Table 2

Summary of pharmacological secondary prevention strategies in patients with lacunar stroke

Secondary stroke prevention strategy interventionStudy descriptionFindingsSuggested treatment
Blood pressure reductionThe Secondary Prevention of Small Subcortical Strokes (SPS3) trial enrolled patients with lacunar stroke in the prior 180 days and randomised them to a goal systolic blood pressure (SBP) of <130 mm Hg vs 130–149 mm Hg53 SPS3 failed to show a significant reduction in recurrent stroke for a goal SBP of <130 mm Hg (HR 0.81, 95% CI 0.64 to 1.03)53 Due to the direction of effect seen in SPS3 as well as other studies with a SBP target of <120 mm Hg,54 A target SBP of <130 mm Hg in lacunar stroke patients is reasonable after hospital discharge.
Antiplatelet therapyThe SPS3 trial enrolled patients with lacunar stroke in the prior 180 days and randomised them to aspirin vs aspirin plus clopidogrel.
The trial enrolled 1879 participants with a recent non-cardioembolic stroke, of which 49% had lacunar stroke, and randomised to cilostazol 100 mg twice daily in addition to aspirin or clopidogrel vs aspirin or clopidogrel alone.55 61
SPS3 showed that aspirin monotherapy had a 1.1% yearly rate of major haemorrhage compared with a 2.1% rate for patients randomised to aspirin and clopidogrel, without a benefit of secondary stroke prevention.55
The trial showed that in the subgroup of patients with lacunar stroke (n=925), cilostazol had a HR of 0.41 (95% CI 0.21 to 0.81) for recurrent stroke.61
A meta-analysis of 17 trials stroke with 42 324 participants showed a benefit of any single antiplatelet agent in reducing the risk of any stroke (RR 0.77 95% CI 0.62 to 0.97) as well as ischaemic stroke (RR 0.48 95% CI 0.30 to 0.78) without any clear benefit of ticlodipine, cilostazol, or dipyridamole over aspirin.56
In line with stroke prevention guidelines, antiplatelet monotherapy remains the treatment of choice for long-term stroke prevention in patients with lacunar stroke.
Lipid-lowering agentsThe Stroke Prevention by Aggressive Reduction of Cholesterol Levels stroke (SPARCL) trial tested atorvastatin 80 mg vs placebo in patients a recent stroke or TIA with low-density lipoprotein levels stroke >100 mg/dL.57 Atorvastatin 80 mg daily reduced the risk of recurrence (HR 0.84 95% CI 0.71 to 0.99, p=0.03), without any heterogeneity across stroke subtypes including small vessel disease. In SPARCL patients whose stroke was attributed to small vessel disease, there was a non-significantly lower rate of recurrent stroke during follow-up in patients randomised to atorvastatin vs placebo (13.1% vs 15.5%). Furthermore, there was an increased haemorrhage (ICH) risk with high intensity statin therapy seen in SPARCL.While the increased ICH risk with statin use was not seen in other studies,58 the benefit of high intensity statin therapy for secondary stroke prevention in patients with lacunar stroke should be carefully weighed against the ICH risk as it remains unknown whether the possible ICH risk with statin use is potentiated in the presence of cerebral small vessel disease.
Glycaemic controlPost hoc analysis of SPS3 investigating the association between diabetes and recurrent stroke risk.Patients with diabetes mellitus were had a higher risk of recurrent ischaemic stroke (HR, 1.8; 95% CI 1.4 to 2.4), and death (HR, 2.1 95% CI 1.6 to 2.8) compared with patients without diabetes mellitus.Glycaemic control might be potentially beneficial in reducing stroke risk.
Treatment of insulin resistanceThe insulin resistance in stroke (IRIS) trial randomised patients with a recent ischaemic stroke or TIA and evidence of insulin resistance but no diabetes to pioglitazone vs placebo.59 Pioglitazone was associated with reduced risk of incident lacunar stroke (HR 0.46 95% CI 0.22 to 0.93, p=0.03). There was no significant heterogeneity in the effect of pioglitazone on the risk of stroke based on index ischaemic stroke subtype.60
In the IRIS trial, pioglitazone was associated with increased frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs 33.7%, p<0.001), oedema (35.6% vs 24.9%, p<0.001), and bone fracture requiring surgery or hospitalisation (5.1% vs 3.2%, p=0.003).
In patients with insulin resistance, but without diabetes, insulin sensitising agents may be considered to reduce the risk of recurrence. The side effect profile of these drugs including bone fractures and oedema should be weighed against the potential benefit, however.