrombolytic agent given regardless of timing

• Benefit: No benefit for survival or reduced disability

• Harm: Results in an increase of about 30 deaths and

about 68 more intracranial hemorrhages.

Thrombolytic agent given within 3 hours

• Benefit: Prevents about 50 deaths at 3-6 months and

results in about 160 fewer dead or disabled patients at 3-

6 months.

• Harm: Causes about 58 more intracranial hemorrhages

at 14 days.

Anti-Platelet Therapy

with acute ischemic stroke show aspirin is modestly more effective than placebo in preventing mostThree trials involving more than 40,000 adults

adverse outcomes. Researchers gave doses of 160 to

300 mg as soon as possible after stroke, usually within

48 hours.

In 1,000 patients, evidence showed that aspirin prevented about 5 deaths and 11 strokes within the first

month, and at six months, resulted in about 13 fewer

instances of death or disability. On the downside, aspirin is blamed for causing two hemorrhagic stokes

in 1,000 patients.

Anti-coagulant Therapy

The recent International Stroke Trial indicatessubcutaneous heparin given in doses of 5,000 to

12,000 units twice daily does not prevent death or dependency from stroke at 6 months. It is associated

with a modest decrease in recurrent ischemic strokes

at 14 days which is offset by a similar increase in hemorrhagic strokes.

Meta-analysis of 15 trials show anticoagulation

therapy with either heparin or warfarin does prevent

deep venous thrombosis, a major complication of

stroke, in about a third of patients treated.

Acute Stroke Units

Twelve trials show that stroke patients managedin a specialized, multidisciplinary stroke unit are

more likely to be alive and living at home a year later

than those managed in general medical wards. Length

of hospital stay has not been increased by such units.

Insufficient Evidence

Systematic reviews of over 50 clinical stroke trials

testing the treatments listed below concluded that

current evidence is insufficient to recommend routine use of:

• hemodilution

• corticosteroids

• fibrinogen-depleting agents

• prostacyclins

• theophylline, caffeine and analogues

• glycerol

• gangliosides

It is unclear whether high blood pressure should,

or should not, be altered medically during the acute

phase of stroke. But a large thrombolytic trial with

positive outcomes controlled blood pressure to <185/

105 mmHg.
PRACTICE Matters 3

EXPERT OPINION

Thrombolytic Therapy

By the end of 1996 several large well designed trialsof thrombolysis for stroke have been completed

(1,2). Although some observers have characterized

the results as contradictory, and some meta-analyses

have inappropriately combined disparate trials, if one

carefully looks at the several trials, a pattern emerges

that is useful to the treating physician. Clinical trials

established that intravenous rt-PA is safe and highly

effective for acute stroke victims, if therapy is initiated

within 3 hours of stroke onset. A large European trial

showed that rt-PA given in the first 6 hours after stroke

was effective, but only if certain "high risk" patients

were excluded. Meanwhile, 3 large multi-center trials

indicated that streptokinase was associated with higher

risk and poor outcomes, as was predicated by the

animal studies. To lump all of these trials into one

meta-analysis is not only inappropriate, but

scientifically unjustifiable.

There is a hope that subgroups who are at

particular risk of harm or benefit can be identified.

Retrospective analyses using formal regression methods have been done to identify such subgroups. Unfortunately there are no subgroups that clearly demonstrate increased risk or benefit from rt-PA for acute

stroke. Therefore, the standard guidelines contained

in the package insert and published by the American

Heart Association and the American Academy of

Neurology (3,4) should be used to guide therapy.

There is no special subgroup from whom therapy

should be withheld.

Stroke code teams have been established in VA

Medical Centers. At the San Diego VAMC, door-toneedle times under 45 minutes can be accomplished.

Given the burden that stroke causes our patients and

health care system, I believe that it is imperative that

VA Medical Centers establish stroke treatment teams.

No additional equipment or staff are needed. All that

is required is a willingness to examine pre-conceived

notions and to change nihilistic attitudes. The benefits, measured in disability and dollars saved, are potentially enormous.

Future trials must address a number of remaining

questions. What is the latest safe time point to treat

stroke? Can an agent other than rt-PA be used safely?

Should heparin or aspirin or warfarin be used within

the first 24 hours after stroke; currently NINDS

Continued on page 4

RECOMMENDATIONS

• Early aspirin therapy is recommended for patients

who don't receive treatment with rt-PA.

Intravenous rt-PA given within 3 hours of symptom onset should be considered for patients who:

do not have bleeding contraindications, have blood

pressure < 185/110 mmHg, have had stroke diagnosed by an experienced physician, and have had a

CT ruling out hemorrhagic stroke.

In patients on rt-PA, avoid any antiplatelet or anticoagulant agents for first 24 hours.

Thrombolytic therapy should not be used unless

facilities to handle bleeding complications exist.

To prevent deep venous thrombo-embolism, low

dose heparin (5,000 units subcutaneously twice

daily) may be given concomitantly with aspirin. Alternatively, intermittent pneumatic compression,

which is proven beneficial in neurosurgical patients,

may be considered.

Local institutions should aim for routine provision

of specialized multidisciplinary care for patients

with acute stroke. Initial care should be coordinated by a team consisting of an emergency medical person, a radiologist and a neurologist.

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Acknowledgments

This Acute Stroke Treatment issue of Practice Matters was prepared by the VA San Antonio Cochrane

Center staff, Karen Stamm, Elaine Chiquette,

PharmD and Cindy Mulrow, MD using the Cochrane

Library of Systematic Reviews 1997 Issue 3, the Stroke

Council of the American Heart Association, and the

scientific publications cited in the evidence table.

Other major contributors were: Lawrence M. Brass,

MD, Chief, Neurology Service, VAMC West Haven,

John Booss, MD, Director of Neurology, John R.

Feussner, MD, Chief Research and Development

Officer, Patrick Lyden, MD, Staff Physician, VAMC

San Diego.
EXPERT OPINION

Continued from page 3

guidelines prohibit the use of such drugs. What are

the risk factors that seem to predispose patients to

hemorrhage? What is the pathophysiology of hemorrhage and can it be prevented? While studies are

underway to address these questions, acute stroke

therapy with rt-PA should be implemented.

Patrick D. Lyden, MD

Staff Physician

VAMC, San Diego

LITERATURE CITED:

1. Kaste M. Hacke W, Fieschi C, and ECASS Study Group. Results of

the European Cooperative. Acute Stroke Study (ECASS). 1995;

Keywords: stroke; rt-PA; hemorrhage; human; Barthel; Rankin,

NIHSS In File, pp.225-273. Cerebrovasc. Dis. 5.

2. The National Institute of Neurological Disorders and Stroke rt-PA

Stroke Study Group. Tissue Plasminogen Activator for Acture

Ischemic Stroke. N Eng J Med 333;1581-7, 1995.

3. Report of the Quality Standards Subcommittee of the American

Academy of Neurology. Thrombolytic therapy for acute ischemic

stroke -Summary Statement. Neurology 47:835-9, 1996.

4. Adams HP, Jr., Brott TG, Furlan AJ, Gomez CR, Grotta J.

Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Tomer J, et

al. Guidelines for thrombolytic therapy for acute stroke; A

supplement to the guidelines for the management of patients with

acute ischemic stroke. Circulation 94:1167-74.

Practice Matters is a new series for VA decision makers and practitioners that summarizes

the results of important research and promotes

the application of research for improved

health care delivery and decision making

within VA. It is produced by HSR&D’s Information Dissemination Program in collaboration with topic experts in the field. For more

information or to provide us with your suggestions, please contact:

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Phone: COM (617) 278-4433

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Email: geraldine.mcglynn@med.va.gov

PRACTICE Matters

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Evidence Chart for Acute Stroke Treatments

MAJOR THROMBOLYTIC TRIALS

Study Participants Interventions Outcomes

ASK JAMA. N= 340 Streptokinase (SK) 1.5 MU within 4 Intracranial Hemorrhage

1996; 276:96 Cortical and lacunar ischemic stroke hrs of symptom onset with aspirin 13% vs 2.4% (SK vs Placebo)

1-966 (ASA) 100 mg qd. No other anticoagu- Mortality@3mo.

Excluded subjects with SBP>200 lants allowed in first 48 hrs. Trial 36% vs. 21% (SK vs Placebo)

mmHg or DBP>120mmHg terminated prematurely due to excess Death & disability@3mo.

mortality in streptokinase group 48% vs 45% (SK vs Placebo)

MAST E N=310 Streptokinase 1.5MU within 6 hrs of Intracranial Hemorrhage

N Engl J Med Subjects with symptoms of large acute symptom onset 21% vs. 3% (SK vs Placebo)

1996; 335:145-50 ischemic stroke in the middle cerebral Heparin ±ASA allowed in first 24 hrs Mortality @6mo.

artery territory. Excluded subjects with and later at MD discretion 47% vs 38% (SK vs Placebo)

SBP>220 and DBP>110 Trial terminated prematurely due to Death & disability@6mo

excess cerebral hemorrhages and 79% vs 82% (SK vs Placebo)

mortality in the streptokinase group

MAST I N=622 Streptokinase 1.5 MU within 6 hrs Intracranial Hemorrhage

Lancet 1995; All acute ischemic stroke (cortical, P ASA SK SK+ASA

346: 1509-14 lacunar and posterior circulation) 0.6 % 2% 6% 10%

Factorial study design: streptokinase Trial suspended because of slow Mortality @6mo.

alone, aspirin 300mg alone, both or randomization rate. P ASA SK SK+ASA

neither 29% 20% 28% 44%

Death & disability@6mo.

P ASA SK SK+ASA

68% 61% 62% 63%

ECASS N=620 rt-PA 1.1 mg/kg MAX: 100mg or Intracranial Hemorrhage

JAMA. 1995; Acute ischemic hemispheric stroke with placebo within 6 hrs 19.8% vs. 6.5% (rt-PA vs Placebo)

274: 1017-1025 moderate to severe neurological deficits Mortality @3mo.

Excluded subjects with DBP>110 and No anticoagulants or ASA allowed in 22% vs 16% (rt-PA vs Placebo)

SBP>200 first 24 hours except heparin SQ Death & disability@3mo.

63% vs 72% (rt-PA vs Placebo)

NINDS N=624 rt-PA 0.9 mg/kg MAX:90 mg or Intracranial Hemorrhage

N Engl J Med Ischemic stroke in either the carotid or placebo within 3 hrs 6.4% vs. 0.6% (rt-PA vs Placebo)

1995; 333: vertebrobasilar circulation with Mortality @3mo.

1581-7 neurological deficit measurable on NIH No antithrombotic agents allowed for 17% vs 21% (rt-PA vs Placebo)

Stroke Scale the first 24 hrs Death & disability@3mo.

57% vs 73% (rt-PA vs Placebo)

*All patients had pre-entry CT scans to exclude cerebral hemorrhage. Delivery of drug was intravenous.

MAJOR ASPIRIN TRIALS

Study Participants Interventions Outcomes

IST Lancet 1997; N= 19435 ASA 300mg Death from all causes @14 days

349: 1569-81 Acute stroke irrespective of severity Heparin SQ (5000U or 12500U) Alone, 9.0% vs 9.4% (ASA vs no ASA)

in combination or neither Death or disability @6mo.

62.2% vs 63.5% (ASA vs no ASA)

First dose immediately, then daily x 14 Hemorrhagic stroke

days 0.5 vs 0.3% (ASA vs no ASA)

CAST Lancet N=21106 ASA 160mg/d within 48 hrs, continue x Death from all causes @4 weeks

1997; 349: Suspected acute ischemic stroke 4 wks 3.3% vs 3.9% (ASA vs placebo)

1641-49 Death or disability @4 weeks

30.5% vs 31.6% (ASA vs placebo)

Hemorrhagic stroke

1.1% vs 0.9% (ASA vs placebo)

MAST I Lancet N=622 ASA 300mg qd x 10 days Death from all causes @6mo.

1995; 346: All acute ischemic stroke (cortical, 20% vs 29% (ASA vs placebo)

1509-14 lacunar and posterior circulation) Factorial study design: streptokinase Death & disability @6mo.

alone, aspirin 300mg alone, both or 61% vs 68%

neither. Hemorrhagic stroke

2% vs 0.6% (ASA vs placebo)

PRACTICE Matters

Compiled by VA San Antonio Cochrane Center.
PRAMatters CTICE

Information Dissemination Program

Management Decision and Research Center (152-M)

150 South Huntington Avenue

Boston, MA 02130

Phone: COM (617) 278-4433

or FTS 839-4433

FAX: (617) 278-4438

Email: geraldine.mcglynn@med.va.gov