Description

Acute secondary stroke prevention

Transient ischemic attack. Transient ischemic attack is associated with a high risk of early recurrent stroke, with stroke rates as high as 35% in some subgroups by 7 days (133). A meta-analysis of 18 studies reported a stroke risk of 3.1% at 2 days and 5.2% at 7 days (64). Early risk of stroke after transient ischemic attack has also been quantified, with 6-hour, 12-hour, and 24-hour stroke risks of 1.2%, 2.1%, and 5.1%, respectively; 42% of strokes during the first 30 days occur within 24 hours (33). Secondary prevention should, therefore, be initiated urgently after transient ischemic attack. Clinical prediction scores such as the ABCD2 score have been developed to improve early stroke risk stratification after transient ischemic attack (83; 84; 133) and have also been recommended for use in international guidelines. ABCD2 score is calculated as follows:

Age of 60 years or older [1 point]

Blood pressure of 140/90 mm Hg or higher [1 point]

Clinical features of weakness [2 points] or speech impairment [1 point]

Duration of symptoms 60 minutes or longer [2 points] or 10 to 59 minutes [1 point]

Diabetes mellitus [1 point]

In a population-based cohort of all referrals with suspected transient ischemic attack, 19/20 early recurrent strokes occurred in 27% of the patients with a score of 5 or higher. The 7-day risk was 0.4% (95% CI, 0 to 1.1) in 274 patients (73%) with a score lower than 5, 12.1% (4.2 to 20.0) in 66 patients (18%) with score of 5, and 31.4% (16.0 to 46.8) in 35 patients (9%) with score of 6. In a hospital-referred weekly clinical cohort, all patients who suffered a stroke before their scheduled appointment (n=14, 7.5%) had a score of four or higher (133). The scores also indicate severity of recurrent events; that is, patients with low scores have a high risk of recurrent transient ischemic attack, and those with high scores have a high risk of early disabling stroke (32).

CT and MRI also provide prognostic information and diffusion-weighted MRI is especially informative (63; 108).

The Early Use of Existing Preventive Strategies for Stroke (EXPRESS) study (132) was a prospective population-based study of all transient ischemic attacks and stroke that compared urgent assessment and treatment (phase 2) with appointment-based clinical assessment and primary-care-initiated treatment (phase 1). Median delay to assessment in the study fell from 3 days in phase 1 to less than 1 day in phase 2, and the median delay to the first prescription of treatment fell from 20 days to 1 day. The 90-day risk of recurrent stroke in patients referred to the study clinic was 10.3% in phase 1 versus 2.1% in phase 2. Good prognosis associated with urgent, intensive treatment was also confirmed in the SOS-TIA study (94).

Acute ischemic stroke. Early recurrence rates for ischemic stroke caused by atherosclerosis are higher than those for other subtypes (122). A meta-analysis of four studies reported that, compared with other subtypes, patients with stroke due to large-artery atherosclerosis had the highest odds of recurrence at 7 days (OR 3.3, 95% CI 1.5 to 7.0), 30 days (OR 2.9, 95% CI 1.7 to 4.9), and 3 months (OR 2.9, 95% CI 1.9 to 4.5). Odds of recurrence at 30 days for other subtypes included cardioembolic (OR 1.0, 95% CI 0.6 to 1.7), undetermined (OR 1.0, 95% CI 0.6 to 1.6), and small-vessel stroke (OR 0.2, 95% CI 0.1 to 0.6) (104). Two trials including a total of 40,000 randomized patients observed that oral aspirin (160 to 300 mg) within 48 hours of ischemic stroke onset reduced 14-day morbidity and mortality; mostly by reducing the risk of early recurrent stroke (35). There is some evidence that a short course of more intensive antiplatelet treatment might be effective in the acute phase after transient ischemic attack and minor stroke. Although long-term treatment with aspirin plus clopidogrel provided no overall benefit compared to clopidogrel alone in the MATCH trial, there was a beneficial trend in the subgroup of patients randomly assigned to treatment within 7 days of transient ischemic attack or stroke. A similar benefit was also seen on aspirin plus clopidogrel versus aspirin alone in patients randomly allocated to treatment groups within 30 days of transient ischemic attack or stroke in the CHARISMA trial (48) as well as in patients with transient ischemic attack or minor stroke in the previous 24 hours in the FASTER trial (86). In the CARESS trial, which included patients with recently symptomatic 50% or greater carotid stenosis (106), and the CLAIR trial, which included patients with symptomatic intracranial stenosis (154), aspirin plus clopidogrel versus aspirin alone was reported to reduce microembolic signals and tended to reduce the risk of recurrent stroke (130). The results of the CHANCE trial of aspirin and clopidogrel compared with aspirin in Chinese patients are consistent with these results. In the CHANCE trial, a bolus loading dose of 300 mg clopidogrel and 75 to 300 mg aspirin was used on day 1 to rapidly inhibit platelet aggregation. In this trial, among patients with TIA or minor stroke treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin was superior to aspirin alone for reducing the risk of stroke in the first 90 days and did not increase the risk of hemorrhage (150). In a meta-analysis, Zhang and colleagues found that compared with monotherapy, short-term aspirin in combination with clopidogrel is more effective as secondary prevention of stroke or TIA without increasing the risk of hemorrhagic stroke and major bleeding events (159).

In the acute phase of ischemic stroke, a series of trials has shown that any benefit of anticoagulants is outweighed by an increased risk of bleeding for all levels of stroke risk (46). A meta-analysis of eight randomized trials involving 22,125 patients found no evidence that the use of anticoagulants (unfractionated heparin, low molecular-weight heparins, heparinoids, thrombin inhibitors, or oral anticoagulants) in the acute phase of stroke improves functional outcomes (139). A meta-analysis of seven trials similarly failed to show improvement in functional outcome with the use of anticoagulant therapy in patients with acute cardioembolic stroke (119).

Carotid endarterectomy has been shown in randomized trials to be highly effective in patients with severe internal carotid artery stenosis when performed within 2 weeks after either transient ischemic attack or nondisabling stroke (131). A systematic analysis of 10 observational studies comparing very early (less than or equal to 48 hours) and early (greater than or equal to 48 hours) carotid endarterectomy in patients with ischemic stroke or transient ischemic attack due to extracranial carotid disease showed that very early carotid endarterectomy carried a significant twofold higher risk of ipsilateral periprocedural stroke in comparison with early carotid endarterectomy (110). Mortality rate in the perioperative period was 1.6% in patients undergoing very early carotid endarterectomy and 1.2% in those who underwent carotid endarterectomy after 48 hours on index stroke, but the difference was not significant. There seems to be a greater benefit in very early carotid endarterectomy for patients with transient ischemic attack as the index event, whereas carotid endarterectomy within 7 days appears to be appropriate in patients with no disabling ischemic stroke as the qualifying event (140).

Long-term secondary prevention of noncardioembolic cerebrovascular events

Aggressive multi-risk factor control. In patients with ischemic stroke or transient ischemic attack due to atherosclerosis, there are several strategies for preventing a recurrence. There are virtually no data on the significance of smoking cessation, abstinence from alcohol, or the treatment of diabetes for secondary prevention of stroke or transient ischemic attack although the merit of controlling these risk factors seems to be self-evident. The effects of obesity and lack of physical exercise on stroke recurrence have not been fully investigated. One study suggests that folic acid and vitamins B6 and B12 supplements lower the risk of recurrent stroke, but the results have not been statistically significant (145). Also, controlling risk factors such as hypertension and dyslipidemia are very important although the number of trials addressing these risk factors have been, to date, few compared to primary prevention. Leung and colleagues found that a majority of symptomatic high-grade intracranial plaques had regressed or remained quiescent by 12 months under intensive medical therapy (97).

In a double-blind, placebo-controlled clinical trial of 3876 patients over 40 years of age with insulin resistance (defined as homeostasis model assessment of insulin resistance [HOMA-IR] index over 3.0) and a prior ischemic stroke or transient ischemic attack within the previous 6 months, 1939 patients were randomized to receive pioglitazone (45 mg/day target dose), and the rest received a placebo. Patients in both groups continued to receive recommended pharmacological secondary stroke prevention measures. During a mean follow-up of 4.8 years, a relative risk reduction of 24% in primary outcome (stroke or myocardial infarction) and 18% in stroke was observed in pioglitazone patients as compared with placebo patients (87). The mechanisms mediating these results are still not defined, although it is probable that pioglitazone activates both α and γ peroxisome proliferator-activated receptors with a variety of favorable effects, among others, on endothelial vascular function and inflammation. Pioglitazone patients had a significantly lower rate of progression to diabetes mellitus (52% relative risk reduction), but a higher rate of weight gain, edema, and bone fractures than the placebo group (87).

One meta-analysis of three randomized controlled trials describes the results of pioglitazone along with standard medical therapy as secondary stroke prevention in patients with previous stroke or transient ischemic attack and abnormal glucose metabolism (diabetes mellitus or insulin resistance) (96). A pioglitazone group (2488 patients) was compared with a control group (2492 patients receiving a different glucose-lowering agent or placebo) after a median follow-up of 3.5 years. The mean age of patients ranged between 62 and 68 years, and the baseline HbA1c ranged from 5.8% to 8.1%. Most patients (85%) were on antiplatelet treatment, and approximately one half were taking statins. Pioglitazone was associated with a one-third reduction in the risk of recurrent stroke and a one-fourth reduction in the risk of major cardiovascular events (composite of nonfatal stroke, nonfatal myocardial infarction, and vascular death). The results of this meta-analysis were unfortunately dominated by the Insulin Resistance Intervention After Stroke (IRIS) trial, comprising 1939 patients in the pioglitazone group and 1937 in the placebo group, with insulin resistance as the major inclusion criteria (96).

Moreover, the effect of pioglitazone on secondary prevention of stroke in nondiabetic patients with insulin resistance and prior ischemic stroke was assessed in 3876 patients (65% male, mean age of 63 years) in the Insulin Resistance Intervention After Stroke (IRIS) trial, a randomized, double-blind, placebo-controlled study (156). In the previous 6 months, most of these patients (87%) had had a cerebral infarct, and the remainder had had a transient ischemic attack. They were randomly assigned to placebo (1937 patients) or pioglitazone (1939 patients) at an initial dose of 15 mg per day and a target dose of 45 mg/day with a 5-year follow-up. In both patient groups, the etiology of the qualifying stroke was small vessel disease (30%), large vessel disease (25%), and cardioembolism (7%), based on TOAST criteria. The cause of the index event could not be identified in a third of the patients with cerebral infarct and in half of the patients with transient ischemic attack. The 5-year risk for recurrent stroke (hazard ratio 0.75) was significantly less for the pioglitazone group (8%) than for the placebo group (10.7%). For patients in the pioglitazone group whose qualifying event was a cerebral infarct, the rate of recurrent stroke was 7.8%, compared with a recurrent stroke rate of 11.3% for those in the placebo group (hazard ratio 0.70, p 0.003) (156).

When the benefit of pioglitazone was analyzed by ischemic stroke subtype, the reduction was significantly higher in patients with lacunar infarct (hazard ratio 0.46); a similar though not significant trend also occurred in patients with cerebral infarct due to large artery disease (hazard ratio 0.59). However, pioglitazone did not reduce the recurrent stroke rate in patients whose index event was a transient ischemic attack (hazard ratio 1.40). Furthermore, pioglitazone did not prevent hemorrhagic strokes. Thus, these results suggest that, compared with placebo, pioglitazone reduces by one fourth the risk of any new cerebral infarct in nondiabetic patients with insulin resistance and a prior ischemic stroke. This benefit may occur mainly in patients with a first-ever cerebral infarct due to small and large atherosclerotic disease (156).

There is emerging evidence that dulaglutide, semaglutide, and liraglutide – glucagon-like peptide 1 receptor agonists – may reduce ischemic stroke risk in middle-aged and older patients with type 2 diabetes mellitus and concomitant previous cardiovascular disease or cardiovascular risk factors, particularly in the primary prevention setting (100). In a multicenter, randomized, double-blind, placebo-controlled trial, 9901 diabetic patients with or without previous cardiovascular disease and with a wide range of glycemic control were randomly assigned to either dulaglutide (subcutaneous 1.5 mg once weekly) or a placebo. Compared to placebo, dulaglutide reduced the rate of ischemic stroke by one fifth in 899 patients (9.1%) with previous stroke or transient ischemic attack who were included in this trial (62). Another trial also found a reduced stroke rate in diabetic patients over 50-years-old with established cardiovascular disease or cardiovascular risk factors; 1591 diabetic patients who received oral semaglutide (14 mg per day) had a 26% lower risk of nonfatal stroke than those receiving placebo (78). Empagliflozin, dapaglifozin, and canagliflozin – sodium glucose transporter protein 2 inhibitors – have also proven to reduce the risk of major cardiovascular events and stroke in adult patients with type 2 diabetes and atherosclerotic cardiovascular disease (100). Current guidelines for diabetic patients with cardiovascular disease recommend a combination of a glucagon-like peptide 1 receptor agonist or sodium glucose transporter protein 2 inhibitor with proven cardiovascular benefit and a glucose lowering regimen (22; 51). The precise mechanism of glucagon-like peptide 1 receptor agonists and sodium glucose transporter protein 2 inhibitors in macrovascular event reduction in diabetic patients, particularly of stroke, is not yet well understood, though it seems to be due to something besides their glucose-lowering effects.

Despite a lack of solid evidence showing that intense glycemic control reduces macrovascular complications such as stroke, the current AHA stroke prevention guidelines recommend a glycated hemoglobin (HbA1c) level between 7% and 8% as a reasonable goal for long-term prevention of vascular events in diabetic or prediabetic patients with a transient ischemic attack or ischemic stroke (91). The European Stroke Organization (ESO) guidelines advise a glycated hemoglobin (HbA1c) level lower than 7% to reduce macro- and microvascular complications in patients with type 2 diabetes mellitus and transient ischemic attack or ischemic stroke (44). However, this target may be individualized according to age, comorbidities, and duration of diabetes mellitus. ESO guidelines also recommend pioglitazone use to reduce the risk of stroke recurrence in patients with a previous transient ischemic attack or ischemic stroke and insulin resistance or type 2 diabetes mellitus, though only after appropriate assessment of the benefit-risk profile (44).

A metaanalysis compared the effect of three new antihyperglycemic therapies on stroke risk (99). This survey included 155,027 patients with type 2 diabetes mellitus from 19 randomized controlled trials (eight from glucagon-like peptide-1 agonists, five from sodium-glucose cotranporter-2 inhibitors, and six from dipeptidyl peptidase-4 inhibitors). The median of diabetes duration ranged from 9.2 to 15.8 years, median of HbA1c ranged from 7.3% to 8.91%, and median follow-up ranged from 1.3 to 10.5 years. Previous stroke varied from 5.5% to 25%. Glucagon-like peptide-1 (GLP-1) agonists significantly reduced the risk of nonfatal stroke and total stroke by 15% and 16%, respectively, compared to placebo. Sodium glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors did not reduce the total number of strokes (99). GLP-1 agonists may have neuroprotective and atherosclerotic properties by decreasing the production of pro-inflammatory factors, promoting antiapoptotic mechanisms, reducing oxidative stress, and limiting the formation and accumulation of advanced glycation end-products (66).

Hypertension. Age and hypertension are the most powerful risk factors for stroke. In a pooled analysis of 61 prospective studies including about 1 million individuals, the risk of stroke increased progressively with blood pressure from values as low as 115/75 mm/Hg; each increment of 20/10 mm/Hg doubled the risk of cardiovascular disease. Such a correlation was consistent at all ages (98). In 2010, it was estimated that 1.39 billion adults worldwide, of which 75% living in low- and middle-income countries, had hypertension (blood pressure higher than 140/90 mm Hg) (111). Hypertension was responsible for some 10.8 million deaths in 2019, almost one fifth the global total (60). The burden of hypertension is growing globally, and it is expected that one in three (1.56 billion) adults will be affected by hypertension by 2025.

Lowering blood pressure strongly reduces the risk of either first stroke or recurrent stroke (53; 85). In a meta-analysis of 344,716 participants enrolled in 48 large, randomized trials of pharmacological blood pressure-lowering treatment, a 5 mm Hg reduction in systolic blood pressure in patients with previous cardiovascular events lowered the relative risk of stroke by 11% (27).

Despite such conclusive evidence showing that antihypertensive therapy reduces stroke and other major cardiovascular events, there are still differences in awareness, treatment, adherence to treatment, and optimal blood pressure control in terms of geographical regions and country levels of economic development. Overall, 46% of 57,840 hypertensive individuals aged 35 to 70 years were aware of their condition, but awareness was better in hypertensive individuals living in high-income and upper-middle income countries than in those living in lower-middle and low-income countries (39). A substantial proportion of individuals, particularly in low-income and middle-income countries, neither receive pharmacological treatment nor achieve adequate blood pressure control (61; 114). Availability and affordability of blood pressure-lowering drugs is better in high-income than low-income and middle-income countries (20). Up to 80% of hypertensive individuals have either partially or completely poor adherence to antihypertensive treatment (146). In addition, hypertensive individuals often have other cardiovascular risk factors that increase their stroke risk even more and, in such a context, broader therapies are needed to offer a comprehensive secondary stroke prevention strategy at the individual and population levels (146).

Using data from 14 randomized controlled secondary stroke prevention trials between 1970 and 2013, a systematic review and meta-regression analysis of the association between blood pressure reduction, recurrent stroke, and major cardiovascular events has been reported (85). These trials had a duration ranging from 12 to 60 months and included 42,736 patients (64% men). In a pairwise meta-analysis, antihypertensive treatment was associated with a significant reduction in the risk of recurrence of all strokes and in disabling or fatal stroke (27% and 29%, respectively). In meta-regression analyses, both systolic and diastolic blood pressure reduction was linearly related to a lower risk of recurrent stroke. In fact, patients who achieved a mean systolic blood pressure less than 130 mm Hg had a significantly lower stroke recurrence (8.3%) than patients whose systolic blood pressure ranged between 130 and 140 mm Hg (9.2%) and those with systolic blood pressure greater than 140 mm Hg (11.7%). Correspondingly, patients who achieved a mean diastolic blood pressure less than 85 mm Hg had a significantly lower stroke recurrence (11.9%) than patients whose diastolic blood pressure ranged between 85 and 90 mm Hg (12.3%) and those with diastolic blood pressure greater than 90 mm Hg (19.2%) (85).

A report by Wang and colleagues assessed the effects of blood pressure-lowering agents in reducing recurrent stroke and major adverse cardiac and cerebrovascular events in 39,329 patients with previous stroke included in 15 randomized controlled trials with a median follow-up of 2.6 years (148). A pairwise meta-analysis and a network meta-analysis showed that, compared with placebo, angiotensin-converting enzyme inhibitors along with diuretics significantly reduced the risk of recurrent stroke by 46%, followed by diuretics combined with beta blockers, which resulted in a 39% reduction. Beta blockers alone, on the other hand, resulted in a 9% reduction in stroke recurrence (148).

A few studies have demonstrated significant benefits with hypotensive drugs in secondary prevention of stroke--but with different results due to the fact that different hypotensive drugs were evaluated. To this regard, the HOPE study investigated the effect of ramipril in patients who were at high risk for cardiovascular events; because 11% of the included patients had prior stroke, an approach to secondary stroke prevention efficacy could be made for this subgroup of patients. The study showed a nonsignificant 17% reduction in the relative risk of stroke recurrence (157).

PROGRESS was a randomized trial of a perindopril-based, blood pressure-lowering regimen among 6105 individuals with previous stroke or transient ischemic attack (123). Patients were randomly assigned active treatments (n=3051) or placebos (n=3054). The study was designed to determine the effects of blood pressure-lowering regimens in hypertensive and nonhypertensive patients, all of whom had a history of stroke or transient ischemic attack. Active treatment consisted of a flexible regimen based on perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or nonfatal). Over 4 years of follow-up, active treatment reduced blood pressure by 9/4 mm/Hg; primary events occurred in 307 patients (10%) in the active group and in 420 (14%) in the placebo group (relative risk reduction 28%, 95% CI 17 to 38). Active treatment also reduced the risk of total major vascular events (relative risk reduction 26%, 95% CI 16 to 34). There were similar reductions in the risk of stroke in hypertensive and nonhypertensive subgroups. Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm/Hg and stroke risk by 43%. Single drug therapy reduced blood pressure by 5/3 mm/Hg and produced no discernible reduction in the risk of stroke. In PROGRESS, the analysis of the specific ischemic stroke subtypes demonstrated a significant benefit from active treatment with the combination of perindopril and indapamide in reducing atherothrombotic (relative risk reduction 39%) and lacunar strokes (relative risk reduction 23%) as well as hemorrhagic stroke (relative risk reduction 50%), with no effects on cardioembolic strokes.

The HYVET study provided evidence that antihypertensive treatment with indapamide, with or without perindopril, is also beneficial in persons 80 years of age or older (25).

In the MOSES trial, a total of 1405 well-defined, high-risk hypertensives with cerebral events over the last 24 months were randomized to eprosartan (an angiotensin II type receptor antagonist) or nitrendipine (calcium antagonist) (mean follow-up 2.5 years) (142). The primary endpoint was the composite of total mortality and all cardiovascular and cerebrovascular events, including all recurrent events. Blood pressure was reduced to a comparable extent without any significant differences between the two groups during the whole study period (150.7/84 mm/Hg and 152.0/87.2 mm/Hg with eprosartan and nitrendipine therapy to 137.5/80.8 mm/Hg and 136.0/80.2 mm/Hg, respectively, confirmed by ambulatory blood pressure monitoring). During follow-up, a total of 461 primary events occurred: 206 in the eprosartan group and 255 in the nitrendipine group (incidence density ratio 0.79; 95% CI 0.66 to 0.96). Cardiovascular events occurred in 77 patients taking eprosartan and 101 taking nitrendipine (incidence density ratio 0.75; 95% CI 0.55 to 1.02); cerebrovascular events occurred in 102 in the eprosartan group and 134 in the nitrendipine group (incidence density ratio 0.75; 95% CI 0.58 to 0.97). In a combined analysis of PROFESS and TRASCEND, the incidence of composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85 to 0,98, p=0.013) (47).

A meta-analysis of the trials described above, excluding the MOSES trial, reported that antihypertensive therapy was effective in reducing recurrent stroke (odds ratio 0.76), myocardial infarction (odds ratio 0.79), and vascular events (odds ratio 0.79) (127). Heterogeneity between drug classes was apparent: beta-receptor antagonists did not seem to reduce any vascular events; diuretics alone reduced stroke but not myocardial infarction; and angiotensin-converting inhibitors reduced myocardial infarction but not stroke. However, the most effective intervention was dual therapy (angiotensin-converting inhibitors and diuretics), which reduced each of the three outcomes. This systematic review did not include angiotensin II receptor blockers as no data on secondary prevention randomized clinical trials were available. Another systematic review has confirmed the importance of blood pressure reduction in primary and secondary stroke prevention, and in a meta-regression analysis calcium channel blockers were found to be better than angiotensin-converting inhibitors in stroke prevention (158). The conclusion after this meta-analysis was that lowering blood pressure is an effective method for reducing the risk of subsequent stroke. Most patients will need two or more drugs, and the combination should be logical and based on class pharmacological activities, especially taking into account effects on the renin system (23).

In the Secondary Prevention of Small Subcortical Strokes (SPS-3) Trial – a randomized, open-label (for systolic blood pressure) study for secondary stroke prevention that compared a higher systolic blood-pressure target of 130 to 149 mm Hg versus a lower target of less than 130 mm Hg in 2747 patients with a recent symptomatic lacunar infarct demonstrated on brain MRI – all major classes of antihypertensive agents were used thanks to an algorithm based on the guidelines of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). After a mean follow-up of 3.7 years, the higher-target group achieved a mean systolic and diastolic blood pressure of 137 mm Hg and 75 mm Hg, respectively, whereas the lower-target group achieved a mean systolic and diastolic blood pressure of 126 mm Hg and 69 mm Hg, respectively. The lowest risk of stroke occurred at values of systolic and diastolic blood pressures of 124 mm Hg and 65 mm Hg, respectively (116).

In the Recurrent Stroke Prevention Clinical Outcome (RESPECT) study, a prospective open clinical trial, 630 out of 1263 Japanese patients aged between 50 and 85 years who had had an ischemic or hemorrhagic stroke in the preceding 3 years were randomly assigned to a target blood pressure of below 140/90 mm Hg (the standard treatment group) and the target for the remaining patients was less than 120/80 mm Hg (the intensive treatment group). When patients in the standard group had diabetes mellitus, chronic kidney disease, or myocardial infarction, the blood pressure goal was 130/80 mm Hg (90). In both groups, distinct combinations of angiotensin 2 receptor blockers, diuretics (spironolactone or hydrochlorothiazide), and amlodipine were used to achieve the blood pressure targets. After a mean follow-up of 3.9 years, the stroke recurrence rate was nonsignificantly reduced by 27% in the intensive treatment group compared with the standard treatment group. The results of the RESPECT trial were pooled with three other previous trials assessing intensive blood pressure control for secondary stroke prevention; compared with standard blood pressure lowering treatment, larger blood pressure reductions significantly decreased the risk of recurrent stroke by 22% in 4895 patients with a first index stroke. Risk reduction was particularly clear for hemorrhagic stroke (90).

The current guidelines of secondary stroke prevention recommend starting treatment with antihypertensive agents in previously untreated patients who have an established systolic or diastolic blood pressure higher than 140 mm Hg or 90 mm Hg, respectively, in the first few days after an ischemic stroke or transient ischemic attack (152; 91). In neurologically stable patients with known arterial hypertension, antihypertensive medication may be resumed after the acute phase of ischemic stroke or transient ischemic attack. Antihypertensive drug regimens should aim for a blood pressure consistently lower than 130/80 mm Hg (152; 91; 44). For secondary stroke prevention, efficacious reduction of blood pressure is more important and essential than the choice of antihypertensive drugs. Selection of antihypertensive agents should be individualized mainly on the basis of a patient’s comorbidities. Thiazide diuretics, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers have been found to reduce recurrent stroke risk in randomized controlled trials and systematic reviews of randomized controlled trials (91). Evidence of the effectiveness of calcium channel blockers in reducing stroke recurrence is less conclusive than that of other blood pressure-lowering drugs; nonetheless, they may be used according to patient characteristics (91).

Apart from pharmacological therapy, lifestyle modification may be of substantial benefit for blood pressure reduction; such measures include salt restriction, healthy diet, weight loss in the overweight or obese, regular aerobic physical activity, limited alcohol intake, and smoking cessation (91).

Blood pressure and stroke recurrence in patients with intracranial or carotid stenosis. Clinical trials and epidemiological studies of stroke patients have demonstrated that lowering blood pressure reduces the risk of recurrence. However, it is common practice to allow blood pressure of 140/90 mm/Hg or higher in patients with intracranial stenosis. This practice is based on expert opinion and studies that suggest that lowering blood pressure may increase the risk of stroke in some patients with severe carotid stenosis (135). The WASID trial compared aspirin and warfarin in patients with symptomatic 50% to 99% stenosis of a major intracranial artery (37). Time to ischemic stroke and stroke in the same territory of the stenotic vessel were compared in patients grouped by mean systolic blood pressure and mean diastolic blood pressure. However, ischemic stroke risk increased with increasing mean systolic blood pressure and mean diastolic blood pressure after adjustment for risk factors. The increased risk of stroke with increasing systolic blood pressure was driven largely by patients in the highest systolic blood pressure group. Patients with moderate (less than 70%) stenosis had increased risk of stroke and stroke in the territory of the stenotic vessel with increased systolic and diastolic blood pressure. Patients with intracranial severe (70% or more) stenosis had increased risk of stroke and stroke in the territory of the stenotic vessel with increased diastolic blood pressure. These results argue against the common clinical practice of maintaining high blood pressure in patients with intracranial stenosis. Rothwell and colleagues have shown that the relationship between blood pressure and stroke risk is less steep in patients with extracranial symptomatic carotid stenosis than in more general populations of patients with stroke or transient ischemic attack but that it remains positive overall (135). It is, thus, safe to treat hypertension in the vast majority of patients with stroke or transient ischemic attack. However, there was a negative relationship between blood pressure and stroke risk in the small proportion of patients who have bilateral 70% or greater carotid stenosis, suggesting that aggressive blood pressure lowering may not be advisable in this group or that they may require revascularization to render the treatment of their hypertension safe.

Oestrogen use. To date, there is no conclusive evidence showing that hormone replacement therapy is beneficial in lowering the risk of first and recurrent stroke in postmenopausal women (105; 38).

Metabolism of lipids. Abnormalities of serum lipids [triglyceride, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)] are known risk factors for vascular disease. Cholesterol and LDL have a direct relationship with the incidence of coronary heart disease whereas HDL has an inverse relationship. Whether increased serum cholesterol levels are a risk factor for stroke remains controversial. A meta-analysis of 45 prospective cohorts that included 450,000 subjects (total of 7.3 million patient-years; average follow-up of 16 years) and 13,000 stroke incidents found no association between total cholesterol levels and stroke (124). However, another meta-analysis of prospective studies on hypercholesterolemia found a relative stroke risk of 1.2 among those with cholesterol levels higher than 220 mg/dL. Low HDL and elevated triglycerides have been found to increase stroke risk (136). In the Copenhagen City Heart Study, total cholesterol was positively associated with a risk of nonhemorrhagic stroke, but only for levels higher than 8 mmol/L (greater than 309 mg/dL), corresponding to levels in the upper 5% of the study cohort (101). An analysis of cohort studies by stroke subtypes has shown that the risk of nonhemorrhagic stroke increases as LDL concentration increases (a 15% increase for each 1-mml/L increase in LDL concentration) whereas the risk of hemorrhagic stroke increases as LDL concentration falls (a 19% increase for each 1 mmol/L in LDL concentration decrease) (95).

There are several possible explanations for these different results and for the apparent lack of association between cholesterol levels and ischemic stroke. Most studies have selected cohorts of patients to study coronary heart disease, and these patients have all been young subjects at higher risk for myocardial infarction than stroke. Moreover, cerebrovascular events were not analyzed according to stroke subtypes (ischemic or hemorrhagic) in most of these studies. The Multiple Risk Factor Intervention Trial (MRFIT) showed that the risk of death due to ischemic stroke increased with increasing serum cholesterol levels. Conversely, in the same study, there was a negative association between hemorrhagic stroke and lower serum cholesterol levels, suggesting a possible U-shaped relationship between cholesterol and stroke (80). Because of the U-shaped relationship, counting hemorrhagic strokes together with ischemic strokes could have masked a small, but significant relation between cholesterol levels and ischemic stroke (08). Finally, regarding the etiology of ischemic stroke, cholesterol is an important risk factor for atherosclerosis, but the cause of stroke could be cardioembolic or due to other causes unrelated to cholesterol levels. Unfortunately, however, there are limited data on a possible correlation between cholesterol and ischemic stroke subtypes.

Lipid-lowering agents have been mostly tested in patients with coronary heart disease and recent myocardial infarction. Furthermore, results from subpopulations with stroke or transient ischemic attack are most relevant in terms of primary prevention. However, other data indicate that statins may be effective in reducing stroke recurrence. Effects seem to be mostly not due to lipid lowering but, rather, reflect “pleiotropic effects,” which are still not completely understood. A subgroup analysis of the Heart Protection Study showed a relative risk reduction of 4.9% in patients with a qualifying cerebrovascular event treated with 40 mg simvastatin, irrespective of their initial lipid values (77). Due to the small number of stroke patients included in this big trial (1820 out of a total of 20,536), this result did not reach statistical significance. Although the PROSPER failed to report similar effects (57), the first analysis of the Anglo-Scandinavian Cardiac Outcome Trial Lipid Lowering Trial (ASCOTLLT) showed--for the first time--a significant reduction in nonfatal ischemic strokes in patients with a first transient ischemic attack or stroke who were treated with atorvastatin (10 mg/day) versus placebo.

The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) study was the first to investigate the effect of statins on the risk for cerebrovascular events in patients without a history of coronary heart disease. This double-blind, randomized, placebo-controlled, multicenter trial examined the effect of aggressive atorvastatin therapy (80 mg/day) on specified cerebrovascular endpoints. Patients were eligible for the study if they had had a previous transient ischemic attack or stroke, an LDL level between 100 mg/dL (2.58 mmol/L) and 190 mg/dL (4.91 mmol/L), and no evidence of coronary heart disease. The primary clinical endpoint was the time to first occurrence of a fatal or nonfatal stroke. In this study, 4731 patients who had suffered a stroke or transient ischemic attack within the past 6 months were randomized. After 6 years of follow-up, 265 patients in the atorvastatin group had a fatal or nonfatal stroke compared with 311 in the control group. There was a 16% risk reduction in time to first occurrence of stroke with atorvastatin (adjusted HR 0.84, 95% CI 0.71-0.99; NNT=46). For the secondary endpoint, time to stroke or transient ischemic attack, there was a 23% risk reduction (HR =0.77, 0.67 to 0.88) with 375 events in the atorvastatin group and 476 in controls. Moreover, there was a 35% reduction in coronary events (HR 0.65, 95% CI 0.49 to 0.87) (144).

Theoretically, lipid-lowering medications may increase the risk of cerebral hemorrhage. In a meta-analysis including 83,205 subjects, an increase in the rate of intracerebral hemorrhage among patients treated with statins was not observed when used for primary prevention (OR 0.90, 95% CI 0.76 to 1.05), but an increased incidence of hemorrhagic stroke was observed in secondary prevention trials (OR 1.7, 95% CI 1.19 to 2.50) (07). In the SPARCL study, 55 of the 88 patients who had at least one intracerebral hemorrhage were in the atorvastatin group and 33 were in the placebo group. In this trial, the relative risk of intracerebral hemorrhage increased by 66% among patients in the atorvastatin group, but the overall benefit in terms of stroke risk reduction was significant, despite the increase in intracerebral hemorrhage for the atorvastatin group. Secondary analyses of the SPARCL study have been conducted to address the implications of statin therapy for patients having intracerebral hemorrhages during the trial. This analysis suggests that brain hemorrhage is not related to a major lowering of LDL cholesterol levels, but power here may be lacking, thereby not showing a lower threshold effect. To date, study results suggest that statins have a good overall safety profile, but despite this, further studies need to be carried out to exclude that statins in secondary prevention of stroke are not causing brain hemorrhage.

The results of the Treat Stroke to Target trial revealed that statin therapy obtaining cholesterol LDL levels below 70 mg/dL is better for reducing major cardiovascular events than less strict cholesterol-lowering therapies in patients aged 18 years and over with either ischemic stroke within the preceding 3 months or transient ischemic attack within the previous 15 days, both of atherosclerotic etiology (06). The 2860 patients in the Treat Stroke to Target trial were randomly assigned either to an LDL cholesterol target of less than 70 mg/dL (lower-target group) or an LDL cholesterol target ranging from 90 to 110 mg/dL (higher-target group). In both groups, proper control of other cardiovascular risk factors was encouraged. In the lower-target group, 66% of patients received a statin as single therapy and 34% were given a statin in combination with ezetimibe. For 94% of patients in the higher-target group, statin was the only cholesterol-lowering drug, and the remainder received a statin in combination with ezetimibe. After a mean follow-up of 3.5 years, the composite primary end point of major cardiovascular events (nonfatal cerebral infarction, myocardial infarction, urgent carotid or coronary revascularization, and vascular death) was significantly reduced by 22% in the lower-target group compared with the higher-target group. Due to the study’s design, it was not possible to keep count of the mean differences in the number of ischemic strokes between the two groups. In the lower-target group, the mean LDL cholesterol level was 65 mg/dL whereas it was 96 mg/dL in the higher-target group. There was no significant difference in the intracranial hemorrhage rate between the groups (06).

The latest American Heart Association guidance for recurrent stroke prevention recommends different lipid-lowering therapies in accordance with the patient’s atherosclerotic cardiovascular risk. An 80 mg daily dose of atorvastatin is recommended for patients with previous ischemic stroke who have no major cardiac sources of embolism, no known coronary artery disease, and LDL-cholesterol greater than or equal to 100 mg/dl. In patients with clinical atherosclerotic disease and either a previous transient ischemic attack or ischemic stroke, lipid-lowering therapy should include a statin, and ezetimibe may be added if needed. The target of LDL-cholesterol is less than 70 mg/dl (91; 44). Similar recommendations are proposed by the European Atherosclerosis Society Task Force for patients with atherosclerotic cardiovascular disease who are considered to be at high or very high risk of recurrent cardiovascular events (21).

Management of carotid disease

Carotid endarterectomy. Carotid endarterectomy has been shown to reduce the risk of ischemic stroke in patients with symptomatic carotid stenosis. To this regard, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) studied patients who had suffered a transient ischemic attack or minor stroke as well as an ipsilateral carotid stenosis of 70% or more. This study had to be stopped early because of the significant benefit seen in the surgical group. It found the 2-year risk of ipsilateral stroke to be 9% in the surgical group and 26% in the medical group (aspirin 1300 mg/day) whereas the absolute risk reduction was reported to be 17%. Risk reductions were less for those with moderate stenosis (50% to 69%) and dependent on concomitant risk factors (136). The Veterans Administration Cooperative Study showed that among those with greater than 50% carotid stenosis the risk of stroke after a mean follow-up of 11.9 months was 7.7% in the surgical group and 19.4% in the nonsurgical group. The European Carotid Surgery Trial (ECST) also showed a benefit for high-grade symptomatic carotid stenosis, but there was no significant benefit for surgery for those with 0% to 29% stenosis (10). Therefore, the consensus is that for patients with a transient ischemic attack or minor stroke and ipsilateral carotid stenosis of more than 70%, carotid endarterectomy is the best option for preventing a recurrent event, but for those with less than 50% stenosis, endarterectomy has no benefit, and for those with 50% to 69% stenosis and ipsilateral symptoms, the use of endarterectomy depends on the risk strata of the patient.

Greater benefit is seen with early surgery. In fact, treatment within 2 weeks of symptoms affords an absolute risk reduction of 23%, compared to an absolute risk reduction of 7.4% for those treated after 12 weeks. In order to prevent one ipsilateral stroke at 5 years, the number needed to treat is 5 within 2 weeks and 125 if surgery is delayed beyond 12 weeks (134). These benefits of early treatment are particularly pronounced in women, where significant efficacy of revascularization is seen only in the first 2 weeks.

An updated pooled data analysis of three relevant multicenter randomized controlled trials compared carotid endarterectomy coupled with best medical treatment versus best medical treatment alone in 6343 patients with ipsilateral carotid stenosis and either recent transient ischemic attacks or non-disabling ischemic strokes (128). The degree of carotid stenosis was recalculated according to the NASCET method in carotid angiographies, and outcome events were redefined and standardized to allow comparability between the trials. Carotid endarterectomy was beneficial, particularly in patients with severe carotid stenosis (70% to 99% narrowing of the lumen diameter), significantly reducing the cumulative 5-year risk of ipsilateral stroke and any operative stroke or death by about 50%, whereas in patients with 50% to 69% carotid stenosis, surgery reduced the cumulative 5-year risk of ipsilateral stroke and any operative stroke or death by 16%. Both results have moderate quality of evidence according to the GRADE method. Carotid endarterectomy was not beneficial in patients with stenosis lower than 50%, and the benefit was marginal in patients with carotid near-occlusion (128).

To date, there is high-quality evidence suggesting that carotid endarterectomy prevents ipsilateral stroke in patients with high-grade (70% to 99%) extracranial carotid-artery stenosis who have had a transient ischemic attack or ischemic stroke in the previous 6 months, whereas moderate-quality evidence exists for its prevention of stroke in any territory (28). American and European stroke practice guidelines state that carotid revascularization may be recommended for patients with recent symptomatic, moderate (50% to 69%), ipsilateral carotid stenosis depending on patient-specific factors, such as age, sex, and comorbidities (28; 91). Regarding patients with moderate carotid stenosis, there is low-quality evidence for the prevention of ipsilateral stroke by carotid endarterectomy and moderate-quality evidence for the prevention of stroke in any vascular territory (28). Furthermore, based on high-quality evidence, the Society of Vascular Surgery guidelines recommend carotid endarterectomy over transfemoral carotid stenting for symptomatic patients with between 50% and 99% of carotid stenosis and low or standard surgical risk (01). Consequently, carotid endarterectomy remains a gold standard for secondary prevention in symptomatic carotid stenosis (28; 91).

In patients with severe and moderate carotid-artery stenosis, carotid endarterectomy is beneficial if the estimated perioperative morbidity and mortality risk is below 6%. Carotid endarterectomy should preferably be done within 2 weeks after the index event in patients with recent transient ischemic attack or nondisabling ischemic stroke (28; 91). Carotid-artery stenting is a viable option for treating severe symptomatic carotid stenosis in high-risk surgical patients, those with unsuitable anatomy, or for other medical reasons, such as radiation-induced stenosis or restenosis after carotid endarterectomy (91).

Angioplasty and stent. Nonsurgical treatment of carotid disease with angioplasty and stent placement through endovascular techniques is becoming more widespread. It is now a technically feasible option and has even been used in patients who are not good surgical candidates, either because of the location of the stenosis or because of a high risk for undergoing anesthesia. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) was a larger, randomized study comparing angioplasty and endarterectomy (17). More than 500 patients with symptomatic carotid stenosis deemed necessary for treatment and amenable to either procedure were randomized. The study found no significant differences in death and disabling or nondisabling stroke between the two groups (10%). Additionally, there was a lower incidence of cranial nerve palsy in the nonsurgery patients (0% vs. 9%). The Stenting and Angioplasty with Protection in Patients at High Risk of Endarterectomy (SAPPHIRE) study randomized 307 high-risk patients to stent versus endarterectomy. These patients had a history of concurrent cardiac disease, and approximately 70% of the patients had asymptomatic carotid stenosis. Patients in the angioplasty group had a better 30-day outcome, with 4.5% developing stroke or death versus 6.6% in the endarterectomy group. The 30-day outcome of stroke, death, or myocardial infarction was 5.8% in the angioplasty group versus 12.6% in the surgical group (69). The International Carotid Stenting Study (ICSS), the largest trial of endarterectomy versus endovascular treatment to date, reported a nearly 2-fold higher procedural risk of stroke in the endovascular treatment group (79). Even without the inclusion of the ICSS results and other trials that report only periprocedural risks, a meta-analysis of all the available data on long-term outcome in randomized trials concerning endovascular treatment versus endarterectomy for symptomatic carotid stenosis show a significant worse outcome after endovascular treatment (129; 113).

The results of long-term outcome for patients included in the International Carotid Stenting Study (ICSS) are available. This international, multicenter, open-label, prospective clinical trial compared the long-term rate of fatal or disabling stroke in 1713 symptomatic carotid-stenosis patients over the age of 40 who were randomly allocated to either carotid endarterectomy (858) or carotid stenting (855). In both groups, 90% of patients suffered from severe carotid stenosis (luminal narrowing of more than 70%, as determined according to the NASCET method), which presented as ischemic hemispheric stroke in 45% of patients, followed by hemispheric transient ischemic attacks in nearly one third, and retinal infarction and transient monocular blindness in 20% of patients. Qualifying symptoms occurred within 6 months prior to randomization in around 95% of patients in both groups (54). In the intention-to-treat analysis, a significant difference was observed in major outcome (disabling stroke, procedural myocardial infarction, and death) within the first 120 days after randomization, with rates of 8.5% in the stenting group and of 5.2% in the endarterectomy group. The stenting group also showed a significantly higher rate of “any” stroke (7.6%) in comparison with the endarterectomy group (4.1%). In the first 120 days after randomization, the rate of ipsilateral stroke was 6.8% in the stenting group and 3.5% in the endarterectomy group. The nondisabling stroke rate was nearly three times higher in the stenting group (4.6%) than in the endarterectomy group (1.6%), whereas disabling stroke was only slightly more frequent in the endarterectomy group (2.3%) than in the stenting group (2.0%) (54).

During a mean follow-up of 4.2 years, the rate of fatal or disabling stroke (primary outcome measure) was essentially the same for both stenting and endarterectomy patients: 6.4% and 6.5%, respectively. In the intention-to-treat analysis, “any” stroke was significantly more frequent during follow-up in the stenting group than in the endarterectomy group (15.2% vs. 9.4%), as was the “any procedural stroke, ipsilateral stroke, or procedural death” combination (11.8% in the stenting group vs. 7.2% in the endarterectomy group). The long-term rate of severe carotid restenosis was higher in the stenting group, although not significantly (10.8% vs. 8.6%). No differences in functional outcome were observed between the groups after a 1-year and a 5-year follow-up, however (54).

Outcomes in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), up to 10 years afterwards, have also been published. In this multicenter trial, symptomatic and asymptomatic patients – the former within 6 months before randomization with at least 50% of diameter stenosis and the latter with 60% or greater diameter stenosis – were randomly allocated to carotid endarterectomy or stenting (30). In the periprocedural period, the rate of the primary composite endpoint (stroke, myocardial infarction, or death) was higher in the stenting group (5.2%) than in the endarterectomy group (4.5%), although this difference was not statistically significant. Periprocedural stroke, however, was significantly more frequent in the stenting group (4.1% vs. 2.3%). Over a mean long-term follow-up of 7.4 years, the rate of “any” postprocedural ipsilateral stroke was 6.9% in patients who underwent stenting and 5.6% in the endarterectomy group; this difference was not statistically significant, however. Major postprocedural stroke was more frequent in the stenting group (2.7% vs. 1.1%), and minor postprocedural stroke was more common in the endarterectomy group (4.5% vs. 4.2%), but neither of these two rates was statistically significant. Moreover, the rate of postprocedural stroke at 5 years in symptomatic patients was quite similar for both patients undergoing endarterectomy (2.7%) and those undergoing carotid stenting (2.5%). Restenosis occurred in 12.7% of patients assigned to stenting and in 9.7% of those assigned to endarterectomy, but this difference was not significant (30). In conclusion, this trial did not show striking differences between endarterectomy and stent-treated patients in the periprocedural period with respect to stroke, myocardial infarction, or death, nor in the postprocedural period with respect to ipsilateral stroke.

Updated guidance from the American Heart Association considers carotid stenting preferable to carotid endarterectomy as a reasonable treatment of choice in patients with severe symptomatic extracranial stenosis (≥70%) in whom anatomical or medical conditions increase the periprocedural morbidity and mortality risk (91). According to the ESO guidelines, carotid stenting is an alternative to carotid endarterectomy in symptomatic carotid stenosis patients under 70 years of age requiring carotid revascularization (28).

Antiplatelets. Platelets have a pivotal role in the pathogenesis of atherothrombosis. To this regard, findings from randomized trials and meta-analyses have shown the efficacy of antiplatelet therapies for secondary prevention after ischemic stroke. Antiplatelet drugs including aspirin, ticlopidine, clopidogrel, dipyridamole, cilostazol, and triflusal have been studied for their role in long-term secondary prevention of stroke.

Aspirin. Numerous clinical trials have compared aspirin with placebo for the prevention of stroke and death after transient ischemic attack or minor stroke; it was the Antithrombotic Trialists’ Collaboration that performed a meta-analysis on these results (18). In their analyses of 21 trials of subjects with a past history of stroke or transient ischemic attack, they reported an odds reduction of 22% for nonfatal stroke, nonfatal myocardial infarction, or vascular death with a 2-year risk of 17.8% for those treated with antiplatelets and 21.4% for controls. Similar reductions were found for women and men, young and old, hypertensives and normotensives, and diabetics and nondiabetics. Recommendations for dose of aspirin ranged from 30 mg per day to 1300 mg per day. In the same meta-analysis, benefit from 75 mg or more aspirin was equivalent to less than 75 mg in preventing vascular events. The risks of extracranial bleeding were similar with aspirin doses less than 325 mg. The odds ratio was 1.7 for less than 325 mg aspirin compared with controls. The odds ratio was 1.5 for doses less than 75 mg and 1.4 for doses of 160 to 325 mg. The latest meta-analysis by the Antithrombotic Trialists’ Collaboration has confirmed that in the secondary prevention trials, aspirin allocation yields a greater absolute reduction in serious vascular events (6.7% vs. 8.2% per year, p< 0.0001), with a nonsignificant increase in hemorrhagic stroke as well as reductions of about a fifth in both total stroke (2.08% vs. 2.54% per year, p=0.002) and coronary events (4.3% vs. 5.3% per year, p< 0.0001) (19).

According to the latest American Heart Association guidelines, secondary stroke prevention for patients with an index noncardioembolic ischemic stroke or transient ischemic attack includes either aspirin 50 to 325 mg daily, clopidogrel 75 mg daily, or aspirin 25 mg along with extended-release dipyridamole 200 mg twice daily (91).

Ticlopidine. Another antiplatelet agent that has proven effective in stroke prevention is ticlopidine. The Canadian American Ticlopidine Study, comparing ticlopidine versus placebo in a triple-blind, randomized, multicenter study after noncardioembolic stroke included 1053 patients. Ticlopidine resulted in a 23% risk reduction in an intention-to-treat analysis and a 30% reduction in an efficacy analysis. The risk reduction for nonfatal or fatal recurrent stroke was 33%. In the Ticlopidine Aspirin Stroke Study, ticlopidine was compared with aspirin (1300 mg/day) among 3069 patients having transient ischemic attack or minor stroke. Overall, there was a 12% reduction in stroke or death at 3 years, along with a 47% risk reduction in fatal or nonfatal stroke during the first year for those treated with ticlopidine compared with aspirin. Benefits were found for both sexes and were also observed in the subgroup with minor stroke. The African American Antiplatelet Stroke Study, however, failed to show any benefit from ticlopidine compared with aspirin in this high-risk population (67). Currently, ticlopidine is rarely utilized due to its severe side effects including neutropenia.

Dipyridamole. Past studies have indicated that dipyridamole may have a benefit similar to aspirin for the prevention of recurrent stroke. Results from the European Stroke Prevention Study have indicated that 200 mg twice daily of extended-release dipyridamole was as effective as 25 mg twice daily aspirin, with the combination of the two being even better than aspirin alone for the prevention of stroke after transient ischemic attack or minor stroke (49). The relative risk reduction of stroke or death was 13% for aspirin, 15% for dipyridamole, and 24% for the combination. The ESPRIT trial found that primary outcome events (composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication) arose in 13% patients on aspirin and dipyridamole and in 16% on aspirin alone (hazard ratio 0.80, 95% CI 0.66 to 0.98; absolute risk reduction 1.0% per year, 95% CI 0.1 to 1.8) (70).

Clopidogrel. The antiplatelet agent clopidogrel has been studied in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. In this study, 19,185 patients with ischemic stroke, myocardial infarction, or peripheral vascular disease were randomized to clopidogrel 75 mg versus aspirin 325 mg. For the primary endpoint of combined stroke, myocardial infarction, or vascular death, there was a relative risk reduction of 8.7% and an absolute risk reduction of 0.9% with clopidogrel. The stroke subgroup had a nonsignificant 7.3% relative risk reduction of stroke, myocardial infarction, or vascular death (14).

Cilostazol. Cilostazol is an antiplatelet drug that inhibits phosphodiesterase 3, increases cAMP concentrations, and consequently inhibits platelet aggregation. Cilostazol has been compared with aspirin in the secondary prevention of stroke in Japan in the CSPS-2 trial, which reported a reduction in the risk of both recurrent stroke (hazard ratio 0.74, 95% CI 0.56 to 0.98) and hemorrhagic complications (hazard ratio 0.46, 95% CI 0.30 to 0.71) (143). In the last few months, a meta-analysis of 10 studies comprising 5429 patients who received cilostazol as single antiplatelet therapy and 2456 patients treated with cilostazol plus clopidogrel or acetylsalicylic acid found that cilostazol in combination with another antiplatelet agent was more effective than acetylsalicylic acid alone in preventing recurrent noncardioembolic ischemic stroke in Asian individuals and did not increase cerebral hemorrhage risk (89).

Triflusal. Triflusal is an antiplatelet agent structurally related to the salicylate group of compounds, but it is not derived from aspirin. Platelet antiaggregant properties of triflusal and its active 3-hydroxy-4-trifluoro-methylbenzoic acid metabolite are primarily mediated by specific inhibition of platelet arachidonic acid metabolism. Triflusal is similar to aspirin both structurally and in its efficacy for the prevention of vascular events (risk ratio for aspirin vs. triflusal 1.03, 95% CI 0.89 to 1.20) but has a lower risk of bleeding (risk ratio 0.63, 95% CI 0.54 to 0.74) (42).

Ticagrelor. Ticagrelor is an oral reversible blocker of the P2Y12 adenosine-5'-diphosphate (ADP) platelet receptor. A prespecified exploratory analysis of a subset of 3081 patients (23% of all the trial patients) included in the Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial compared the efficacy of ticagrelor versus aspirin in preventing the occurrence of stroke, myocardial infarction, and death within 90 days of an index event (05). Patients included in this prespecified analysis were over 40 years of age and had either nonsevere acute cerebral infarct (NHISS score less than or equal to 5) or high-risk transient ischemic attack (ABCD2 score greater than or equal to 4) combined with a potential symptomatic ipsilateral stenosis as defined by the ASCOD phenotyping system. Patients were randomly allocated to the ticagrelor group (1542 patients, initial oral loading dose of 180 mg and 90 mg twice daily from day 2 to 90) or the aspirin group (1537 patients, initial oral loading dose of 300 mg and 100 mg/daily from day 2 to 90). At 90 days, the ticagrelor group showed a stroke rate of 6.4% as opposed to an 8.5% stroke rate in the aspirin group, amounting to a nonsignificant 27% reduction of stroke in the ticagrelor group. Conversely, at 90 days, a significant reduction of nearly 30% was observed in the rate of stroke, myocardial infarction, and death, which was 7.1% in the ticagrelor group, whereas the respective rate in the aspirin group was 9.6% (05).

The multicenter, double blind, placebo-controlled, randomized THALES (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial compared early dual antiplatelet therapy (ticagrelor plus aspirin in 5523 patients) versus single antiplatelet therapy (aspirin alone plus placebo in 5493 patients). All included patients had a mild to moderate acute non-cardioembolic stroke (NIHSS score of 5 of less) or a high-risk transient ischemic attack (ABCD2 score ≥ 6). No patient received intravenous thrombolysis or endovascular treatment. (82). In the treatment arm, a loading dose (180 mg) of ticagrelor was administered followed by 90 mg twice daily; a loading dose (300 to 325 mg) of aspirin followed by 75 to 100 mg a day was administered in the treatment and comparison groups. Antiplatelets in both groups were started within 24 hours after stroke onset and were given for 30 days. Mean age of patients was 65.2 years, the qualifying event was ischemic stroke in 90.6% of patients and transient ischemic attack in the remainder. Compared to aspirin alone, ticagrelor plus aspirin significantly reduced the incidence of subsequent ischemic stroke by 21% without a significant impact on the incidence of overall disability (modified Rankin score ≥ 1). In addition, ticagrelor plus aspirin significantly increased the risk of intracranial hemorrhage threefold (82).

Combination regimens. Combination antiplatelet regimens such as extended-release dipyridamole plus aspirin have proven their efficacy for long-term prevention of stroke or death after stroke or transient ischemic attack. Other antiplatelet combinations have been investigated, including clopidogrel plus aspirin. The Management of Atherothrombosis with Clopidogrel in High-risk patients with recent transient ischemic attack or stroke (MATCH) trial randomized high-risk patients (prior ischemic stroke, myocardial infarction, peripheral vascular disease, or diabetes) to therapy with clopidogrel or clopidogrel plus aspirin (48). The authors assessed for outcomes of ischemic stroke, myocardial infarction, or death at 18 months. There was no significant difference in outcome for the two treatment groups, but the combination of clopidogrel plus aspirin significantly increased the risk of major bleeding events. The SPS3 study was a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging (26). Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16) nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P< 0.001). All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004). The PROFESS trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke for aspirin plus dipyridamole versus clopidogrel (138). In a meta-analysis, Zhang and colleagues found that compared with monotherapy, long-term aspirin in combination with clopidogrel does not reduce the risk of stroke recurrence and is associated with increased major bleeding events (159).

The PROFESS trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke for aspirin plus dipyridamole versus clopidogrel (138). There is no evidence that either of the two treatments is superior to the other in the long-term prevention of recurrent stroke.

In a meta-analysis, Kwok and colleagues found that any of the single antiplatelet agents compared with placebo is adequate for secondary stroke prevention after lacunar stroke (93). Dual antiplatelet therapy should not be used for long-term stroke prevention in this stoke subtype.

A meta-analysis compared the secondary stroke prevention efficacy of combined, or dual, antiplatelet therapy versus antiplatelet monotherapy in 29,032 patients with a previous transient ischemic attack or cerebral infarct included in 16 randomized controlled trials from 2004 to 2018 (88). Clopidogrel (usually 75 mg per day) with aspirin and aspirin alone were the most common dual and mono antiplatelet therapies, respectively. Compared to monotherapy, dual antiplatelet therapy significantly reduced the risk of any stroke by 20% and the risk of a recurrent ischemic stroke by 25%. No significant differences were found between the two antiplatelet regimens regarding the risk of subsequent transient ischemic attack. Dual antiplatelet therapy significantly reduced the risk of ischemic stroke in patients who experienced a minor stroke or a transient ischemic attack as index event by 25%. Dual antiplatelet therapy for less than 3 months significantly reduced the risk of a recurrent cerebral infarct compared to a single antiplatelet agent whereas there were no differences between the antiplatelet therapy groups regarding the risk of recurrent stroke when the duration of treatment was longer than 3 months. In addition, compared to monotherapy, dual antiplatelet therapy was better at reducing stroke risk when started within 7 days of index event; however, there were no differences in relative risk reduction compared to a single agent when dual antiplatelet therapy was started 1 month after the index event. Concerning safety, dual antiplatelet therapy was associated with a nearly 2-fold higher risk of major bleeding and a one-and-a-half-fold higher risk of intracranial bleeding. Short-term dual antiplatelet therapy (less than 3 months) was not associated with a significantly higher risk of bleeding complications compared to monotherapy (88).

In the last few years, a pooled analysis of the large-scale randomized placebo-controlled clinical trials POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) and CHANCE (Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events) assessed the efficacy and safety of dual antiplatelet therapy compared to monotherapy for secondary stroke prevention after an index ischemic stroke (120). In both trials, minor stroke patients and high-risk transient ischemic attack patients were randomized to early dual antiplatelet therapy or antiplatelet monotherapy. Antiplatelet therapy was started within 12 hours of stroke onset in the POINT trial and within 24 hours in the CHANCE trial. The individual data of 10,051 patients who had a minor stroke (National Institute of Health Stroke Scale ≤ 3) or high-risk transient ischemic attack (ABCD2 score ≥ 4) were analyzed; 5016 patients were assigned to dual antiplatelet therapy (clopidogrel and aspirin) and 5035 to antiplatelet monotherapy (aspirin). In the clopidogrel-aspirin arm, therapy was given for 90 days in the POINT trial and 21 days in the CHANCE trial; in the latter, this was followed by 22 to 90 days of clopidogrel monotherapy. Compared to aspirin monotherapy, clopidogrel plus aspirin significantly reduced the risk of ischemic stroke and the composite of major ischemic events (ischemic stroke, myocardial infarction, and death from ischemic vascular causes) by one third at 90 days. Dual antiplatelet therapy provided a clinical benefit within 90 days – and particularly in the first 21 days of treatment – but the risk of hemorrhagic adverse outcome was nonsignificantly higher compared with antiplatelet monotherapy (120).

A network meta-analysis of 16 randomized controlled trials between 1983 and 2018 evaluated the efficacy and safety of short-term (less than 3 months) and long-term (at least 1 year) dual antiplatelet therapies for secondary stroke prevention (126). This meta-analysis comprised 55,261 patients aged 17 and over who were treated with dual antiplatelet therapy (aspirin and clopidogrel or aspirin and dipyridamole) or antiplatelet monotherapy (either aspirin or clopidogrel) after a transient ischemic attack or ischemic stroke (126). Compared to aspirin alone, the addition of clopidogrel to aspirin reduced the stroke recurrence risk by 33% and 16% in the short and long term, respectively. In contrast, compared with antiplatelet monotherapy, hemorrhagic complications were higher when clopidogrel was combined with aspirin in the short-term and even more so in the long-term. There was no greater reduction in stroke recurrence in the long-term between dual antiplatelet therapy (aspirin plus clopidogrel) and clopidogrel as a single antiplatelet agent. In the long-term, aspirin combined with dipyridamole was the least effective in preventing stroke.

Dual antiplatelet therapy (aspirin and clopidogrel or ticagrelor in carriers of CYP2C19 loss-of-function alleles) for 21 to 30 days, followed by long-term single antiplatelet therapy, is currently recommended in patients with minor noncardioembolic ischemic stroke (NIHSS ≤ 3) or high-risk transient ischemic attack (ABCD2 score ≥ 4) in the past 24 hours. Short-term dual antiplatelet therapy is also advised for patients with symptomatic high-grade atherosclerotic intracranial stenosis (58; 91; 149).

In a prespecified analysis of the CHANCE-2 trial, the efficacy and safety of two regimens of early dual-antiplatelet therapy was assessed according to etiology in 6336 patients (all carrying CYP2C19 loss-of-function alleles) with minor stroke (80.5%) or transient ischemic attack (19.5%) (155). Based on the TOAST criteria, there were 2890 patients (45.6%) with undetermined stroke, 1750 patients (27.6%) with small-vessel occlusion, and 1696 patients (26.6%) with large-artery atherosclerosis. All patients were randomized (1:1) to ticagrelor-aspirin or clopidogrel-aspirin groups. Patients with large-artery atherosclerosis had the highest risk of stroke recurrence at 90 days after the index event. At 3 months, relative reduction in stroke recurrence was 23% in the whole cohort, with the largest reduction (nearly 50%) occurring in ticagrelor-aspirin patients with small-vessel occlusion. Both regimens of dual antiplatelet therapy reduced stroke recurrence by 14% and 20% in patients with large-artery atherosclerosis and undetermined etiology, respectively. At 90 days, no significant differences in bleeding complications were found in patients with different stroke etiologies and different regimens of dual antiplatelet therapy (155).

In a prospective, randomized, open-label, blinded endpoint superiority trial, the safety and efficacy of three antiplatelet agents was assessed within the first 48 hours after a noncardioembolic transient ischemic attack (27% of patients, median ABCD2 score 5) or cerebral infarct (73% of patients, mean NHISS 4, 11% of whom had undergone thrombolysis before randomization) (24). The mean age of patients was 69 years, and etiologies of ischemic stroke were small vessel disease (40%), large vessel disease (16%), and undetermined (39%) according to TOAST criteria. In this trial, 1556 patients were randomly assigned to triple antiplatelet therapy (intensive treatment group) and 1540 to guideline treatment. The intensive treatment group received a loading dose of clopidogrel and aspirin, then daily maintenance doses of aspirin, clopidogrel, and dipyridamole. Patients in the guideline treatment group received a loading dose of aspirin and dipyridamole or clopidogrel alone, then daily maintenance doses of the antiplatelet drug. These treatments lasted for 30 days, after which the patients were treated according to local guidelines, usually with aspirin and dipyridamole or clopidogrel alone. At a final 90-day follow-up, no difference was found in the incidence of transient ischemic attack (6%) and cerebral infarct (7%) between the treatment groups (common adjusted OR 0.90), whereas the risk of severe bleeding was found to be 2.5 times greater with triple antiplatelet therapy (24). Because of these results, the data monitoring committee recommended the trial be stopped for primary endpoint futility, after which more than 70% of the target sample of 4200 patients were randomly assigned to either of the antiplatelet regimens.

Oral anticoagulants. Warfarin is an oral anticoagulant that has been demonstrated to be effective in the prevention of cardioembolic stroke. In fact, several warfarin studies have provided evidence that warfarin is the therapy of choice in patients with a cardiac source and a transient ischemic attack or minor stroke, provided there is no contraindication to its use. There has been considerable ongoing debate regarding the use of warfarin after noncardioembolic stroke or transient ischemic attack. The Warfarin Aspirin Recurrent Stroke Study (WARSS) was designed to answer questions about warfarin’s role in the treatment of these strokes (112). WARSS was a randomized, double-blind trial of warfarin with an INR of 1.4 to 2.8 versus aspirin 325 mg in 2206 patients with noncardioembolic stroke. These patients were followed for 2 years with the primary endpoint being stroke or death. Death or recurrent stroke occurred in 16.9% of patients. There was no difference between patients treated with warfarin or aspirin. There was also no difference seen in hemorrhage rates. Although warfarin with an INR of 1.4 to 2.8 appears to be safe, there was no increased benefit in preventing recurrent stroke compared with aspirin. In contrast, the WASID study has investigated warfarin versus aspirin in symptomatic intracranial arterial stenosis. In this trial, warfarin was associated with significantly higher rates of adverse events and reported no benefit over aspirin. The authors recommended the use of aspirin over warfarin for patients with intracranial arterial stenosis (37). A long-term, follow-up trial with careful warfarin monitoring suggested a remarkable reduction in stroke recurrences without more adverse events. Being so, antiplatelets continue to be the treatment of choice for the prevention of stroke after noncardioembolic stroke or transient ischemic attack.

Terutroban. The PERFORM trial reported that Terutroban, a specific antagonist of the thromboxane A2 receptor, was no more effective than aspirin in the prevention of stroke in 19,119 patients with transient ischemic attack or ischemic stroke (29); 9562 patients were assigned to terutroban (9556 analyzed) and 9558 to aspirin (9544 analyzed); mean follow-up was 28.3 months. The primary endpoint, a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal myocardial infarction, or other vascular death (excluding hemorrhagic death) occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1.02, 95% CI 0.94-1.12). Some increase in minor bleedings were seen with terutroban compared with aspirin (1147 [12%] vs. 1045 [11%]; HR 1.11, 95% CI 1.02-1.21), but no significant differences in other safety endpoints. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee.

Stenting for intracranial arterial stenosis. Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. In the SAMMPRIS Trial, patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70% to 99% of the diameter of a major intracranial artery were randomized to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary endpoint was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Enrollment was stopped after 451 patients underwent randomization because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002) (36).

The latest international clinical practice guidelines do not recommend carotid stenting as the first-choice treatment for patients with high-grade (70% to 99%) symptomatic intracranial stenosis. Instead, dual antiplatelet therapy (aspirin and clopidogrel) is recommended over single antiplatelet therapy up to 90 days after the index event to reduce the risk of recurrent stroke (91; 125).

Long-term secondary prevention of cardioembolic cerebrovascular events

Dose-adjusted warfarin to maintain an international normalized ratio (INR) between 2.0 and 3.0 is effective for stroke prevention in patients with atrial fibrillation. A meta-analysis of six randomized trials showed that warfarin provided a 62% risk reduction of ischemic stroke in comparison to placebo (72). A similar risk reduction is seen in patients who receive warfarin for secondary prophylaxis (141; 74). Aspirin is not effective at preventing recurrent stroke in patients with ischemic stroke or TIA with atrial fibrillation (HR 0.83, 95% CI 0.65 to 1.05) (12; 71). A meta-analysis of five randomized trials that compared dose-adjusted warfarin to aspirin 325 mg per day showed that warfarin provided a 36% risk reduction for all strokes and a 46% risk reduction for ischemic strokes versus aspirin (72). Anticoagulants prevent more severe and disabling strokes as compared to aspirin (73).

In the ACTIVE-W trial, warfarin was also significantly more effective than aspirin plus clopidogrel for stroke prevention in patients at high risk of stroke (02). However, among patients with atrial fibrillation for whom antithrombotic therapy was considered unsuitable, the combination of clopidogrel and aspirin was associated with a reduction in the primary outcome of stroke, myocardial infarction, noncerebral systemic embolism, or death from vascular causes compared with aspirin alone. The difference was primarily due to a reduction in the rate of stroke. Major bleeding was significantly more common in patients assigned to the combination of clopidogrel and aspirin (40).

Anticoagulants are associated with an increased risk of bleeding, particularly intracranial hemorrhage and gastrointestinal bleeding, with respect to aspirin or no treatment (0.3%, 0.2%, and 0.1% per year respectively) (72). Anticoagulants also increase the odds of major extracranial hemorrhage (141). Anticoagulant use accounts for a significant proportion of iatrogenic emergency room admissions. About 4% of admissions to stroke units for intracranial hemorrhages are due to warfarin treatment within therapeutic range (118).

Stroke risk rises sharply when the INR falls below 2.0, and the risk of intracranial bleeding increases sharply when the INR increases beyond 3.0.

New oral anticoagulants in development for stroke prevention in atrial fibrillation

The ideal profile of a new oral anticoagulant includes the following: a predictable pharmacological profile so that INR monitoring and dose modifications are not required, rapid onset and offset of action and fixed, and oral dosing that would be most convenient for patients and could potentially improve adherence to the prescribed regimen.

Oral direct thrombin inhibitors. The SPORTIF trials showed that ximelagatran was at least as effective as warfarin for the prevention of stroke, with no difference in rates of major bleeding and a lower rate of total bleeding (117; 04). Ximelagatran was withdrawn from the market in 2006 due to liver toxicity. Nevertheless, this drug provided the proof of concept for direct thrombin inhibition and showed that oral anticoagulation is possible without regular INR monitoring.

In the landmark phase III RE-LY trial, dabigatran was the first oral anticoagulant to show superior efficacy to warfarin for stroke prevention in atrial fibrillation (41). Dabigatran 110 mg twice daily resulted in a rate of stroke and systemic embolism similar to that in patients treated with warfarin (1.53% per year vs. 1.69% per year, p< 0.001 for noninferiority) but with a lower rate of major hemorrhage (2.71 per year vs. 3.36 per year, p=0.003). Dabigatran 150 mg twice daily resulted in a lower rate of stroke and systemic embolism than warfarin (1.11% per year vs. 1.69% per year, p< 0.001 for superiority) and a similar rate of major hemorrhage to patients treated with warfarin (3.11% per year vs. 3.36% per year, p=0.31). Dabigatran was associated with higher rates of treatment discontinuation, myocardial infarction, major gastrointestinal bleeding and dyspepsia.

Oral direct factor Xa inhibitors. Several randomized phase III trials explored the use of oral direct Factor Xa inhibitors for stroke prevention in patients with atrial fibrillation. Rivaroxaban and apixaban have provided cumulative evidence in favor of these novel anticoagulants. Their main advantages, apart from their treatment efficacy, include the reduced rate of intracranial hemorrhage, the lack of need for routine coagulation monitoring, the predictable anticoagulation response, and the limited interaction with food and drugs.

In the double-blind ROCKET trial, 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke were randomly assigned to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. In the primary analysis, the primary endpoint (stroke or systemic embolism) occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P< 0.001 for noninferiority). In the intention-to-treat analysis, the primary endpoint occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P< 0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group (121).

A randomized, double-blind trial (ARISTOTLE) compared apixaban (at a dose of 5 mg twice daily) with warfarin (target INR, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P< 0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P< 0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P< 0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42) (68).

Edoxaban is another direct oral factor Xa inhibitor with proven antithrombotic effects. ENGAGE AF-TIMI 48 was a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5%, CI, 0.63 to 0.99; P< 0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P< 0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P< 0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32) (65).

In a meta-analysis including 14,527 patients, nonvitamin-k-antagonist (VKA) oral anticoagulants were associated with a significant reduction of stroke or systemic embolism (odds ratios, 0.85 [95% CI, 074-0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8 to 2.0 years) compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischemic attack. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075-0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032-0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139) (115).

Currently, anticoagulation remains the optimal treatment choice for secondary stroke prevention in patients with atrial fibrillation, regardless of its pattern (paroxysmal, permanent, or persistent) (91). The updated American Heart Association guidelines for secondary stroke prevention recommend anticoagulation with new oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) over vitamin K antagonists for patients with atrial fibrillation and either ischemic stroke or transient ischemic attack who do not have moderate to severe mitral stenosis or a mechanical heart valve (91). The latest guidelines of the European Stroke Organization also recommend nonvitamin K antagonist oral anticoagulants rather than vitamin K oral anticoagulants to prevent recurrent ischemic stroke in patients with nonvalvular atrial fibrillation and either previous cerebral infarct or transient ischemic attack (92).

It is recommended to start anticoagulation immediately in patients with atrial fibrillation and transient ischemic attack. Starting anticoagulation between 2 and 12 days after the event is recommended for patients with atrial fibrillation and ischemic stroke who have a low risk of hemorrhagic transformation, whereas it is advisable to delay anticoagulation for at least 14 days in patients with atrial fibrillation and ischemic stroke with a high risk of hemorrhagic transformation (91).

Moreover, the latest AHA/ACC/HRS guidelines recommend oral anticoagulation for thromboembolism prevention in patients with atrial fibrillation who have an elevated CHA2DS2-VASc score (2 or higher in men, 3 or higher in women). The following oral anticoagulants may be used in the setting of secondary stroke prevention in nonvalvular atrial fibrillation: warfarin (level of evidence A); dabigatran, rivaroxaban, and apixaban (level of evidence B); and edoxaban, which has a lower quality of evidence compared with other new oral anticoagulants. In addition, based on the results of four randomized controlled trials comparing the new oral anticoagulants with warfarin in atrial fibrillation patients, the guidelines recommend anticoagulation with new oral anticoagulants over warfarin when their use is not contraindicated (81).

On the other hand, the role of anticoagulation in secondary prevention of embolic stroke of undetermined source has been addressed in two large, randomized trials. The NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) assessed rivaroxaban (in 3609 patients) versus acetylsalicylic acid (in 3604 patients). After a median follow-up of 11 months, no differences in the annualized cerebral infarct rate occurred in either treatment group, although the symptomatic intracranial hemorrhage rate was four times higher in the rivaroxaban group than in the acetylsalicylic acid group (75). In the RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source), 5390 patients aged 60 years and over were randomly assigned to either dabigatran or acetylsalicylic acid. There were no differences between dabigatran and acetylsalicylic acid in terms of efficacy or safety outcomes (50). Two other trials, ATTICUS and ARCADIA, which aim to evaluate apixaban versus acetylsalicylic acid in secondary stroke prevention in patients with an index cerebral infarct of undetermined source, are ongoing.

The latest guidelines from the American Heart Association state that patients with embolic stroke of undetermined source should receive neither direct oral anticoagulants nor ticagrelor (91). Despite low-quality evidence, the ESO guidelines recommend antiplatelet therapy in patients with embolic stroke of undetermined source (44).

Left atrial appendage closure for secondary stroke prevention in atrial fibrillation. The left atrial appendage is the major source of thrombus in most patients with atrial fibrillation. Blood stasis associated with atrial fibrillation and extensive left atrial appendage trabeculation contribute to thrombus formation. Thus, left atrial appendage closure, which can be performed by either surgical or percutaneous approaches and is cost-effective relative to warfarin and new oral anticoagulants, may be an alternative treatment to pharmacological therapy for stroke prevention in atrial fibrillation.

Long-term efficacy in secondary stroke prevention was assessed in a retrospective cohort of 139 patients with nonvalvular atrial fibrillation who underwent left atrial appendage occlusion with a Lariat device (103). The stroke group consisted of 37 patients with previous stroke, and the remaining patients (the control group) had nonvalvular atrial fibrillation alone. Compared with the control group, the patients in the stroke group were older and had a higher risk of thromboembolism based on CHA2DS2-VAS score (4.6 versus 2.3) and a higher risk of hemorrhagic complications based on HAS-BLED score (4 versus 2.8). Although the figures were not significant, the estimated reduction in thromboembolism risk was 89% in the stroke group and 91% in the control group after an average follow-up of 51 months. Furthermore, four patients in the control group experienced nonfatal major bleeding whereas no patient in the stroke group had any bleeding complications, and one patient in the stroke group developed an ischemic stroke (103).

Closure of patent foramen ovale

Despite thorough investigation, up to 40% of ischemic strokes are cryptogenic; that is, they have no clearly identifiable cause. Moreover, nearly half of cryptogenic stroke patients under 60 years of age had a patent foramen ovale as the only potential cause. This high frequency of patent foramen ovale is nearly double the rate of this interatrial septum abnormality found in the general population. Therefore, stroke in this group of patients may be due to paradoxical embolism, and the appropriate management for preventing recurrent stroke—either by percutaneous patent foramen ovale closure (umbrella or disc occluder) or by antithrombotic treatment (anticoagulation or antiplatelet therapy)—is a matter of ongoing controversy.

A meta-analysis comprising 3440 patients (mean age 44.9 years) from five randomized controlled trials (in which index cerebral infarct occurred between 6 and 9 months before enrollment) estimated the efficacy and safety of transcatheter device closure along with antiplatelet therapy against medical therapy alone for prevention of further stroke (primary efficacy endpoint) in patients with patent foramen ovale and no other identified cause of a first-ever cerebral infarct (03). Device closure was randomly assigned to 1829 patients, whereas the remaining 1611 patients received medical therapy alone. The patent foramen ovale occluders were the Amplatzer device (two trials), the Gore septal occluder (one trial), and the Startflex device (one trial; device no longer available). Multiple devices were employed in the remaining trial. After device placement, long-term (1 month minimum) single or dual antiplatelet therapy was prescribed. Patients on medical therapy alone received either one antiplatelet agent (aspirin or clopidogrel) or dual antiplatelet therapy (aspirin with dipyridamole or aspirin and clopidogrel) or anticoagulation (warfarin or new oral anticoagulants). The imaging modality in four trials when a new brain infarct was suspected any time during follow-up based on clinical grounds was brain CT or MRI, whereas brain CT alone was used in the remaining trial. At a median follow-up of 4 years, the incidence of new brain infarction (fatal and nonfatal) was significantly reduced in the patent foramen ovale closure group compared with the medical therapy group (2.02% vs. 4.46%, respectively; HR: 0.32; p 0.018). In addition, patent foramen ovale closure significantly reduced the incidence of recurrent stroke (HR 0.33 p 0.005) in patients with large shunts (1.46%) in comparison with patients with large shunts treated medically (4.72%). There were no differences in risk reduction of new cerebral infarct in patients with small shunts (HR 0.90 p 0.71) between the groups. The presence or absence of atrial septal aneurysm had no effect on the rate of stroke recurrence in either group (03).

With respect to safety, major bleeding complications were no different between the groups, whereas patients with patent foramen ovale closure had a 4-fold higher risk of new-onset atrial fibrillation as compared with patients treated medically. Patients who underwent patent foramen ovale closure showed a 3.2% rate of procedural events (03).

The latest recommendations of the American Academy of Neurology state that an unequivocal causality between patent foramen ovale as the source of brain embolism and ischemic stroke should be established in individuals aged under 60 years before considering a percutaneous patent foramen ovale closure procedure (grading of recommendations assessment, development, and evaluation level of evidence B). The decision to perform a percutaneous patent foramen ovale closure procedure should be based on the benefit of reducing absolute recurrent ischemic stroke risk (3.4% at 5 years) versus the risk of periprocedural complications (3.9%) and the annual risk rate of nonperiprocedural atrial fibrillation (0.33%) (level of evidence C). Antiplatelet monotherapy or anticoagulation (vitamin K antagonists or direct oral anticoagulants) are indicated in patients under ongoing medical treatment (109).

The updated secondary stroke prevention guidelines from the American Heart Association also recommend closing patent foramen ovale percutaneously in patients aged 18 to 60 years with a non-lacunar ischemic stroke who have patent foramen ovale with high-risk anatomical signs of embolism and no other identified cause of stroke after a thoroughly etiological investigation (91). Long-term antiplatelet therapy should be maintained after percutaneous patent foramen ovale closure. The benefit of percutaneous patent foramen ovale closure coupled with long-term antiplatelet therapy has still not been established for patients with ischemic stroke and patent foramen ovale considered a low embolism risk based on anatomical features (91).

Conclusions

Stroke prevention is a crucial issue given that stroke is a frequent and severe disorder. To reduce the risk of any new vascular events after a first ischemic stroke or transient ischemic attack, strategies include conventional approaches to vascular risk factor management (blood pressure lowering, cholesterol reduction with statins, and smoking cessation), antithrombotic therapy, and more specific interventions, such as carotid revascularization or percutaneous closure of patent foramen ovale.

Clinical applications

See Description section above.