General references on stroke, including treatment guidelines:

National Stroke Association

www.stroke.org

American Stroke Association

www.strokeassociation.org

Washington University Stroke Center

www.neuro.wustl.edu/stroke

American Speech-Language-Hearing Association

www.asha.org

Mayo Clinic

www.mayo.edu/cerebro

Lecture notes with references

9-14-2000

Carolyn VanCouwenberghe RN PhD

1. Hypertension
1. ~50 million Americans have hypertension. 32% don’t know they have it, 15% are on no therapy, 26% are on inadequate therapy, 27% are treated adequately.
2. Many classes of drugs are available to treat hypertension, including: diuretics, sympatholytics, direct-acting vasodilators, calcium antagonists and renin-angiotensin cascade inhibitors.
3. Hypertension usually has no symptoms. It can be challenging to get someone to take medications (which may have side effects) when they don’t feel bad to begin with.

JAMA 2000 Jul 26;284(4):465-71

Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).
Perry HM Jr, Davis BR, Price TR, Applegate WB, Fields WS, Guralnik JM, Kuller L, Pressel S, Stamler J, Probstfield JL

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10904510&dopt=Abstract

Lancet 2000 Mar 11;355(9207):865-72

Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials.
Staessen JA, Gasowski J, Wang JG, Thijs L, Den Hond E, Boissel JP, Coope J, Ekbom T, Gueyffier F, Liu L, Kerlikowske K, Pocock S, Fagard RH

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

BMJ 2000 Aug 12;321(7258):412-9

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.
Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10938049&dopt=Abstract

2. Diabetes
1. ~16 million Americans have diabetes. 1/3 of them are undiagnosed.
2. Most diabetics have the type of diabetes that does not usually require insulin. Other drugs include: sulfonylureas (increases insulin production from pancreas), biguanides and troglidazole (enhance insulin sensitivity of target cells), acarbose (decreases GI glucose absorption).
3. There is good evidence that "tight" (close to normal 125mg/100cc blood) control of blood glucose reduces small vessel vascular complications of diabetes (blindness, renal failure, neuropathy). Stroke generally involves larger vessels. Less evidence exists to support the statement that tight control of blood sugar will reduce the incidence of strokes in diabetic patients. (One study in England did demonstrate risk reduction in intensively treated obese diabetic patients.) Pending more research in this area, diabetics are encouraged to get diagnosed and manage blood sugar levels close to normal.

Stroke 1995 May;26(5):774-7

Nonfasting serum glucose and the risk of fatal stroke in diabetic and nondiabetic subjects. 18-year follow-up of the Oslo Study.
Haheim LL, Holme I, Hjermann I, Leren P

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7740565&dopt=Abstract

Diabetes Care 2000 Apr;23 Suppl 2:B30-4

Optimal glycemic control in type 2 diabetic patients. Does including insulin treatment mean a better outcome?
Vaaler S

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10860188&dopt=Abstract

Stroke 1997 Jun;28(6):1153-7

Stroke recurrence in diabetics. Does control of blood glucose reduce risk?
Alter M, Lai SM, Friday G, Singh V, Kumar VM, Sobel E

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9183342&dopt=Abstract

3. High cholesterol
1. Reduction of elevated cholesterol levels by 9% is enough to reduce incidence of stroke. Overall stroke risk reduction for treatment of middle-aged adults was 23-30%. (Data not available on effectiveness in the elderly.)
2. Drugs known as HMG-CoA reductase inhibitors, or "statins", (such as pravastatin or simvastatin), are the most effective.

Cerebrovasc Dis 2000 Mar-Apr;10(2):85-92

Cholesterol reduction and stroke occurrence: an overview of randomized clinical trials.
Di Mascio R, Marchioli R, Tognoni G

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

Neurology 2000 Feb 22;54(4):790-6

HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention.
Hess DC, Demchuk AM, Brass LM, Yatsu FM

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

Curr Opin Lipidol 1999 Dec;10(6):535-41

Effects of statins on carotid disease and stroke.
Crouse JR

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

Drugs Aging 2000 Jul;17(1):33-51

The relationship between cholesterol and stroke: implications for antihyperlipidaemic therapy in older patients.
Sarti C, Kaarisalo M, Tuomilehto J

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

N Engl J Med 2000 Aug 3;343(5):317-26

Pravastatin therapy and the risk of stroke.
White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, Kirby AC, West MJ, Tonkin AM

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10752701&dopt=Abstract

Curr Opin Neurol 2000 Feb;13(1):57-62

Biological basis for statin therapy in stroke prevention.
Rosenson RS

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10719651&dopt=Abstract

Drugs 2000 Jan;59(1):1-6

HMG-CoA reductase inhibitors in the prevention of stroke.
van Mil AH, Westendorp RG, Bollen EL, Lagaay AM, Blauw GJ

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10718096&dopt=Abstract

4. Excessive alcohol use
1. Light-to-moderate drinking (≤2 drinks/day) has been associated with decreased overall mortality which has been attributed to less heart disease and stroke. Heavy drinking is associated with increased risk of stroke.
2. Attempts to increase alcohol consumption in the general population is not recommended. Benzodiazepine drugs may be needed to prevent potentially lethal withdrawal reactions in alcoholics

Acta Cardiol 2000 Jun;55(3):151-6

Alcohol and its relation to all-cause and cardiovascular mortality.
Sasaki S

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10902038&dopt=Abstract

Alcohol Clin Exp Res 2000 Mar;24(3):386-9

Prospective study on alcohol intake and risk of subarachnoid hemorrhage among Japanese men and women.
Sankai T, Iso H, Shimamoto T, Kitamura A, Naito Y, Sato S, Okamura T, Imano H, Iida M, Komachi Y

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10776682&dopt=Abstract

5. Low estrogen (post-menopausal)
1. Epidemiological studies suggest post-menopausal hormone replacement reduces the risk of stroke. Controlled studies are still underway.
2. Discontinuation of postmenopausal replacement therapy is not recommended.

Int J Dev Neurosci 2000 Jul-Aug;18(4-5):347-58

Neuroprotective effects of estrogens: potential mechanisms of action.
Green PS, Simpkins JW

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10817919&dopt=Abstract

6. Smoking
1. Risk of stroke increases progressively with increased exposure to smoke. With cessation, risk returns to baseline within 2-5 years.
2. Drugs which may help a person quit smoking include nicotine replacement therapy (patch or gum) and bupropian (an antidepressant that probably works on neurochemistry of nicotine addiction by enhancing brain dopamine levels and affecting noradrenergic neurons. Dopaminergic and noradrenergic pathways are involved in nicotine addiction and withdrawal.)
7. Folic acid deficiency
1. Elevated levels of the amino acid homocysteine have been associated with atherosclerotic vascular disease. Folic acid reduces homocysteine levels.
2. Studies have been inconsistent in showing whether folic acid ingestion beyond the RDA can reduce this risk. Currently, the AHA does not recommend supplements. However, since a significant proportion of the population does not meet the current RDAs, a better diet or supplements may be indicated.

Neurolog Sci 2000 Apr;21(2):67-72

Prevention of recurrent stroke.
Boysen G, Truelsen T

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10938183&dopt=Abstract

Circulation. 1999;99:178-182

Homocyst(e)ine, Diet, and Cardiovascular Diseases. A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association

M. René Malinow, MD; Andrew G. Bostom, MD; Ronald M. Krauss, MD

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884399&dopt=Abstract

8. Multiple risk factors greatly increases risk of stroke.

Ann Epidemiol 2000 Aug;10(6):380-8

Stroke risk from multiple risk factors combined with hypertension. A primary care based case-control study in a defined population of northwest england.
Du X, McNamee R, Cruickshank K

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10964004&dopt=Abstract

 

BMJ 2000 Aug 12;321(7258):412-9

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.
Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10938049&dopt=Abstract

9. Anyone who has ever tried to lose weight, quit smoking, exercise regularly or take the full course of an antibiotic knows how difficult it is to be compliant and stick to the program. Finding successful ways to help people reduce their risk factors is probably the greatest health challenge that faces us in America.

1. Aspirin
1. Mechanism: Blocks enzyme in platelet preventing development of substance necessary for platelet aggregation. Works right away! Effect lasts for life of platelet (7-10 days).
2. Use of low dose aspirin (80-325 mg/day) is associated with lower risk of thrombosis related stroke in patients with vascular risk factors and emobolus related stroke 22% risk reduction. High dose aspirin increases risk of hemorrhagic stroke. Although aspirin is not dramatically effective in reducing stroke risk, it is very inexpensive and thus could have a major impact on stroke reduction world-wide. There are several other "antiplatelet" drugs on the market, such as dipyridamole (given in combination with aspirin), clopidrogrel, and ticlopidine.

Stroke 2000 Jun;31(6):1240-9

Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups.
Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10835439&dopt=Abstract

Cochrane Database Syst Rev 2000;(2):CD000029

Antiplatelet therapy for acute ischaemic stroke.
Gubitz G, Sandercock P, Counsell C

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10796284&dopt=Abstract

Am J Med 2000 Feb 15;108(3):205-9

Does prior use of aspirin affect outcome in ischemic stroke?
Kalra L, Perez I, Smithard DG, Sulch D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10723974&dopt=Abstract

Arch Neurol 2000 Mar;57(3):326-32

Aspirin for the primary prevention of stroke and other major vascular events: meta-analysis and hypotheses.
Hart RG, Halperin JL, McBride R, Benavente O, Man-Son-Hing M, Kronmal RA

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10714657&dopt=Abstract

Stroke 1999 Sep;30(9):1764-71

Prospective study of aspirin use and risk of stroke in women.
Iso H, Hennekens CH, Stampfer MJ, Rexrode KM, Colditz GA, Speizer FE, Willett WC, Manson JE

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10471421&dopt=Abstract

Drug Saf 1998 Nov;19(5):373-82

Drug therapy for acute ischaemic stroke: risks versus benefits.
Lindley RI

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9825950&dopt=Abstract

Neurology 1998 Sep;51(3 Suppl 3):S17-9

Dipyridamole trials in stroke prevention.
Diener HC

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9744826&dopt=Abstract

Am J Cardiol 1995 Feb 23;75(6):34B-38B

Antithrombotic agents in cerebral ischemia.
Albers GW

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7863971&dopt=Abstract

2. Warfarin (COUMADIN)
1. Mechanism: Antagonizes vitamin K thus preventing liver from making coagulation factors. Requires several days of therapy before anticoagulation effect is seen.
2. Warfarin has been consistently associated with an impressive (68%) reduction of stroke risk in patients with atrial fibrillation (upper chambers of heart quiver rather than contracting and blood slows promoting thrombus formation). For every 1000 atrial fibrillation patients treated with warfarin, 25 strokes and 12 deaths could be prevented every year.
3. At least one study documents that warfarin may also be more effective than aspirin in preventing stroke in patients with with intracranial vascular disease (aspirin treated patients had a stroke rate of 10.4/100 patient-years, while warfarin treated patients had a rate of 3.6/100 patient-years).
4. Unlike aspirin, patients on warfarin must have bloodwork done to monitor the international normalized ratio (INR). Goal is usually about 2-3 (normal 1). Higher INRs (4-5) are associated with serious bleeding problems, including intracranial hemorrhage.

Drugs 1999 Dec;58(6):997-1009

Guidelines for stroke prevention in patients with atrial fibrillation.
Howard PA

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10651387&dopt=Abstract

J Gen Intern Med 2000 Jan;15(1):56-67

Prevention of thromboembolism in atrial fibrillation. A meta-analysis of trials of anticoagulants and antiplatelet drugs.
Segal JB, McNamara RL, Miller MR, Kim N, Goodman SN, Powe NR, Robinson KA, Bass EB

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10632835&dopt=Abstract

JAMA 1999 Dec 1;282(21):2058-67

Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis.
Anand SS, Yusuf S

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10591389&dopt=Abstract

Ann Intern Med 1999 Oct 5;131(7):492-501

Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.
Hart RG, Benavente O, McBride R, Pearce LA

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10507957&dopt=Abstract

Neurology 1995 Aug;45(8):1488-93

The Warfarin-Aspirin Symptomatic Intracranial Disease Study.
Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, Pessin MS, Weichel E, Sila CA, Furlan AJ, et al

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7644046&dopt=Abstract

Cochrane Database Syst Rev 2000;(2):CD001927

Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks.
Benavente O, Hart R, Koudstaal P, Laupacis A, McBride R

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10796453&dopt=Abstract

3. Heparin and low molecular weight heparin (LMWH)
1. Mechanism of action: Inhibits thrombin and/or clotting factors working on immediate precursors of thrombin. Therapeutic effect seen in 4-6 hours.
2. Despite its wide spread use, no form of heparin has consistently been shown to provide a clinical benefit in acute stroke. (Only one study showed a lower death/disability rate at 6 months in patients treated with LMWH vs. placebo.) Heparins are useful in preventing venous thrombosis, which can be a complication of the immobility associated with stroke paralysis, but most experts agree that the risk of hemorrhage outweighs any potential benefit and that venous thrombosis should be prevented with other means.

Thromb Haemost 1999 Sep;82 Suppl 1:139-47

Low-molecular weight heparins in venous and arterial thrombotic disease.
Bijsterveld NR, Hettiarachchi R, Peters R, Prins MH, Levi M, Buller HR

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10695506&dopt=Abstract

Cochrane Database Syst Rev 2000;(2):CD000024

Anticoagulants for acute ischaemic stroke.
Gubitz G, Counsell C, Sandercock P, Signorini D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10796283&dopt=Abstract

Blood Coagul Fibrinolysis 1999 Aug;10 Suppl 2:S123-7

Anticoagulation in acute ischaemic stroke: deep vein thrombosis prevention and long-term stroke outcomes.
Lensing AW

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10493241&dopt=Abstract

Lancet 2000 Apr 8;355(9211):1205-10

Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial.
Berge E, Abdelnoor M, Nakstad PH, Sandset PM

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10770301&dopt=Abstract

Stroke 2000 Jul;31(7):1770-8

Low-molecular-weight heparins and heparinoids in acute ischemic stroke : a meta-analysis of randomized controlled trials.
Bath PM, Iddenden R, Bath FJ

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10884486&dopt=Abstract

Cochrane Database Syst Rev 2000;(2):CD000119

Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke.
Counsell C, Sandercock P

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10796301&dopt=Abstract

Neurology 1998 Sep;51(3 Suppl 3):S56-8

Heparin and heparinoids in stroke.
Sherman DG

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9744837&dopt=Abstract

Thromb Haemost 1997 Jul;78(1):173-9

Acute ischemic stroke and heparin treatments.
Samama MM, Desnoyers PC, Conard J, Bousser MG

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9198148&dopt=Abstract

JAMA 1998 Apr 22-29;279(16):1265-72

Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9565006&dopt=Abstract

Thromb Haemost 1999 Sep;82 Suppl 1:139-47

Low-molecular weight heparins in venous and arterial thrombotic disease.
Bijsterveld NR, Hettiarachchi R, Peters R, Prins MH, Levi M, Buller HR

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10695506&dopt=Abstract

 

4. Neuroprotectants: A variety of drugs are being investigated to see if they can help brain tissue tolerate lack of oxygen for a longer period of time before becoming damaged. Time prohibits discussion of these drugs during this conference.
5. Tissue plasminogen activator (t-PA, alteplase, ACTIVASE)
1. Mechanism: Unlike aspirin, warfarin and heparin, all of which prevent clot development, this drug dissolves a clot which is already formed. Clots have a substance inherently present known as plasminogen, which degrades fibrin. The natural evolution of a clot repairing a damaged blood vessel is for it to dissolve when the vessel has healed. (Your mother apparently knew about plaminogen and so repeated told you not to pick at your scabs.) Plasminogen is activated by t-PA promoting more rapid dissolution of the clot. In stroke, this allows blood flow to be restored.
2. Clinical studies show patients treated with t-PA were at least 30% more likely to have minimal or no disability at 3 and 12 months than were patients given placebo. This drug should not be given to the small percentage of patients having a hemorrhagic stroke (for obvious reasons!).
3. It needs to be given with 3 hours of onset of stroke symptoms to be effective. Delays in symptom recognition by patients, arrival at the emergency room, and ruling out of hemorrhagic stroke by computerized tomography (CT) scan have limited the number of patients eligible for this important therapy.