Pharmacotherapy for Secondary Stroke Prevention
An estimated 700,000 strokes occur in the United States each year, which translates to an American experiencing a stroke every 45 seconds.1 Of these strokes, more than 200,000 are recurrent episodes. The morbidity associated with a stroke is devastating; it is the most common cause of long-term disability in the United States. Stroke survivors are often unable to function independently.2 Mortality remains high with strokes, and the rate is behind only heart disease and cancer for the leading cause of death in adults.1
While these grim statistics are sobering, a great many pharmacotherapy options are available to help patients prevent a recurrence of stroke. The American Heart Association (AHA) recently published guidelines for antiplatelet therapy for secondary stroke prevention. Along with antiplatelet therapy, control of hypertension, hyperlipidemia, and hyperglycemia are important components of a prevention regimen.
The vast majority (88%) of strokes are ischemic in nature.1 Therefore, antiplatelet therapy is the cornerstone of secondary stroke prevention (Table). Antiplatelet therapy is preferred over oral anticoagulation such as warfarin for patients with noncardioembolic ischemic stroke.2 Medications used for this purpose include aspirin, clopidogrel, dipyridamole, and ticlopidine. In addition, combination therapy with aspirin and dipyridamole is commercially available.
Aspirin is a commonly used antiplatelet therapy because of its low cost and nonprescription status. Doses ranging from 50 to 1300 mg daily have proved effective for the purpose of secondary stroke prevention.2 In the United States, formulations containing 81 to 325 mg are used. No evidence is available to prove that higher-dose aspirin has superior efficacy to low-dose, according to a trial from the United Kingdom.3 A doserelated increase in gastrointestinal (GI) bleeding has been established, however.4 Aspirin inhibits thromboxane A2, which promotes platelet aggregation and vasoconstriction.
Clopidogrel and ticlopidine belong to the thienopyridine family, whose antiplatelet effect is exerted by antagonizing adenosine diphosphate-dependent fibrinogen adhesion to platelet membranes. Ticlopidine is rarely used due to its bone marrow suppression and adverse effects, and it is not among the agents recommended in the AHA guidelines.2 Clopidogrel is at least as effective as aspirin and, in some patient subgroups (eg, those with peripheral arterial disease), it is more effective in preventing vascular death.5 Clopidogrel causes less GI bleeding and dyspepsia than aspirin, so it is a beneficial treatment for those patients who cannot tolerate the adverse effects of aspirin. Clopidogrel also is an excellent alternative for patients who have aspirin allergies.2 Combination therapy with aspirin and clopidogrel should not be recommended due to the increase in hemorrhagic complications and lack of added efficacy.6 Clopidogrel is dosed at 75 mg daily and is now available as a generic.
Dipyridamole causes vasodilation and indirectly inhibits platelet aggregation. The inhibition of adenosine deaminase and phosphodiesterase by dipyridamole causes buildup of cyclic adenosine monophosphate, adenosine, and andenine nucleotides?all of which inhibit platelet aggregation. While dipyridamole is available as an immediate-release tablet dosed 50 to 100 mg 3 times daily, it should be avoided as monotherapy for secondary stroke prevention because it is less effective than aspirin.7 An extended-release capsule formulation of dypridamole 200 mg plus aspirin 25 mg taken twice daily, however, is recommended by the AHA as one of the first-line treatments for patients with previous ischemic stroke (IS) or transient ischemic attack (TIA).2 In a large clinical trial, the combination therapy prevented more secondary strokes (but not mortality) than either component alone or placebo.7 Dipyridamole does not add to the risk of bleeding, compared with aspirin, but it does cause significantly more headaches than aspirin. Elderly women seem to be most vulnerable to this adverse effect, but the headaches are self-limiting and decrease after a week of therapy.8
The benefit of antihypertensive therapy extends beyond its ability to lower blood pressure. Patients with and without hypertension can significantly reduce the risk of recurrent stroke and other vascular events with antihypertensive therapy. While several proposed mechanisms of this protective benefit have been theorized, no human evidence exists.9
Goals of therapy for hypertensive patients are not set by the AHA, but it does cite the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).10 The JNC-7 found that a blood pressure reduction of approximately 10/5 mm Hg showed recurrent stroke reduction.9 Patients should be lowered to their goal slowly over months to reduce adverse effects associated with rapid blood pressure reduction. Elderly patients, especially those older than 80 years, may have a difficult time reaching their goal and have increased mortality associated with overly aggressive antihypertensive therapy.11
Particular classes of antihypertensive drugs are not recommended by the AHA, but it does align with the JNC-7, which suggests the use of angiotensin-converting enzyme inhibitors plus thiazide diuretics. Angiotensin receptor blockers (ARBs) also have promise as therapy for secondary stroke patients. Randomized, controlled trials have shown increased stroke reduction in patients treated with ARBs versus beta-blockers12 or calcium channel blockers (Table).13
Unlike antihypertensive therapy, statin therapy should be reserved for patients who have not met their individualized, risk factor-based lipid goals or for patients whose strokes are thought to be atherosclerotic in nature.2 Many patients with IS or TIA, however, will qualify for statin therapy based on the AHA guidelines due to the presence of diabetes or coronary artery disease (Table). Hyperlipidemia pharmacotherapy should be directed by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults guidelines. The low-density lipoprotein (LDL) cholesterol goal for each patient is determined by carefully assessing the risk category. For very-high-risk patients, an LDL <70 mg/dL should be obtained. Many well-designed trials assessing the safety and efficacy of high-dose statin therapy make these stringent goals more achievable.
The majority of evidence regarding glycemic control in diabetics relates to primary prevention of stroke. In secondary stroke patients, normoglycemia is emphasized to reduce microvascular complications such as retinopathy, neuropathy, and nephropathy.2 Patients should have blood glucose goals of <100 mg/dL fasting and an A1C goal of <7%. Control of hypertension and hyperlipidemia has the greatest benefit in preventing stroke in patients with diabetes.
High-dose atorvastatin (80 mg daily) was recently compared with placebo for patients with stroke or TIA in a large trial published in August 2006.14 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial results showed that even patients without coronary heart disease reduced their risk for a second stroke and other cardiovascular events with atorvastatin 80 mg.
The maker of Aggrenox (dipyridamole/ aspirin) and Micardis (telmisartan) is conducting the largest secondary stroke trial to date, dubbed PRoFESS (Prevention Regimen for Effectively avoiding Second Strokes).15 The trial will place patients in the following 4 categories: dipyridamole/aspirin plus telmisartan; dypridamole/aspirin plus placebo; clopidogrel plus telmisartan; and clopidogrel plus placebo. The trial recently met its recruitment goal of more than 20,000 patients. The results of ProFESS and SPARCL will no doubt affect future AHA guidelines for secondary stroke prevention.
Pharmacotherapy plays an integral role in secondary stroke prevention. Health care practitioners must be vigilant in identifying risk factors in patients who have suffered a stroke so that their pharmacotherapy is appropriately goal-directed. Pharmacists in both hospital and ambulatory settings can have a great impact on these patients by enforcing guidelines, adjusting medication, and monitoring for adverse events.
Dr. Thune is an infectious diseases resident and visiting instructor for Midwestern University, College of Pharmacy?Glendale.
1. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics?2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85-151. Epub January 11, 2006.
2. Sacco R, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: cosponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577-617.
3. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
4. Farrell B, Godwin J, Richard S. Warlow C. The United Kingdom transient ischaemic attack (UKTIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044-1054.
5. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-1339.
6. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.
7. Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
8. Leonardi-Bee J, Bath PM, Bousser MG, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke. 2005;36:162-168.
9. Strandberg T. Secondary prevention of stroke is important: but all hypertensive drugs are not created equal? Stroke. 2005;36:1225-1226.
10. Chobanian AV, Bakris GL, Black HR, et al for the National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
11. Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials. INDIANA Group. Lancet. 1999;353:793-796.
12. LIFE Study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.
13. Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke: Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36:1218-1226.
14. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
15. PRoFESS. The largest secondary stroke prevention trial ever. Available at: www.profess-study.com. Accessed November 2, 2006.