- Author: Brian Silver, MD, FRCPC, FAHA, FAAN; Chief Editor: Stephen Kishner, MD, MHA more...
Primary stroke prevention refers to the treatment of individuals with no history of stroke. Secondary stroke prevention refers to the treatment of individuals who have already had a stroke or transient ischemic attack.
Essential update: Updated guidelines on primary prevention of stroke released
The American Heart Association and American Stroke Association have released updated guidelines on the primary prevention of stroke. New recommendations include the following[1, 2] :
Use of new oral anticoagulants, including dabigatran, apixaban, and rivaroxaban, in patients with nonvalvular atrial fibrillation
Home self-monitoring of blood pressure in hypertensive patients
Use of nonestrogen oral contraceptives in female patients with migraine with aura
All patients should follow the Mediterranean diet supplemented with nuts and reduce sodium intake
Screening for sleep apnea
Primary Prevention of Stroke
Risk-reduction measures in primary stroke prevention may include the use of antihypertensive medications; warfarin; platelet antiaggregants; 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins); smoking cessation; dietary intervention; weight loss; and exercise.
Modifiable risk factors include the following:
Sickle cell disease
Diet and activity
Weight and body fat
Secondary Prevention of Stroke
Secondary prevention can be summarized by the mnemonic A, B, C, D, E, as follows:
A - Antiaggregants (aspirin, clopidogrel, extended-release dipyridamole, ticlopidine) and anticoagulants (warfarin)
B - Blood pressure–lowering medications
C - Cessation of cigarette smoking, cholesterol-lowering medications, carotid revascularization
D - Diet
E – Exercise
Smoking cessation, blood pressure control, diabetes control, a low-fat diet (eg, Dietary Approaches to Stop Hypertension [DASH] or Mediterranean diets), weight loss, and regular exercise should be encouraged.
Primary prevention of stroke refers to the treatment of individuals with no previous history of stroke. Risk-reduction measures may include the use of antihypertensive medications; warfarin; platelet antiaggregants; 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins); smoking cessation; dietary intervention; weight loss; and exercise.
Secondary prevention refers to the treatment of individuals who have already had a stroke or transient ischemic attack (TIA). Measures may include the use of platelet antiaggregants, antihypertensives, statins, and lifestyle interventions.
Most primary and secondary stroke prevention recommendations focus on ischemic stroke, but some apply to hemorrhagic stroke, or to cerebral venous thrombosis.
Primary Prevention of Stroke
In December 2010, the American Heart Association (AHA) and the American Stroke Association (ASA) published newly revised Guidelines for the Primary Prevention of Stroke. The guideline provides an overview of established and emerging risk factors for stroke, and gives evidence-based recommendations to reduce the likelihood of a first stroke in individuals at risk. Modifiable risk factors and recommendations for management are summarized below. While the previous version of the guidelines focused only on ischemic stroke, the 2010 revision added recommendations for prevention of hemorrhagic stroke.
Diagnosis and management of a rare form of stroke, cerebral venous thrombosis (CVT), was the subject of a 2011 AHA/ASA statement for healthcare professionals. Primary prevention of CVT has not been the focus of randomized clinical trials, but the AHA/ASA statement suggests that primary prevention strategies for venous thromboembolism in general may have some efficacy with respect to CVT. Most CVT prevention is secondary and will be discussed in Secondary Prevention.
Hypertension is the most important modifiable risk factor for stroke and intracerebral hemorrhage (ICH), and the risk of stroke increases progressively with increasing blood pressure, independent of other factors.[5, 6] Both behavioral lifestyle changes and pharmacologic therapy are important parts of the comprehensive strategy recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (also see Diet and nutrition, Physical inactivity, and Obesity and body fat distribution, below).
In a meta-analysis of 23 randomized trials on antihypertensive medication compared with no drug therapy, a 32% reduction in stroke risk was found with pharmacologic treatment. The risk of both stroke and cardiovascular events is lower when systolic blood pressures are < 140 mm Hg and diastolic blood pressures are < 90 mm Hg. Regular blood pressure screening and a combination of behavioral lifestyle modification and drug therapy are recommended to achieve these goals. Studies on the comparative benefits of specific classes of antihypertensive agents have not shown definitive results. In patients who have hypertension with diabetes or renal disease, the blood pressure goal is < 130/80 mm Hg.
Data from the Women's Health Initiative show an increased risk of stroke over 5.4 years among postmenopausal women who have greater visit-to-visit variability in blood pressure measurements. Risk is particularly high among women with systolic blood pressures below 120 mm Hg. Whether treatment of visit-to-visit variability reduces stroke risk requires evaluation in a clinical trial.
Cigarette smoking is directly correlated with an increased risk of both ischemic stroke and subarachnoid hemorrhage (SAH), with risk for the former approximately doubled by smoking and risk for the latter increased 2- to 4-fold.[9, 10, 11, 12, 13, 14, 15] Smoking also appears to increase the risk of hemorrhagic stroke, especially in younger individuals.[16, 17] Data on smoking and the risk of ICH are inconclusive. Smoking also potentiates other stroke risk factors such as hypertension and oral contraceptive use. Counseling, nicotine replacement, and oral smoking-cessation medications are options that should be offered to all individuals who smoke. Cessation of smoking has been shown to reduce the risk of both stroke and cardiovascular events to levels approaching those of individuals who have never smoked.[18, 19, 20, 21]
As with heart disease, epidemiologic evidence indicates that environmental smoke (ie, passive or “secondhand” smoke) is associated with an increased risk of stroke.[22, 23, 24, 25, 26, 27] Although data are unavailable to date that show that avoidance of environmental tobacco smoke decreases stroke risk, avoiding exposure to environmental smoke is reasonable.
Diabetes is estimated to increase the relative risk of ischemic stroke 1.8- to nearly 6-fold, independent of other risk factors. In addition, many diabetics have hypertension and dyslipidemia, both significant risk factors for stroke. Multiple studies on glycemic control in type 2 diabetics have shown no effect or inconclusive results in reducing stroke risk. However, aggressive control of hypertension in diabetics reduces stroke incidence. Antihypertensive agents that are useful in the diabetic population include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). The use of beta-adrenergic blockers has been associated with an increased risk of new-onset type 2 diabetes.
Several studies have shown that HMG-CoA reductase inhibitors (statins) are beneficial in reducing stroke risk in diabetic individuals, especially those with other risk factors such as retinopathy, albuminuria, current smoking, or hypertension.[31, 32, 33] Treating adult diabetics with statins is recommended. Monotherapy with fibrates has also shown some benefit in reducing stroke risk in diabetics, and may also be considered. Taking aspirin is reasonable in patients who are at high risk for cardiovascular disease (CVD); however, the efficacy of aspirin for reducing stroke risk in diabetic patients remains uncertain.
Elevated total cholesterol has been linked to increased risk of ischemic stroke in a number of epidemiological studies.[35, 36, 37, 38, 39] Epidemiological studies have also shown an inverse relationship between high-density lipoprotein (HDL) cholesterol and stroke risk. The approach to treatment of dyslipidemia for primary prevention of ischemic stroke is based on recommendations from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III).[41, 42]
Statin therapy and therapeutic lifestyle changes are recommended for patients with coronary artery disease or certain high-risk conditions such as diabetes, with low-density lipoprotein (LDL) cholesterol goals as outlined in the NCEP ATP III guideline. Intensive-dose statin therapy increases the risk of new-onset diabetes by 12% compared with moderate-dose statin therapy. Intensive-dose statin therapy may still yield a net benefit in terms of overall outcomes. Niacin may be used in patients with low HDL cholesterol or elevated lipoprotein(a), but its efficacy in preventing ischemic stroke has not been established. Fibric acid derivatives, niacin, bile acid sequestrants, and ezetimibe may be useful in patients who have not achieved target LDL with statin therapy or who cannot tolerate statins; however, the effectiveness of these agents in reducing stroke risk in patients with dyslipidemia has not been established.
Embolism from atrial fibrillation (AF)–associated left atrial thrombi accounts for approximately 10% of all ischemic strokes in the United States, and AF is associated with a 4- to 5-fold increase in the risk of ischemic stroke, independent of cardiac valve disease.[44, 45] Because a substantial minority of AF-related stroke occurs in older patients with previously undiagnosed AF, it may be useful to screen patients older than 65 years of age for AF in the primary care setting using pulse taking followed by an ECG.
The choice of therapy for primary stroke prevention in patients with AF depends on several factors, including estimated stroke risk, risk of bleeding with anticoagulation therapy, and patient preference. Among several risk stratification schemes, two widely used systems are the CHADS2 scoring system and the American College of Cardiology/AHA/European Society of Cardiology (ACC/AHA/ESC) 2006 guideline recommendations for stroke risk stratification in AF patients.[46, 47, 48, 49, 50] Adjusted-dose warfarin (target INR 2-3) anticoagulation is highly effective for preventing stroke in patients with AF, and also reduces stroke severity and poststroke mortality.[50, 51, 52, 53, 54]
The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE A and ACTIVE W) has shown that adjusted-dose warfarin is superior to clopidogrel plus aspirin, and clopidogrel plus aspirin is superior to aspirin alone in preventing stroke in patients with AF.[55, 56] However, the risk of major bleeding complications, such as ICH, is higher with warfarin therapy than with the antiplatelet agents. Regular monitoring of patients on warfarin is required, especially during the first 3 months of treatment, when the risk of bleeding is greatest.
Adjusted-dose warfarin anticoagulation is recommended for all patients with nonvalvular AF at high risk or moderate risk of stroke. Aspirin is recommended for low- and moderate-risk patients with AF. For high-risk patients in whom anticoagulation is unsuitable, a combination of clopidogrel and aspirin may provide more protection against stroke than aspirin alone. In addition to antithrombotic prophylaxis, managing blood pressure aggressively in elderly patients with AF may be useful.
Other cardiac conditions
Approximately 20% of ischemic strokes are caused by cardiogenic embolism. Compared with noncardiogenic strokes, these strokes tend to be relatively severe, with greater neurologic deficits at admission, discharge, and 6 months after discharge. Cardiac conditions associated with an increased risk of stroke include atrial arrhythmias, cardiac tumors, valvular vegetations, valvular disease, prosthetic valves, dilated cardiomyopathy, coronary artery disease, endocarditis, and congenital cardiac anomalies (patent foramen ovale, atrial septal defect, atrial septal aneurysm). The risk of stroke is inversely proportional to left ventricular ejection fraction, a relationship that is also seen in acute coronary syndrome.[59, 60, 61, 62]
Recommended strategies to reduce the risk of stroke in patients with valvular heart disease, unstable angina, chronic stable angina, and acute MI are provided in practice guidelines from the American College of Cardiology and the American Heart Association (ACC/AHA).[63, 64, 65, 66] Warfarin therapy to prevent stroke may be reasonable in patients with left ventricular mural thrombi or an akinetic left ventricular segment after ST-segment elevation MI.
Asymptomatic carotid conditions
Atherosclerotic stenosis in the extracranial internal carotid artery or carotid bulb is associated with an increased risk of stroke. Because of recent advances in both medical and interventional therapies, data comparing these modalities for asymptomatic carotid stenosis are not available at present. However, recent studies indicate that the annual rate of stroke in patients with asymptomatic stenosis who are treated medically is approximately 1% or less.[67, 68, 69]
It is recommended that patients with asymptomatic carotid artery stenosis be evaluated for other treatable risk factors for stroke; in general, these patients should be managed with appropriate medical therapy and lifestyle modifications. Selected patients with asymptomatic carotid stenosis may be appropriate for carotid revascularization, based on an assessment of the patient's comorbid conditions, life expectancy, and other individual factors. Prophylactic carotid endarterectomy (CEA) performed with less than 3% morbidity and mortality may be useful in highly selected patients with asymptomatic carotid stenosis (≥60% stenosis on angiography or ≥70% on Doppler ultrasonography). Patients undergoing CEA should also be treated with aspirin unless contraindicated.
Prophylactic carotid artery angioplasty and stenting (CAS) may be considered in highly selected patients with asymptomatic carotid stenosis (≥60% stenosis on angiography, ≥70% on Doppler ultrasonography, or ≥80% on computed tomography angiography or magnetic resonance angiography [MRA] if stenosis on ultrasonography was 50-69%). The value of CAS as an interventional alternative to CEA in asymptomatic patients at high risk for a surgical procedure remains uncertain as yet. Population screening for asymptomatic carotid artery stenosis is not recommended.
Sickle cell disease
Sickle cell disease (SCD) typically presents early in life with hemolytic anemia and vaso-occlusive manifestations, including stroke, particularly in children with homozygous disease. The risk of stroke during childhood in patients with SCD is 1% per year; the prevalence of stroke by age 20 years is estimated to be at least 11%.[70, 71] In children with high cerebral blood flow rates (time-averaged mean velocity > 200 cm/s) on transcranial Doppler ultrasonography (TCD), the rate of stroke is greater than 10% per year. TCD and other predictive criteria have not been evaluated in adults. Prior to the advent of TCD monitoring, observational data showed that children with an asymptomatic MRI lesion had a greatly increased risk of stroke in the subsequent 5 years, as compared with children with a normal MRI (8.1% vs 0.5%).
Regular, long-term red cell transfusion is the only therapy that has been shown in clinical trials to prevent stroke in children with SCD. Discontinuation of therapy typically results in poor outcomes, with reversion to high-risk TCD characteristics.[74, 75] MRI-guided transfusion is under study. Promising therapies under investigation include bone marrow transplantation and hydroxyurea.[77, 78, 79, 80]
It is recommended that children with SCD be screened with TCD at 2 years of age. It is reasonable to screen younger children and those with borderline abnormal TCD velocities more frequently to detect development of high-risk TCD indications for intervention. Children with elevated stroke risk may require transfusion therapy, which is effective in reducing stroke risk. Administration of hydroxyurea or bone marrow transplantation may be reasonable in children who are at high risk for stroke and are unable or unwilling to undergo regular red blood cell transfusion. MRI and MRA criteria for selection of children for primary stroke prevention using transfusion have not been established.
Postmenopausal hormone replacement therapy
The Women's Health Initiative (WHI), a randomized clinical trial comparing conjugated equine estrogens (CEE) combined with medroxyprogesterone acetate (MPA) versus placebo in postmenopausal women aged 55-79 years, has provoked a major reconsideration of postmenopausal hormone replacement therapy. Among other findings, the WHI showed an increased risk of stroke with CEE therapy, particularly in older subgroups.[81, 82, 83] Similar findings have been reported in other studies.[84, 85]
Selective estrogen receptor modulators (SERMs) such as raloxifene, tamoxifen, or tibolone have been used for the prevention of breast cancer and osteoporotic bone density loss and for treatment of menopausal symptoms. Studies of these agents have also evaluated lowering of cardiovascular and stroke risk as secondary outcomes. No benefit in lowering the risk of MI has been found for any of these therapies, and stroke risk appears to be increased with raloxifene (HR for fatal stroke, 1.49; absolute risk, 0.07 per 100 women after 1 year) and tibolone (relative hazard, 2.19).[86, 87] Stroke rates with raloxifene and tamoxifen appear to be similar.
Hormone therapy and SERMs such as raloxifene, tamoxifen, or tibolone should not be used for primary prevention of stroke in postmenopausal women.
Randomized clinical trials evaluating stroke risk with oral contraceptive (OC) use have not been performed. Meta-analyses of cohort and case-control studies have indicated an approximate doubling of relative risk, though findings of individual studies are inconsistent.[89, 90, 91] Nevertheless, the highest estimated absolute stroke risk with OC use (20 per 100,000) remains well below that associated with pregnancy (34 per 100,000 deliveries).[92, 93]
As the 2011 AHA/ASA CVT statement notes, both OC use and pregnancy are risk factors for CVT. Among younger women diagnosed with CVT who were not pregnant, the great majority were OC users.
On the other hand, well-established risk factors that increase stroke risk with OC use include older age, cigarette smoking, hypertension, and migraine headache. More recently, obesity and hypercholesterolemia, factor V Leiden, and methyl tetrahydrofolate reductase mutation (MTHFR 677TT) have been identified as factors that increase stroke risk in OC users compared with women with these risk factors who do not use OCs.[95, 96]
Oral contraceptives may be harmful in women with additional risk factors for stroke such as smoking or prior thromboembolic events. The combination of a hereditary prothrombotic factor with OC use increases the risk of CVT. Aggressive therapy for stroke risk factors may be reasonable in women who choose to take oral contraceptives despite their increased risks.
Depression is increasingly being recognized as a possible contributor to stroke. In a prospective study of 9601 Western European middle-aged men, baseline depression nearly doubled the risk of stroke during years 5-10 of the 10-year study. The risk of coronary artery disease increased 43% during the first 5 years, after adjusting for age, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment.
Diet and nutrition
Several aspects of diet and nutrition can lead to increased blood pressure, including increased salt or sodium intake, decreased potassium intake, excess weight, and excess alcohol consumption. Because hypertension is the major modifiable risk factor for stroke, a diet that is low in sodium and high in potassium, as indicated in the Dietary Guidelines for Americans from the US Department of Health and Human Services and Department of Agriculture, is recommended to reduce blood pressure. Diets that promote the consumption of fruits, vegetables, and low-fat dairy products, as well as reduced intake of saturated fats (eg, DASH-style diets) help lower blood pressure and may lower risk of stroke.
Reduction of homocysteine levels through folate supplementation has not resulted in a reduced rate of stroke in randomized trials. The effect may largely be mitigated by the fact that the studies were performed in regions of baseline high-folate consumption. Uncertainty exists about a possible benefit in regions of low-folate consumption.
Physical inactivity is associated with an increased risk of stroke and other adverse effects, such as cardiovascular morbidity and mortality. Increased physical activity may decrease the risk of stroke by 25-30%.[102, 103, 104] Physical activity is also known to have a positive effect on control of blood pressure and diabetes, two significant risk factors for stroke.
The recommended goal for physical activity for adults, as indicated in the 2008 Guidelines for Physical Activity Guidelines for Americans from the US Department of Health and Human Services, is to engage in at least 150 minutes (2 hours and 30 minutes) per week of moderate intensity or 75 minutes (1 hour and 15 minutes) per week of vigorous intensity aerobic physical activity.
Obesity and body fat distribution
Although no clinical trials have tested the effect of weight loss on stroke risk, numerous studies have examined the relationship between weight or adiposity and risk of stroke. In one meta-analysis of body mass index (BMI) and stroke risk, each 5 kg/m2 increase in BMI was associated with a 40% increased risk of stroke mortality in individuals with BMI greater than 25 kg/m2. Furthermore, in studies comparing the predictive value of BMI and abdominal body fat, abdominal body fat has also been found to be a stronger predictor of stroke risk.[106, 107, 108, 109] Multivariate analyses controlling for risk factors such as hypertension, diabetes, and dyslipidemia show a consistent, though weaker, relationship between BMI and stroke risk, suggesting that the effects of adiposity are mediated in part through these other risk factors.
Thus, in overweight and obese persons, weight reduction is recommended to reduce blood pressure and risk of stroke.
A healthy lifestyle includes elements such as smoking avoidance, appropriate body mass index, physical activity, vegetable consumption, and alcohol moderation. At least one study has found a reduced incidence of total, ischemic, and hemorrhagic stroke when there is an adherence to more of the elements of a healthy lifestyle. The partial population attributable risk associated with adherence to 3, 4, and 5 elements was 26.3%, 43.8%, and 54.6% for all types of stroke. The corresponding numbers for ischemic stroke were 22.7%, 45.3%, and 59.7%; and for hemorrhagic stroke were 35%, 35%, and 36.1%. The lack of increase of attributable risk with hemorrhagic stroke suggests a ceiling effect and a greater contribution of genetic factors.
In addition, the INTERSTROKE study found that the population attributable risk for all stroke was 90.3% when 10 risk factors were considered (hypertension, current smoking, waist-to-hip ratio, diet risk score, regular physical activity, diabetes mellitus, alcohol intake, psychosocial stress and depression, cardiac causes, and ratio of apolipoproteins B to A1).
Secondary Prevention of Stroke
Secondary prevention can be summarized by the mnemonic A, B, C, D, E, as follows:
A - Antiaggregants (aspirin, clopidogrel, extended-release dipyridamole, ticlopidine) and anticoagulants (warfarin)
B - Blood pressure–lowering medications
C - Cessation of cigarette smoking, cholesterol-lowering medications, carotid revascularization
D - Diet
E - Exercise
Closure with a percutaneous device is often recommended for patients with patent foramen ovale (PFO), but this intervention may not reduce the risk of recurrent stroke. The CLOSURE-I study was a randomized trial of PFO closure plus best medical therapy versus best medical therapy alone. In just over 900 patients, the rate of stroke at 2 years was approximately 3% and did not differ significantly between groups. The rate of stroke was not significantly different among those patients with larger PFOs and those with atrial septal aneurysms. Further, the risk of atrial fibrillation was approximately 5% and the risk of major vascular complications was 3% in the closure group. At this time, PFO closure is not recommended for the general patient with stroke and incidental finding of PFO. Additional randomized trials are forthcoming.
According to the 2011 AHA/ASA guidelines for the prevention of stroke in patients with stroke or transient ischemic attack (secondary prevention), optimal medical treatment in patients with carotid artery stenosis and a TIA includes antiplatelet therapy, statins, and risk factor modification.
A 15% relative risk reduction in vascular events (stroke, death, MI) has been documented for aspirin compared with placebo. No clear evidence suggests that high doses (eg, 1300 mg/d) are more effective than low doses (eg, 50 mg/d). Doses prescribed vary worldwide. The usual dose in North American practice varies from 81 to 325 mg daily. Adverse effects of aspirin include gastritis (common to most antiplatelet agents), tinnitus, and hearing loss (especially at high doses).
A relative risk reduction of approximately 9% for stroke, death, and MI has been reported for ticlopidine (Ticlid) compared with aspirin. Blood monitoring is required (a complete blood count assessed every 2 wk for 3 mo). The recommended dose is 250 mg twice daily (bid). Adverse effects include diarrhea (20%), skin rash (14%), and reversible agranulocytosis (1%). High discontinuation rates are common because of adverse effects.
A relative risk reduction of approximately 9% for stroke, death, and MI has been reported for clopidogrel (Plavix) compared with aspirin (an absolute risk reduction of about 0.25% per year). No blood monitoring is required with clopidogrel (unlike ticlopidine). The recommended dose is 75 mg daily. The adverse effects are similar to those of aspirin. Thrombotic thrombocytopenic purpura is seen in rare circumstances with clopidogrel.
The European Stroke Prevention Study 2 (ESPS-2) showed that extended-release dipyridamole (Persantine) is more effective than placebo in preventing stroke when given as an extended-release formulation at a dosage of 200 mg bid. Furthermore, ESPS-2 and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) trial showed that dipyridamole was more effective in combination with aspirin than was aspirin alone.[120, 121] The typical dose of aspirin in these studies was less than 100 mg per day. At this time, evidence that short-acting dipyridamole is as efficacious as extended-release dipyridamole is insufficient.
The combination of extended-release dipyridamole and aspirin reduces the relative risk of stroke, death, and MI by about 20% (approximately a 1% absolute risk reduction per year). A combination capsule of aspirin 25 mg and extended-release dipyridamole 200 mg is marketed in the United States as Aggrenox for the secondary prevention of ischemic stroke and transient ischemic attacks (TIAs).
The adverse effects profile is similar to that of aspirin, with the exception of an increased incidence of headache and GI disturbance.
The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy suggested that, based on indirect comparisons, the combination of extended-release dipyridamole and aspirin was more efficacious than clopidogrel.
The combination of clopidogrel with aspirin for long-term stroke prevention is discouraged based on the negative findings of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) studies. In the MATCH study, life-threatening bleedings were higher in the group receiving aspirin and clopidogrel than in the group receiving clopidogrel alone (an absolute risk increase of about 1% per year).
In May 2014, the FDA approved vorapaxar (Zontivity) to reduce the risk of MI, stroke, cardiovascular death, and need for revascularization procedures in patients with a previous MI or peripheral artery disease (PAD). It is a first-in-class antiplatelet medication that is a protease-activated receptor 1 (PAR-1) inhibitor. It is not indicated as monotherapy, but in addition to aspirin and/or clopidogrel.
Approval was based on a trial of 26,499 patients that showed that time to cardiovascular death, MI, stroke, or urgent coronary revascularization was decreased by 13% in patients taking vorapaxar. When coronary revascularization was excluded, the secondary endpoint of cardiovascular death, MI, or stroke was also significantly reduced.
Because of vorapaxar’s antiplatelet effects, moderate or severe bleeding occurred in 3.4% of patients compared with 2.1% of the placebo-treated group. Intracranial hemorrhage occurred in 0.6% of those taking vorapaxar compared with 0.4% taking placebo.
HMG-CoA reductase inhibitors (statins)
According to the 2011 AHA/ASA guidelines for secondary stroke prevention, patients with atherosclerotic ischemic stroke or TIA without known coronary heart disease should have LDL cholesterol treated with the goal of at least a 50% reduction or a target of less than 70 mg/dL.
Milionis et al showed a 10-year risk reduction for recurrent stroke when statin therapy was
added after a first stroke. Statin use also reduced the risk of mortality, even after adjustment for potential confounders, such as blood pressure control, the investigators reported. The study was a retrospective, observational analysis of 794 patients hospitalized for a first-time ischemic stroke that linked hospitalization and death records from the Athenian Stroke Registry. The analysis included a period, from January 1997 onward, during which poststroke statin therapy was not common practice.
In patients with a history of coronary artery disease, pravastatin decreases the risk of future stroke (relative risk reduction of 32% compared with placebo), even in patients with normal serum cholesterol levels.
In patients with a history of coronary disease, other vascular disease, or diabetes, the British Heart Study showed a 25% reduction in the risk of stroke with simvastatin at 40 mg per day (an absolute risk reduction of about 1.4% over 5 years). The benefit was independent of the baseline serum cholesterol level, down to a level of 140 mg/dL. The reduction in stroke risk was uniformly reduced after the first year, through the end of the study at 5 years.
The Stroke Prevention by Aggressive Reduction in Cholesterol levels (SPARCL) trial, which looked at patients without a history of coronary artery disease and who had a serum LDL cholesterol level of 100-180 mg/dL, found that 80 mg per day of atorvastatin reduced the risk of recurrent stroke by about 16% over 5 years.
At this time, first-line agents for the treatment of hypertension in stroke include thiazide diuretics, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). Beta blockers are considered second-line agents, given their inferiority in preventing events despite similar reductions in blood pressure.
In the Heart Outcomes Prevention Evaluation (HOPE) study, the addition of an ACE inhibitor (ramipril) to all other medical therapy, including antiplatelet agents, reduced the relative risk of stroke, death, and MI by 32% compared with placebo. Only 40% of the efficacy of ramipril could be attributed to its blood pressure–lowering effects. Postulated mechanisms included endothelial protection.
Whether the beneficial effect of ramipril represents a class effect of ACE inhibitors or whether it is a property unique to ramipril is unclear.
In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a regimen based on perindopril, an ACE inhibitor, was superior to placebo. However, perindopril alone was not superior to placebo, but the combination of perindopril with indapamide (a thiazide diuretic) substantially reduced the recurrence of stroke. Much of the effect in reducing stroke recurrence was due to the lowering of blood pressure, in contrast to findings from the HOPE study.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed slight superiority of chlorthalidone (a thiazide diuretic) to lisinopril (an ACE inhibitor) in terms of stroke occurrence.
The Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) demonstrated that an ARB (losartan) was superior to a beta blocker (atenolol) in reducing the occurrence of stroke.
The Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study found that the ARB eprosartan was superior in the secondary prevention of stroke and TIA to the calcium-channel blocker nitrendipine. This was true despite comparable reductions in blood pressure. The absolute annual difference in stroke and TIA risk was approximately 4%. The study was relatively small, and most events were TIAs.
In secondary stroke prevention, the incidences of stroke with warfarin, aspirin, and placebo are 4%, 10%, and 12% per year, respectively. The relative risk reduction of warfarin was 70% compared with placebo.
Recommendations of the American College of Chest Physicians (ACCP) in cases of atrial fibrillation are as follows:
Warfarin should be used for all high-risk patients and for all patients older than age 75 years regardless of their risk.
Low-risk patients (ie, those with only atrial fibrillation) and patients younger than age 65 years should be treated with aspirin.
Patients aged 65-75 years without risk factors may or may not be given warfarin at the discretion of the treating clinician, as their condition may be based on other underlying disorders (eg, valvular disease, prosthetic valve replacement). 
The dose is variable. The target INR is 2-3. Adverse effects include excessive bleeding. The major concern is intracranial hemorrhage.
The 2011 AHA/ASA secondary stroke prevention guidelines state that for patients with atrial fibrillation who are at high risk for stroke and require brief interruption of oral anticoagulants, subcutaneous low-molecular-weight heparin can be used as bridging therapy.
The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) found that the combination of clopidogrel plus aspirin was less effective for stroke prevention than was warfarin. Furthermore, intracranial hemorrhage was more common in the dual antiplatelet group.
The 2011 AHA/ASA secondary stroke prevention guidelines also advise using aspirin alone, rather than with clopidogrel, in patients with atrial fibrillation with a bleeding contraindication to warfarin. This is because the aspirin/clopidogrel combination has a bleeding risk similar to that of warfarin.
Antiphospholipid antibody syndrome is the presence of lupus anticoagulant and/or cardiolipin antibody. The Antiphospholipid Antibodies and Stroke Study (APASS) showed no advantage to the use of warfarin (INR of 1.4-2.8) over aspirin for secondary stroke prevention in patients with antiphospholipid antibodies. In addition, the risk of stroke did not appear to be increased in patients with positive antibodies.
Patients with the antiphospholipid antibody syndrome and previous thrombosis are treated with warfarin. An INR of 2.0-3.0 is an appropriate therapeutic target. An INR of 3.1-4.0 is not superior.
An interesting observation is that arterial events follow arterial events and that venous events follow venous events in 91% of patients. According to the 2011 AHA/ASA CVT statement, prevention strategies for CVT are focused on venous events such as recurrence of CVT or other venous thromboembolism. Anticoagulation is the mainstay of acute treatment for CVT, and short or extended anticoagulant therapy is often used for secondary prevention after CVT, but no clinical trials have studied this use. Because new systemic venous thromboembolism is more common than recurrent CVT after CVT, it may be generally reasonable to prevent both by adopting venous thromboembolism prevention guidelines. However, the CVT statement recommends testing patients for prothrombotic conditions 2-4 weeks after completion of acute anticoagulant treatment (if they are not taking warfarin) in order to determine individual thrombosis risk.
Patients whose CVT was provoked by a transient risk factor may be treated with vitamin K antagonists for 3-6 months, while patients with unprovoked CVT may continue vitamin K antagonist therapy for 6-12 months. For patients with recurrent CVT, venous thromboembolism after CVT, or initial CVT combined with severe thrombophilia, clinicians may consider indefinitely extended anticoagulation.
The 2011 AHA/ASA secondary stroke prevention guidelines recommend aspirin (50-325 mg/d) and not warfarin for stroke prevention in patients with a stroke or TIA caused by 50-99% stenosis of an intracranial artery. Blood pressure of less than 140/90 mm HG and total cholesterol of less than 200 mg/dL are considered reasonable goals.
Regarding intracranial atherosclerosis, the Warfarin Aspirin Symptomatic Intracranial Disease (WSAID) investigators compared warfarin with aspirin for secondary stroke prevention in patients with stroke and intracranial stenosis documented on angiography. The study was stopped prematurely when an increased risk of major hemorrhage, MI, and death was found in patients taking warfarin, with no difference in prevention of ischemic stroke.
Regarding noncardioembolic stroke, the Warfarin Versus Aspirin Recurrent Stroke Study (WARSS) compared warfarin with aspirin for secondary stroke prevention in patients with assorted causes of noncardioembolic stroke. The risk of hemorrhage was greater with warfarin, and no advantage was seen relative to aspirin.
In patients with a mean age of 59 years who had a patent foramen ovale (PFO), with or without an atrial septal aneurysm, the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) showed no advantage of warfarin over heparin for the prevention of secondary stroke. These cardiac features did not seem to affect the risk of stroke.
Direct thrombin inhibitors and factor Xa inhibitors
Apixaban, dabigatran, rivaroxaban, and edoxaban are alternatives to warfarin for high-risk patients (including those with a history of stroke) who have atrial fibrillation.[139, 140, 141, 142, 143] Apixaban, edoxaban, and rivaroxaban inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor. Apixaban and dabigatran were shown to be superior to warfarin for the prevention of stroke and systemic embolism, while rivaroxaban and edoxaban were shown to be equivalent. The rates of intracranial hemorrhage are lower for all four drugs compared with warfarin. Dabigatran carries a higher risk of gastrointestinal bleeding compared with warfarin, and it appears to increase the risk of myocardial infarction. These medications have not been compared against each other.
Edoxaban (Savaysa) was approved by the FDA in January 2015 to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial (n=21,105), edoxaban was noninferior to warfarin in terms of preventing stroke and systemic embolism. In addition, rates of major bleeding and death from cardiovascular causes were significantly lower with edoxaban than with warfarin.
Apixaban (Eliquis) was approved by the FDA in December 2012. Approval was based on 2 clinical trials. The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial compared apixaban with warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke. Results showed that apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
The second trial, AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment), compared apixaban with aspirin in patients with atrial fibrillation for whom warfarin therapy was considered unsuitable. The trial was stopped early at an interim analysis because apixaban showed a significant reduction in stroke and systemic embolism compared with aspirin (P < 0.0001). A modest increase of major bleeding was observed with apixaban compared with aspirin (P =0.07).
Cerebrovascular bypass of an occluded carotid artery was developed in the late 1960s. The technique involves the anastomosis of the superficial temporal artery to the middle cerebral artery. The extracranial-intracranial bypass study, published in 1985, did not find a benefit with the procedure in addition to best medical therapy. The 30-day risk of stroke was 12.2%. The Carotid Occlusion Surgery Study reviewed patients who had a carotid occlusion and cerebral hemispheric ischemia as determined by positron emission tomography (PET) imaging. Though graft patency was excellent (98%) and blood flow improved on PET, recurrent stroke rates at 2 years were no better in the surgical group compared with the nonsurgical group (21% vs 22.7%). In addition, 30-day rates of stroke were significantly higher in the surgical group (14.4% vs 2%).
Smoking cessation, blood pressure control, diabetes control, a low-fat diet (eg, Dietary Approaches to Stop Hypertension [DASH] or Mediterranean diets), weight loss, and regular exercise should be encouraged as strongly as the medications described above. Written prescriptions for exercise and medications for smoking cessation (nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions.
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