© Springer International Publishing Switzerland 2016
Bruce Ovbiagele (ed.)Ischemic Stroke Therapeutics10.1007/978-3-319-17750-2_1313. Secondary Prevention After Ischemic Lacunar Stroke
(1)
NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy
(2)
NEUROFARBA Department, Neuroscience section, University of Florence, Stroke Unit and Neurology, Largo Brambilla 3, 50134 Florence, Italy
Keywords
Secondary preventionLacunar strokeVascular risk factorsSmall vessel diseaseHypertensionDyslipidemiaAntiplatelet drugsAnticoagulantsCarotid surgeryCase Presentation
A 70-year-old woman affected by hypertension presented to the emergency department for sudden onset of right-hemisensory loss. Brain CT-scan excluded hemorrhage and revealed mild leukoencephalopathy. The patient was on aspirin 100 mg per day for previous myocardial infarction.
At this point, the treating physicians discussed the appropriate therapy for secondary prevention of stroke. Doctor 1 proposed to increase the dose of aspirin up to 300 mg per day. Doctor 2 proposed to replace aspirin with clopidogrel, while doctor 3 proposed to start double antiaggregation with aspirin 100 mg plus clopidogrel 75 mg daily. All the doctors agree upon the introduction of atorvastatin. An MRI examination performed 10 days after the event showed a hyperintense lesion in left thalamus on Fluid Attenuated Inversion Recovery (FLAIR) sequences representing a lacunar infarct and numerous hypointense lesions on gradient echo sequences compatible with diffuse hemosiderin deposits. Which of the 3 proposed drug regimens is the most appropriate? Does the presence of cerebral microbleeds affect in some way the decision?
Introduction
Definitions
The term cerebral small vessel disease (SVD) refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain [1]. The most common forms are age- and hypertension-related SVD and cerebral amyloid angiopathy [1]. The consequences of SVD on the brain parenchyma are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large hemorrhages, and microbleeds. Unlike large vessels, small vessels cannot be currently visualized in vivo; therefore, the parenchyma lesions that are thought to be caused by these vessel changes have been adopted as the marker of SVD, and the term SVD is frequently used to describe these brain parenchyma lesions rather than the underlying small vessel alterations [1]. Of note, the definition of small vessel is not uniform: in one survey, there was less than 50 % agreement among leading neuropathological centers on its definition [2].
Currently, there is an incorrect tendency to use the term SVD to describe only the ischemic component of the SVD process (i.e., lacunar infarcts and white matter lesions) [1, 3]. Instead, a broader view of SVD should be maintained, particularly when considering preventive and therapeutic aspects, because patients with SVD also have an increased risk of hemorrhage [1].
In a recent consensus paper the definition of SVD was extensively revised [4]. According to this new classification, there are at least 6 types of SVD. This consensus position is mainly based on neuroimaging. As a result, the hemorrhagic component of SVD is restricted to microbleeds, and large hemorrhages are not contemplated.
Clinical Correlates
SVD has an important role in cerebrovascular disease in both acute and chronic phases. Lacunar strokes are the cause of about one fifth of all strokes, [5] and SVD is a major contributor of cognitive decline, [6] psychiatric disorders, [7] and functional loss in older people [8, 9]. SVD is the most common cause of vascular dementia, [9] and a major contributor to mixed dementia [10, 11]. Lacunar infarcts and white matter lesions are associated with specific cognitive deficits such as psychomotor retardation, deficits of attention, planning, and set-shifting, and dysexecutive syndrome [12]. There is a correlation between progression of white matter lesion load and decline in cognitive performance [13].
Patients with SVD have also other relevant functional deficits. Gait is frequently affected and patients with SVD have an increased risk of falls [14–17]. Mood disturbances, particularly depressive symptoms and apathy, [18, 19] are also frequent, and urinary disturbances may be present [20]. Patients with severe white matter lesions had more than double the risk of transition to disability than patients with mild lesions, independent of many other predictors of disability [8, 21].
Patients with a lacunar infarct usually present with one of the classical lacunar syndromes (pure motor hemiparesis, pure sensory syndrome, sensorimotor stroke, ataxic hemiparesis or dysarthria-clumsy hand); a number of less frequent lacunar syndromes have been described [22].
SVD ischemic strokes are overall less severe than other types of stroke during the acute phase, and are characterized by lower risk of early mortality and better functional outcome on hospital discharge. However, recurrence rates and mortality reach convergence with that of other stroke subtypes over a longer follow-up period [23, 24]. Risk rate of recurrent stroke 1 year after lacunar stroke is 5–10 % in hospital-based studies, [25–27] and 6–11 % in community-based studies [28]. In clinical trials, the annual recurrent lacunar stroke rate ranges from 3 to 10 % [29–32]. One recent study with a 12-year follow-up reported a higher mortality rate in patients with small vessel occlusion than other stroke subtypes [26]. However, the long-term outcome of these patients is not benign in terms of functional impairment [33, 34]. For this reason, lacunar stroke should be regarded as a potentially severe condition rather than a relatively benign disorder and, therefore, lacunar stroke patients require appropriately rigorous management and timely follow-up.
Pathophysiological Aspects
The pathophysiological mechanisms of SVD are largely unknown, and therefore knowledge on prevention and treatment measures is still limited. For example, it is still unclear how disease of the small vessel relates to the parenchyma lesion. Moreover, as stated above, given the frequent coexistence of different forms of SVD, all the relevant lesion types should be taken into account [1]. According to a classical view, most lacunar infarcts result from disease of small penetrating arteries. However, any etiology of brain ischemia (e.g., atherothrombosis, cardioembolism) may cause a lacunar infarct, [37–40] for example, lacunar infarcts in the pons may be caused by atherosclerosis of the basilar artery involving penetrating branches [41]. Consequently, it may be challenging to manage patients with lacunar strokes who have other potential etiologies when it is unclear if the association is simply coincidental or not.
Because it is assumed that SVD strokes have underlying pathogenic mechanisms different from those of atherosclerotic or cardioembolic strokes, one would expect distinct therapeutic and preventive approaches. However, no specific treatment for stroke caused by SVD has yet been proposed; on the other hand, there are no data that an approach with recognized evidence-based efficacy for strokes in general is not efficacious lacunar strokes in particular.
Stroke caused by SVD has rarely been the specific object of trials for secondary prevention of ischemic stroke, which generally have enrolled participants with heterogeneous stroke subtypes. Many secondary stroke prevention studies, however, have included a significant proportion of patients with SVD and some provided subtype post-hoc analysis (usually without neuroimaging verification) [42]. These data will be discussed in the following sections.
As stated above, SVD includes ischemic and hemorrhagic lesions; thus, a correct approach should consider both aspects of this pathology. Nevertheless in this chapter, because a paucity of specific data about the hemorrhagic component, we focus exclusively on secondary prevention of small vessel ischemic stroke, i.e., lacunar stroke, not including major hemorrhages and microbleeds.
Vascular Risk Factor Control in Patients with Previous Lacunar Stroke
Blood Pressure Control
Hypertension is the most prevalent and powerful modifiable risk factor for small vessel stroke and stroke in general, with an attributable risk between 35 and 50 % [43]. Reduction of blood pressure has consistently been shown to reduce stroke occurrence in multiple primary prevention studies. Lowering systolic blood pressure by 10 mmHg is associated with a 40 % reduction in stroke occurrence [44–46]. Similar benefits of blood pressure reduction are seen in secondary prevention trials. A meta-analysis of seven randomized controlled trials, including 15,527 patients with TIA or stroke randomly allocated to treatment group within 1–14 months after the event, showed that long-term blood pressure reduction reduces stroke by about 28 % [47].
One of the largest randomized placebo-controlled trials included in the meta-analysis, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), enrolled nearly 6,105 patients with stroke and TIA, 35 % of whom had lacunar strokes. The study demonstrated that a mean reduction of 9 mmHg of systolic blood pressure resulted in 28 % risk reduction in stroke (achieved systolic pressure in the active group was 138 mmHg, but the optimum target for blood-pressure control was not established) with the combination of perindopril and indapamide compared to placebo [48, 49]. In this trial, the effects of blood pressure lowering on the risk of different types of stroke were also investigated [49]. Possibly because of the smaller sample sizes within subtypes, a statistically significant effect was seen only for large artery infarction prevention, while only a trend for the active treatment to reduce the risk of lacunar stroke was outlined (23 % reduction; 95 % CI: −7–44 %) [49].
In the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial the effect of blood pressure-lowering, initiated early after a stroke, was evaluated [50]. The study used a two-by-two factorial design to compare four regimens: a combination of aspirin and extended-release dipyridamole compared with clopidogrel, and telmisartan (80 mg daily) compared with placebo. On enrollment, 52 % of patients had SVD strokes. The primary outcome of first recurrent stroke occurred in 880 SVD stroke patients (8.7 %) in the telmisartan group, as compared with 934 patients (9.2 %) in the placebo group (HR 0.95; 95 % CI: 0.86–1.04; p = 0.23). Also the type of recurrent stroke was evaluated together with the predictors of stroke recurrence, including index stroke [50]. Considering the 10,578 patients with SVD ischemic stroke at baseline, recurrent stroke was of the same subtype in 48.7 % of patients, while 19.4 % had a large artery stroke and, of note, 10.0 % had a cerebral hemorrhage [51]. In the multivariable analysis, the predictors of stroke recurrence in the SVD group were older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use [51]. Having an index SVD stroke together with older age, previous stroke, and the association treatment with aspirin and dipyridamole, was a significant predictor of cerebral hemorrhage (OR 1.71; 95 % CI: 1.20–2.45) [51].
The Secondary Prevention of Small Subcortical Strokes (SPS3) trial was the first secondary stroke prevention trial designed specifically to assess therapeutic interventions in patients with symptomatic lacunar infarcts [52]. It was designed to categorically address cerebral SVD and, so far, it is the only randomized trial that included a homogeneous cohort of patients with recent lacunar stroke [52, 53]. The study was a randomized, multicenter trial performed in 81 centers in North and Latin America and Spain between March 2003 and April 2011. Eligible participants had symptomatic lacunar infarcts without severe carotid stenosis or major cardioembolic disease. Patients with prior cortical or hemorrhagic stroke were not included. In this study, 3,020 participants were randomized at least 2 weeks after the index stroke, with a mean time to randomization of 62 days. The treatment was open label; in a two-by-two factorial design, patients were randomized to two interventions: a) antiplatelet treatment (aspirin 325 mg vs. aspirin 325 mg + clopidogrel 75 mg) and b) two target levels of systolic blood pressure control (“higher” 130–149 mmHg vs. “lower” <130 mmHg) [52, 53]. The primary outcomes of the study were the prevention of recurrent stroke (including ischemic strokes and intracranial hemorrhages) and a reduction in cognitive decline frequency. Secondary endpoints were reductions in acute myocardial infarction, need for acute admission to hospital for a major vascular event, and death classified as vascular, nonvascular, or unknown. Analysis was by intention to treat. Patients with SVD were defined on the basis of criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) [54] supplemented by MRI data. The study was of particular interest because it also took into account a cognitive outcome measure [55].
The blood pressure arm of the trial used a prospective, open-label, blinded evaluation (PROBE) design, and investigators were able to use any antihypertensive agents or combination of agents to meet the assigned targets. 1,519 patients with symptomatic lacunar infarct were allocated to the “higher” target group and 1,501 to the “lower” group [52, 53]. After 1 year, mean systolic blood pressure was 138 mmHg (95 % CI: 137–139) in the higher-target group (75 % had blood pressures within the assigned target ranges) and 127 mmHg (95 % CI: 126–128) in the lower-target group (with only 65 % of patients in the target ranges). After a mean follow-up of 3.7 years, nonsignificant rate reductions were seen for all strokes (HR 0.81; 95 % CI: 0.64–1.03; p = 0.08), disabling or fatal stroke (HR 0.81; 95 % CI: 0.53–1.23; p = 0.32), and the composite outcome of myocardial infarction or vascular death (HR 0.84; 95 % CI: 0.68–1.04; p = 0.32) in favor of the lower target. A nonsignificant 13 % reduction in the rate of recurrent lacunar stroke was seen in the lower-target group (HR 0.87; 95 % CI: 0.62–1.22; p = 0.41) compared with higher-target. Serious side effects of blood pressure therapy were infrequent (3 %) and did not differ between the two target groups.
The nonsignificant results of the SPS3 trial might be the result of good blood-pressure control in both treatment groups, the frequent use of statins, and high adherence to antiplatelet therapy. Moreover, the assignment to blood pressure targets was not masked, which could have potentially introduced a bias [52, 53]. Intracerebral hemorrhage was however reduced significantly by 63 % (HR 0.37; 95 % CI: 0.15–0.95; p = 0.03) [53]. This result is consistent with the known association between hemorrhage and hypertension. These data indicate that the patient number needed to treat (NNT) to prevent one intracerebral hemorrhage at 4 years (roughly the average follow-up in SPS3) would be 175. Although the difference in the primary end point was not statistically significant, the study hints at a reduction in stroke recurrence in the lower-blood pressure group [53].
Though the overall results of the SPS3 study did not reach statistical significance, in the context of previous trials demonstrating a benefit for stroke reduction with blood pressure treatment, the SPS3 significant reduction of intracerebral hemorrhage in the lower-target group, and the low rate of major side-effects of blood pressure lowering in both blood pressure groups, it might seem appropriate to target blood pressure reduction to a systolic pressure of 130 mmHg in patients with lacunar stroke [52, 53, 56]. At present, there is no evidence to support the preferential use of one particular antihypertensive agent or combination of agents in lacunar stroke.
Some authors argue that reducing blood pressure to lower levels may delay progression of the cerebral SVD but blood pressure levels slightly higher may sustain cerebral blood flow and potentially improve cognition. In an ongoing trial, the authors are comparing the reduction of blood pressure with usual targets and are carrying out an MRI study to assess the amount of brain damage and blood flow to the brain. The aim is to see whether one of the two treatment regimens is better at reducing brain damage and increasing blood flow to the brain to reduce cognitive problems over a 2 years period [57].
Another question is whether blood pressure should be lowered more aggressively in lacunar stroke patients with diabetes. This question has never been explored in any clinical trials. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Study, [58] the efficacy and safety of setting systolic blood-pressure targets lower than 120 mmHg in 4,733 patients with diabetes were explored. No differences in outcomes in patients allocated to target <120 mmHg systolic compared with those treated to <140 mmHg systolic was detected [58, 59]. In this population, the annual rates of stroke (a prespecified secondary outcome) were 0.32 and 0.53 % in the two groups, respectively (HR = 0.59; 95 % CI: 0.39 to 0.89; p = 0.01). However these results were based on only 100 events.
Lipid Control
Observational studies have shown a modest association between elevated total cholesterol and low-density lipoprotein cholesterol and increased risk of ischemic stroke [60, 61]. However, also for this risk factor, studies specifically addressing possible differences across stroke subtypes do not exist. It would be expected that the association and response to therapy will be stronger in patients with atherosclerotic stroke mechanisms [62, 63].
In The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, 4,731 patients with stroke or TIA and without known coronary heart disease were randomized to atorvastatin 80 mg daily or placebo [31]. The SPARCL primary end point was fatal or nonfatal stroke. In the overall population, patients allocated to atorvastatin had a significant reduction in the primary outcome (HR 0.84; 95 % CI: 0.71–0.99; p = 0.03). Regression models testing for an interaction with treatment assignment were used to explore potential differences in efficacy, based on stroke subtype [31]. In a post-hoc analysis, there was no evidence that one stroke subtype benefited selectively from statin therapy with regard to reduction of stroke or other major vascular events [64]. In particular, 29.8 % of patients (n = 1,409) were classified as having SVD, and in this patient group the primary end point occurred in 13.1 % in those treated with atorvastatin and in 15.5 % of placebo group; this difference was not statistically significant. The study showed an increased risk of hemorrhagic stroke in the group with lacunar stroke as entry event (HR 4.99; 95 % CI: 1.71–14.61) and in the overall population (HR 1.6; 95 % CI: 1.09–2.59). In the multivariate regression analysis however, risk factors for hemorrhage were male sex, increased age and stage 2 hypertension, while there was no evidence that patients with lacunar strokes faced a selectively higher rate of intra-cerebral hemorrhage when treated with atorvastatin [31, 65]. In conclusion, the SPARCL trial does not provide definitive information about the benefit of treatment with statin in SVD patients, nor does it conclusively point to harm from this treatment.
Until further studies examine the association among lacunar infarcts, hyperlipidemia, and response to statins, patients should be treated following the current recommendations on the basis of available data from the American Heart Association/American Stroke Association (AHA/ASA) [66]. Statin therapy with intensive lipid-lowering effect is recommended for secondary prevention among patients with ischemic stroke (or TIA) who have evidence of atherosclerosis, a low-density lipoprotein cholesterol-level ≥100 mg/dL, and who are without known coronary heart disease [66].
A multicenter, open-label randomized controlled trial, whose aim is to examine the role of pravastatin in the secondary prevention of stroke in Japanese patients is ongoing [67]. A total of 1,578 patients with non-cardioembolic ischemic stroke (lacunar, atherothrombotic, and infarction of undetermined etiology) were enrolled. More than 60 % of patients were included because of a lacunar infarction. This study will also evaluate the effect of pravastatin on the recurrence of each stroke subtypes [67]. Follow-ups of patients are in progress [67].
Antiplatelet Therapy for Secondary Stroke Prevention
Although the presence of thrombosis in cerebral small vessels leading to lacunar strokes has not been clearly documented, the process that results in occlusion of a small vessel might also involve platelet aggregation and thrombi formation. It is thus assumed that antithrombotic agents are beneficial in preventing stroke recurrence in lacunar stroke patients. In fact, the benefit of antiplatelet therapy in lacunar stroke patients for secondary prevention is supported by existing evidence from randomized controlled trials. As reviewed by Nakajima et al. [68], some secondary stroke prevention randomized trials, performed between 1983 and 2012 and published before the SPS3, investigated different antithrombotic agents and classified the index event by stroke mechanism [29, 69–78]. These studies provide data about secondary prevention of lacunar infarcts in 28,244 patients [68]. Despite some methodological shortcomings, such as the absence of rigorous stroke subtype definition and the lack of statistical power, the results outline a global superiority of antiplatelet therapy in comparison with placebo in preventing recurrent stroke.
Four studies have compared treatment with different antiplatelet drugs and placebo. The Canadian American Ticlopidine Study (CATS) trial compared ticlopidine with placebo in patients who had suffered from a stroke [69]. After a mean of 24 months of follow-up, the primary end-point stroke was less frequent with ticlopidine, although not significantly (relative risk reduction (RRR) = 50 %; 95 % CI: 0.76–76.0), in the 275 lacunar stroke patients [69]. Results from the Chinese Acute Stroke Trial (CAST) study, comparing aspirin and placebo for early secondary prevention (30 days after stroke), showed a nonsignificant (RRR = 10 %; 95 % CI: −0.5–1.1) in the subgroup of patients with stroke caused by SVD (n = 6,102) [70]. In the Accidents, Ischemiques Cerebraux Lies a l’Atherosclerose (AICLA), trial of aspirin plus dipyridamole versus placebo, out of 604 cerebral ischemic event, a small group of 98 (16 %) were lacunar [71]. In this group, the active treatment resulted in a RRR = 29 % (95 % CI: 2–34) [71]. In the Cilostazol Stroke Prevention Study, 1,095 patients with noncardioembolic ischemic cerebrovascular events were enrolled, and 74 % (n = 810) had a lacunar stroke. Treatment with cilostazol, a phosphodiesterase 3 inhibitor, was associated with a reduction of the risk of stroke also in lacunar stroke patients (RRR = 42 %; 95 % CI: 9.2–62.5) [72].
Six other randomized controlled trials compared different antiplatelet strategies for secondary prevention of lacunar stroke. The African American Antiplatelet Stroke Prevention Study (AAASPS) enrolled 1,809 black patients with a recent non-cardioembolic ischemic stroke, of whom 1,221 (67 %) had lacunar stroke, and randomized them to receive ticlopidine (500 mg/daily) or aspirin (650 mg/daily) [73]. The study was halted after about 6.5 years when futility analyses revealed a <1 % probability of ticlopidine to be superior to aspirin. In the ticlopidine arm the recurrent stroke was of the lacunar type in 36.2 % of cases, while in the aspirin arm the lacunar subtype accounted for 47.1 % of recurrences (p = 0.12) [73].
In the European Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT), patients were assigned to aspirin (30–325 mg daily) with or without dipyridamole (200 mg twice daily) within 6 months of a transient ischemic attack or minor stroke [74]. In patients with lacunar stroke (n = 1,377), combination therapy was not superior to aspirin alone [74].
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