typical in lacunar stroke.¹⁰⁵ This deterioration is referred to variously as early neurological deterioration (END), progressive stroke, progressing stroke, stuttering onset, or capsular warning syndrome (CWS); we use the term 'progressive lacunar stroke'.

‘Progressive lacunar stroke’ is defined quite variably, including as an increase in NIHSS of ≥2 points within 72 h¹⁰⁶,¹⁰⁷ or ≥3 points in total and ≥2 points for limb paresis within 5 days,¹⁰⁸ or ≥4 in total,¹⁰⁹,¹¹⁰ or ≥2 by 48 h¹¹¹ or the seventh day after admission,¹¹² or ≥1 within 5 days of onset,¹¹³,¹¹⁴ or ≥1¹¹⁵,¹¹⁶ in the NIHSS, or ‘any persistent neurological worsening’.¹¹⁷ Capsular warning syndrome (‘capsular’ or ‘stroke warning syndrome’) is variously defined as ‘≥3¹¹⁸⁻¹²¹ or ≥2¹²² stereotyped episodes of lacunar symptoms within 24, 48, or 72 h, with complete neurological resolution between episodes’. ‘Stuttering’ or ‘fluctuating’ lacunar syndrome is defined as ‘neurologic deficit’ with periods of improvement and worsening (with or without full resolution).¹²³

Progressive or stuttering stroke and capsular warning syndrome should be differentiated from early recurrent stroke occurring in the first few days since the mechanism and treatment implications may be different. Progressive stroke is a gradual deterioration whereas early recurrent stroke causes a sudden deterioration in neurological status or different neurological symptoms (indicating different brain region) to those of the initial stroke.

*Frequency, risk factors, outcomes:* Stuttering onset, capsular warning syndrome or progressive worsening of symptoms occur in 20%–36% of patients with lacunar clinical syndrome in the hours to days after first symptom onset.¹⁰⁵,¹²⁴ Risk factors such as motor paresis,¹⁰⁵,¹⁰⁸ larger infarct volume,¹⁰⁸,¹²⁴ more severe stroke at admission,¹⁰¹ worse perfusion in the infarct,¹⁰⁵,¹⁰⁶ more proximal location in the internal capsule or basal ganglia and larger diameter¹⁰⁷,¹⁰⁸ seem fairly consistent between studies. Other risk factors such as male sex,¹⁰⁵,¹⁰⁸ or older age¹⁰⁸ are variable. It is not consistently associated with BP,¹⁰⁵ hypertension, or cardiac embolic sources¹⁰⁴,¹⁰⁵,¹²⁴ An apparent association with D-dimer, thrombin and fibrin formation¹²⁵ may suggest a stuttering thrombotic process. Progressive stroke is associated with worse functional outcomes possibly reflecting the frequent occurrence in patients with motor symptoms.¹⁰⁵,¹⁰⁹,¹¹⁷

The systematic literature search identified 567 titles/abstracts, of which 45 were duplicates (Supplemental PRISMA diagrams). Of the remaining 522, 21 were selected for full text review and of these six were selected for extraction. Some additional papers were identified during searches for the other PICOs and further articles were identified in reviews or other sources.

This provided two randomised trials both testing anti-platelet drugs (cilostazol,¹⁰⁹ clopidogrel¹¹²), plus three prospective observational studies, 14 retrospective observational studies, two case series, one case report (Supplemental

Tables 7 and 8) and one review.¹⁰⁵ The two randomised trials were too different to perform a meta-analysis but we were able to calculate ORs for progressive stroke and mRS.

## Analysis of Current Evidence

*Randomised Trials:* We found two RCTs that assessed interventions to reduce progressive stroke that included patients with lacunar stroke, but unfortunately in both trials, lacunar stroke was a subset (albeit > 50%) of the population, and neither trial reported outcomes including mRS for the lacunar group alone (Supplemental Table 7, Table 4). There were therefore no published RCTs assessing directly the effect of any interventions in progressive lacunar ischaemic stroke on the stated PICO outcomes.

One pilot multicentre RCT¹⁰⁹ (Table 4a) in 55 sites in Japan, randomised 510 non-cardioembolic progressive stroke patients (mean age 63) including 343 with lacunar stroke subtype, to cilostazol versus no cilostazol, open label. All patients received Japanese guideline treatment including antiplatelet or an antithrombin agent. Cilostazol was started within 24 h and continued for 3 months. The outcome was the rate of progressive stroke defined as ≥4pt on NIHSS on day 3 and/or 5, and mRS 0–1 at 3 months, but the authors only reported the rate of progressive stroke in the lacunar subgroup, and we were unable to obtain additional information from the authors. In 343 patients with lacunar stroke, 7/154 (3.2%) allocated cilostazol and 9/175 (6.3%) allocated no cilostazol experienced progression (OR 0.869, 95% CI 0.304, 2.386, *p*=0.143). mRS 0–2 was reported for all 507 patients (of which lacunar made up 68%) did not differ between cilostazol and no cilostazol (221/251, 88.1%, vs 217/256. 84.8%, OR 1.32, 95% CI 0.79, 2.21). There were several sources of bias: the method of randomisation was not given, the trial was open label, it is unclear if follow-up was blinded, and the guideline treatment was heterogeneous.

The other RCT¹¹² (Supplemental Table 7, Table 4b) in Japan enrolled 54 patients with lacunar infarcts (n=29) or branch atheromatous disease (n=23) within 48 h of stroke and randomised 28 to argatroban, aspirin and clopidogrel (AAC) and 26 to argatroban and aspirin (AA) and therefore is a trial of clopidogrel versus no clopidogrel on a background of argatroban and aspirin. The outcomes were progressive stroke, defined as worsening of ≥ 2 NIHSS on the seventh day of admission, and mRS at 3 months, but neither outcome was reported for the lacunar stroke group alone. There were fewer progressive strokes in the AAC group than in the AA group (0 [0%] versus 4 [16%] *p*=0.04) but no difference in dependency (mRS 3–6) at 3 months (AAC 6 [21%] vs AA 8 [32%], *p*=0.53). Sources of bias included randomisation by sealed envelope, open label and follow-up by hospital staff (blinding not mentioned).

We found one entry in a trial registry (UMIN-CTR Clinical Trial) for a RCT of cilostazol + aspirin versus aspirin started within 48 h of symptom onset and continued for
<table><caption>**Table 4.** GRADE evidence profile for PICO 4.</caption><thead><tr><th colspan="4">Certainty assessment</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th colspan="2">Certainty</th><th>Importance</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirectness</th><th>Imprecision</th><th>Cilostazol + standard care treatment</th><th>No cilostazol + standard care treatment</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th><th></th><th></th></tr></thead><tbody><tr><td colspan="11"><strong>a) Shimizu et al.<sup>109</sup></strong></td></tr><tr><td colspan="11">Good outcome (mRS 0-2 at 90 days) all patients (approx 68% were lacunar stroke)</td></tr><tr><td>I</td><td>Randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>22/1/25 (88.1%)</td><td>21/7/256 (84.8%)</td><td>OR 1.32 (0.79, 2.21)</td><td>33 more per 1000 (from 33 fewer to 77 more)</td><td>⊕⊕⊕ Very low</td><td>CRITICAL</td></tr><tr><td colspan="11"><strong>Progressive symptoms (≥4-point increase on NIHSS) in the subgroup (n=343) with lacunar ischaemic stroke</strong></td></tr><tr><td>I</td><td>Randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>7/1/54 (4.5%)</td><td>9/1/73 (5.2%)</td><td>OR 0.87 (0.32, 2.39)</td><td>6 fewer per 1000 (from 35 fewer to 64 more)</td><td>⊕⊕⊕ Very low</td><td>CRITICAL</td></tr><tr><td colspan="11"><strong>b) Nishi et al.<sup>112</sup></strong></td></tr><tr><td colspan="11">Good outcome (mRS 0-2 at 90 days) all patients (29 lacunar stroke, 23 BAD)</td></tr><tr><td>I</td><td>randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>22/2/8 (78%)</td><td>17/2/5 (68%)</td><td>OR 1.73 (0.50, 5.92)</td><td>106 more per 1000 (from 165 fewer to 246 more)</td><td>⊕⊕⊕ very low</td><td>CRITICAL</td></tr><tr><td colspan="11"><strong>Progressive symptoms (≥2 point increase on NIHSS) all patients (29 lacunar stroke, 23 BAD)</strong></td></tr><tr><td>I</td><td>randomised trial</td><td>serious<sup>a</sup></td><td>not serious</td><td>serious</td><td>serious<sup>b</sup></td><td>none</td><td>0/2/8 (0.0%)</td><td>4/2/6 (15.4%)</td><td>OR 0.09 (0.00, 1.72)</td><td>138 fewer per 1000 (from - to 84 more)</td><td>⊕⊕⊕ very low</td><td>CRITICAL</td></tr></tbody></table>

BAD: branch atheromatous disease; CI: confidence interval; OR: odds ratio. Unfortunately data were not available for either outcome for just the lacunar stroke subgroup. Explanations.

<footnote>aOpen-label trial.</footnote>

<footnote>bConfidence interval crosses the clinical decision threshold and optimal information size not met.</footnote>
<table><caption>**Table 4.** GRADE evidence profile for PICO 4.</caption><thead><tr><th colspan="4">Certainty assessment</th><th colspan="2">No of patients</th><th colspan="2">Effect</th><th colspan="2">Certainty</th><th colspan="2">Importance</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirectness</th><th>Imprecision</th><th>Other considerations</th><th>Cilostazol + standard care treatment</th><th>No cilostazol + standard care treatment</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th><th></th><th></th></tr></thead><tbody><tr><td colspan="12"><strong>a) Shimizu et al.<sup>109</sup></strong></td></tr><tr><td colspan="12">Good outcome (mRS 0–2 at 90 days) all patients (approx 68% were lacunar stroke)</td></tr><tr><td>I</td><td>Randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>22/125 (88.1%)</td><td>21/7256 (84.8%)</td><td>OR 1.32 (0.79, 2.21)</td><td>33 more per 1000 (from 33 fewer to 77 more)</td><td>⊕⊕⊕ Very low</td><td>CRITICAL</td></tr><tr><td colspan="12"><strong>Progressive symptoms (≥4-point increase on NIHSS) in the subgroup (n = 343) with lacunar ischaemic stroke</strong></td></tr><tr><td>I</td><td>Randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>7/154 (4.5%)</td><td>9/173 (5.2%)</td><td>OR 0.87 (0.32, 2.39)</td><td>6 fewer per 1000 (from 35 fewer to 64 more)</td><td>⊕⊕⊕ Very low</td><td>CRITICAL</td></tr><tr><td colspan="12"><strong>b) Nishi et al.<sup>112</sup></strong></td></tr><tr><td colspan="12">Good outcome (mRS 0–2 at 90 days) all patients (29 lacunar stroke, 23 BAD)</td></tr><tr><td>I</td><td>randomised trial</td><td>Serious<sup>a</sup></td><td>Not serious</td><td>Serious</td><td>Serious<sup>b</sup></td><td>None</td><td>22/28 (78%)</td><td>17/25 (68%)</td><td>OR 1.73 (0.50, 5.92)</td><td>106 more per 1000 (from 165 fewer to 246 more)</td><td>⊕⊕⊕ very low</td><td>CRITICAL</td></tr><tr><td colspan="12"><strong>Progressive symptoms (≥2 point increase on NIHSS) all patients (29 lacunar stroke, 23 BAD)</strong></td></tr><tr><td>I</td><td>randomised trial</td><td>Serious<sup>a</sup></td><td>not serious</td><td>serious</td><td>serious<sup>b</sup></td><td>none</td><td>0/28 (0.0%)</td><td>4/26 (15.4%)</td><td>OR 0.09 (0.00, 1.72)</td><td>138 fewer per 1000 (from – to 84 more)</td><td>⊕⊕⊕ very low</td><td>CRITICAL</td></tr></tbody></table>

BAD: branch atheromatous disease; CI: confidence interval; OR: odds ratio. Unfortunately data were not available for either outcome for just the lacunar stroke subgroup. Explanations.

<footnote><sup>a</sup>Open-label trial.</footnote>

<footnote><sup>b</sup>Confidence interval crosses the clinical decision threshold and optimal information size not met.</footnote>
14 days to prevent progressive symptoms in lacunar stroke in Japan with outcomes including NIHSS and Barthel Index at 14 days (C000000454, Terayami et al, 2006), but could not find any results.

## Additional information

The 19 observational studies (Supplemental Table 8) included various types of progressive lacunar stroke, were mostly retrospective, or prospective with historical controls, and tested several different interventions: antiplatelets (DAPT 3; cilostazol 2; tirofiban 2; abciximab 2), rt-PA (5), heparin (2), BP lowering (valsartan +/- indapamide 1), BP raising (phenylephrine 2), statin (1). Outcomes also varied: 11 retrospective, one prospective observational study and two case series reported outcomes of mRS, NIHSS, haemorrhagic stroke or recurrent stroke (majority used mRS); the other four retrospective and one prospective study used the outcome of progressive stroke.

The heterogeneity of patients, interventions, outcomes and the low quality of evidence provided by retrospective or prospective studies as regards interventions, makes it very difficult to summarise these data. However, considering the larger studies (n > 50), commoner interventions (antiplatelet, rt-PA, phenylephrine), outcomes (mRS, progression) and ignoring whether the studies were retro- or prospective, we derived the following summary.

**DAPT versus no DAPT**<sup>108,126</sup>: in 458 patients with lacunar stroke, amongst whom 130 patients developed early neurological deterioration, amongst the 97 who received DAPT, mostly for 5 days versus the 33 who did not receive DAPT, NIHSS was better at discharge than admission (68% vs 35%, *p*=0.002), fluctuations were fewer (absent in 79% vs 33%, *p*<0.001) but there was no difference in mRS at discharge (80% vs 73%, *p*=0.46).

**Cilostazol versus aspirin**<sup>111</sup>: In 453 patients with lacunar stroke or branch atheromatous disease, amongst those who received cilostazol versus historical controls who received aspirin, there were fewer episodes of early neurological deterioration (18.5% vs 31.4%, *p*=0.002), and lower mean mRS at 1 month (1.9 SD ± 1.5 vs 2.3 SD ± 1.5, *p*=0.011).

**Alteplase versus no alteplase**<sup>117,121</sup>: In 72 patients with capsular warning syndrome,<sup>121</sup> IV alteplase versus no IV alteplase did not improve mRS 0–2 at 3 months (IV alteplase: 23 [85%] versus no IV alteplase: 38 [84%], *p*=0.993). In 100 patients with anterior choroidal artery ischaemic stroke of whom 46 progressed,<sup>117</sup> 12/21 who progressed, versus 9/54 who did not progress, received alteplase (*p*=0.3) but patients who progressed had more severe strokes at admission.

**Intensive BP lowering**: One study<sup>114</sup> in 119 patients with lacunar stroke confirmed on MRI (<20 mm in DWI) and SBP≥160 mmHg, tested intensive BP lowering with valsartan +/- indapamide (to SBP goal <180 mmHg during

the first 7 days after admission, <160 mmHg days 7–14, and <140 mmHg after day 14), vs historical controls with BP managed according to usual targets. BP was similar between groups in the first 14 days with no difference in progression of motor symptoms (intensive vs control: 14 [24%] vs 16 [27%], *p*=0.87).

**Phenylephrine to elevate BP**: two studies tested phenylephrine to elevate BP in patients with lacunar stroke and progressive motor symptoms (n = 82,<sup>115</sup> 66<sup>116</sup>) on NIHSS and mRS. Amongst patients who received phenylephrine, mean NIHSS at discharge was lower (1.1 SD 1.47 vs 1.86 SD 1.92, *p*=0.042<sup>115</sup>; 4.4 ± 2.5 vs 6.0 ± 3.7, *p* = 0.036<sup>116</sup>) and more patients were independent (mRS 0–2) at discharge (62% vs 50%, *p*=0.044)<sup>115</sup> or at 3 months (18 [72%] vs 15 [36.6%], *p*=0.011).<sup>116</sup> However many patients given phenylephrine did not achieve target BP,<sup>115</sup> and many patients who did not receive phenylephrine had higher systolic BPs than those who were given phenylephrine.<sup>116</sup>

**Cilostazol±edaravone versus other drugs** (argatroban, ozagrelsodium, urokinase)<sup>113</sup>: in 218 patients with large lacunar infarcts, cilostazol+edaravone did not reduce motor progression (int. vs control: 49 [49%] vs 55 [47%], *p*=0.83).

**Statins**<sup>110</sup>: (published in abstract but with details of results) amongst 277 patients with lacunar stroke of whom 24 had early neurological deterioration, in a retrospective analysis of DAPT, anticoagulation and statins, more patients without early neurological deterioration (41.9%) received early statin intervention (newly initiated, dose escalation, or switching to a strong statin) than did patients with early neurological deterioration (20.8%), and statin use was associated with less early neurological deterioration in a multivariate model (OR 0.22, 95% CI 0.06, 0.68, *p*<0.01).

One ongoing multicentre trial in France, Induced hypertension in acute PRogrESSive perforating artery Stroke Using peripheral dilute norepinephrine, PHRC-21-0096 (PRESSURE, NCT06059144) in 358 patients with progressive lacunar ischaemic stroke, may provide further evidence in future on the benefit or harm of drug-induced hypertension on functional independence at 90 days.

Progressive symptoms lead to worse outcome after lacunar stroke but estimates of frequency vary, likely due to varying definitions amongst other factors.

The evidence base on interventions is very limited, mostly made up of retrospective studies or prospective studies that use historical controls.

There is no evidence to recommend any particular antiplatelet, BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment for progressive lacunar stroke that is different to treatment for lacunar stroke in the acute phase without progressive symptoms as described in PICOs 1–3 and 5.

While it is clear that more high-quality trials are needed in progressive lacunar stroke, this should not take
14 days to prevent progressive symptoms in lacunar stroke in Japan with outcomes including NIHSS and Barthel Index at 14 days (C000000454, Terayami et al, 2006), but could not find any results.

## Additional information

The 19 observational studies (Supplemental Table 8) included various types of progressive lacunar stroke, were mostly retrospective, or prospective with historical controls, and tested several different interventions: antiplatelets (DAPT 3; cilostazol 2; tirofiban 2; abciximab 2), rt-PA (5), heparin (2), BP lowering (valsartan +/- indapamide 1), BP raising (phenylephrine 2), statin (1). Outcomes also varied: 11 retrospective, one prospective observational study and two case series reported outcomes of mRS, NIHSS, haemorrhagic stroke or recurrent stroke (majority used mRS); the other four retrospective and one prospective study used the outcome of progressive stroke.

The heterogeneity of patients, interventions, outcomes and the low quality of evidence provided by retrospective or prospective studies as regards interventions, makes it very difficult to summarise these data. However, considering the larger studies (n > 50), commoner interventions (antiplatelet, rt-PA, phenylephrine), outcomes (mRS, progression) and ignoring whether the studies were retro- or prospective, we derived the following summary.

**DAPT versus no DAPT**<sup>108,126</sup>: in 458 patients with lacunar stroke, amongst whom 130 patients developed early neurological deterioration, amongst the 97 who received DAPT, mostly for 5 days versus the 33 who did not receive DAPT, NIHSS was better at discharge than admission (68% vs 35%, *p*=0.002), fluctuations were fewer (absent in 79% vs 33%, *p*<0.001) but there was no difference in mRS at discharge (80% vs 73%, *p*=0.46).

**Cilostazol versus aspirin**<sup>111</sup>: In 453 patients with lacunar stroke or branch atheromatous disease, amongst those who received cilostazol versus historical controls who received aspirin, there were fewer episodes of early neurological deterioration (18.5% vs 31.4%, *p*=0.002), and lower mean mRS at 1 month (1.9 SD ± 1.5 vs 2.3 SD ± 1.5, *p*=0.011).

**Alteplase versus no alteplase**<sup>117,121</sup>: In 72 patients with capsular warning syndrome,<sup>121</sup> IV alteplase versus no IV alteplase did not improve mRS 0–2 at 3 months (IV alteplase: 23 [85%] versus no IV alteplase: 38 [84%], *p*=0.993). In 100 patients with anterior choroidal artery ischaemic stroke of whom 46 progressed,<sup>117</sup> 12/21 who progressed, versus 9/54 who did not progress, received alteplase (*p*=0.3) but patients who progressed had more severe strokes at admission.

**Intensive BP lowering**: One study<sup>114</sup> in 119 patients with lacunar stroke confirmed on MRI (<20 mm in DWI) and SBP≥160 mmHg, tested intensive BP lowering with valsartan +/- indapamide (to SBP goal <180 mmHg during

the first 7 days after admission, <160 mmHg days 7–14, and <140 mmHg after day 14), vs historical controls with BP managed according to usual targets. BP was similar between groups in the first 14 days with no difference in progression of motor symptoms (intensive vs control: 14 [24%] vs 16 [27%], *p*=0.87).

**Phenylephrine to elevate BP**: two studies tested phenylephrine to elevate BP in patients with lacunar stroke and progressive motor symptoms (n = 82,<sup>115</sup> 66<sup>116</sup>) on NIHSS and mRS. Amongst patients who received phenylephrine, mean NIHSS at discharge was lower (1.1 SD 1.47 vs 1.86 SD 1.92, *p*=0.042<sup>115</sup>; 4.4 ± 2.5 vs 6.0 ± 3.7, *p* = 0.036<sup>116</sup>) and more patients were independent (mRS 0–2) at discharge (62% vs 50%, *p*=0.044)<sup>115</sup> or at 3 months (18 [72%] vs 15 [36.6%], *p*=0.011).<sup>116</sup> However many patients given phenylephrine did not achieve target BP,<sup>115</sup> and many patients who did not receive phenylephrine had higher systolic BPs than those who were given phenylephrine.<sup>116</sup>

**Cilostazol±edaravone versus other drugs** (argatroban, ozagrelsodium, urokinase)<sup>113</sup>: in 218 patients with large lacunar infarcts, cilostazol+edaravone did not reduce motor progression (int. vs control: 49 [49%] vs 55 [47%], *p*=0.83).

**Statins**<sup>110</sup>: (published in abstract but with details of results) amongst 277 patients with lacunar stroke of whom 24 had early neurological deterioration, in a retrospective analysis of DAPT, anticoagulation and statins, more patients without early neurological deterioration (41.9%) received early statin intervention (newly initiated, dose escalation, or switching to a strong statin) than did patients with early neurological deterioration (20.8%), and statin use was associated with less early neurological deterioration in a multivariate model (OR 0.22, 95% CI 0.06, 0.68, *p*<0.01).

One ongoing multicentre trial in France, Induced hypertension in acute PRogrESSive perforating artery Stroke Using peripheral dilute norepinephrine, PHRC-21-0096 (PRESSURE, NCT06059144) in 358 patients with progressive lacunar ischaemic stroke, may provide further evidence in future on the benefit or harm of drug-induced hypertension on functional independence at 90 days.

Progressive symptoms lead to worse outcome after lacunar stroke but estimates of frequency vary, likely due to varying definitions amongst other factors.

The evidence base on interventions is very limited, mostly made up of retrospective studies or prospective studies that use historical controls.

There is no evidence to recommend any particular antiplatelet, BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment for progressive lacunar stroke that is different to treatment for lacunar stroke in the acute phase without progressive symptoms as described in PICOs 1–3 and 5.

While it is clear that more high-quality trials are needed in progressive lacunar stroke, this should not take
precedence over the major need for high quality trials in all suspected acute lacunar ischaemic stroke.

We therefore suggest that patients with suspected lacunar ischaemic stroke and progressive symptoms should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup. There is also an urgent need to agree a consensus definition for progressive lacunar ischaemic stroke.

**Evidence-based Recommendation**

There is continued uncertainty regarding intervention with antiplatelets, anticoagulants, thrombolysis or other agents in patients with suspected lacunar ischaemic stroke and progressive symptoms, including early neurological deterioration, stuttering/fluctuating symptoms and capsular warning syndrome.

Quality of evidence: Very low

Strength of recommendation: -

**Expert Consensus Statement 1**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms there is no evidence to recommend any particular antiplatelet regimen (intensive or single), BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment.

**Expert Consensus Statement 2**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, they should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup.

**Expert Consensus Statement 3**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is an urgent need to agree a consensus definition for progressive symptoms.

PICO 4 Risk of bias of randomised controlled trials (outcome: mRS and progressive stroke)

<figure><img src="image_12.png" /></figure>

PICO 5:

In patients with suspected acute lacunar ischaemic stroke, does acute treatment with other agents such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline),

anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase 5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

Analysis of current evidence

The systematic literature searches for PICO 5 and 10 were performed together (Supplement PRISMA diagrams). The search identified 248 titles/abstracts. Of these, 46 articles were selected for full-text review, and 8 were selected for data extraction.<sup>46,127-132</sup> Three additional articles were identified by the searches in other PICO questions.<sup>131-135</sup> After reference screening of reviews, we added another 2 RCTs.<sup>131,136</sup> This delivered 13 RCTs, of which 7 were assigned to PICO 5.

For PICO 5, we ordered the text according to agent. We found two studies on intravenous Magnesium. Due to the heterogeneity of outcomes, the data were not suitable for pooling. We found one study on cilostazol, two studies on anticoagulation, one on glyceryl trinitrate and one on Xueshuantong (Chinese medicinal herb). These are summarised in Supplemental Table 9.

**Magnesium.** Magnesium has been studied as a neuroprotective agent, although the exact mechanism remains uncertain and may be multimodal.<sup>137</sup> Amongst others, magnesium acts as an NMDA glutamate receptor antagonist, blocks calcium cell entry and exhibits cardiovascular effects.

One randomised placebo-controlled, double-blinded trial (IMAGES, 2004) included 2386 previously independent patients with acute ischaemic stroke, in which study treatment could be started within 12h of stroke onset.<sup>138</sup> Of these, 765 patients (32%) had a clinical lacunar stroke syndrome. Patients received intravenous magnesium (4g bolus followed by 16g over 24h) or placebo. The primary outcome was a joint binary outcome of death and disability at 90days, in which Barthel score and mRS were combined. In the whole cohort, the primary outcome was not improved by magnesium (OR 0.95, 95% CI 0.80, 1.13, *p*=0.59). A post-hoc analysis identified patients with lacunar syndrome as a potential subgroup that could benefit from magnesium (common OR 0.70, 95% CI 0.53, 0.92). However, the study was performed between 1997 and 2003 and major changes in acute stroke management occurred since then, like iv-thrombolysis (proportion in the trial not mentioned), stroke unit care and early start of antiplatelet therapy. Furthermore, although the trial aimed at including ischaemic stroke, imaging was not required before trial entry resulting in 8.9% primary haemorrhage among the lacunar stroke syndrome subjects.<sup>139</sup> Therefore, we think the results of this study are hardly generalisable to the lacunar stroke population in current clinical practice.
precedence over the major need for high quality trials in all suspected acute lacunar ischaemic stroke.

We therefore suggest that patients with suspected lacunar ischaemic stroke and progressive symptoms should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup. There is also an urgent need to agree a consensus definition for progressive lacunar ischaemic stroke.

**Evidence-based Recommendation**

There is continued uncertainty regarding intervention with antiplatelets, anticoagulants, thrombolysis or other agents in patients with suspected lacunar ischaemic stroke and progressive symptoms, including early neurological deterioration, stuttering/fluctuating symptoms and capsular warning syndrome.

Quality of evidence: Very low

Strength of recommendation: -

**Expert Consensus Statement 1**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms there is no evidence to recommend any particular antiplatelet regimen (intensive or single), BP management regimen (raising or lowering), rt-PA, anticoagulation, statin, or other treatment.

**Expert Consensus Statement 2**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, they should be included in all trials in acute lacunar ischaemic stroke but identified as a specific subgroup with prespecified planned analysis of the treatment effect in this subgroup.

**Expert Consensus Statement 3**

Twelve of 12 MWG members agreed that in patients with suspected lacunar ischaemic stroke and progressive symptoms, there is an urgent need to agree a consensus definition for progressive symptoms.

PICO 4 Risk of bias of randomised controlled trials (outcome: mRS and progressive stroke)

<figure><img src="image_12.png" /></figure>

PICO 5:

In patients with suspected acute lacunar ischaemic stroke, does acute treatment with other agents such as phosphodiesterase-3 inhibitors (e.g. cilostazol, pentoxifylline),

anti-inflammatory agents (e.g. minocycline), anticoagulants, nitric oxide donors (e.g. transdermal glyceryl trinitrate), phosphodiesterase 5 inhibitors (sildenafil, tadalafil, dipyridamole), or other relevant agents not addressed in the other PICOs, compared to less intense or avoiding this intervention, reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

Analysis of current evidence

The systematic literature searches for PICO 5 and 10 were performed together (Supplement PRISMA diagrams). The search identified 248 titles/abstracts. Of these, 46 articles were selected for full-text review, and 8 were selected for data extraction.<sup>46,127-132</sup> Three additional articles were identified by the searches in other PICO questions.<sup>131-135</sup> After reference screening of reviews, we added another 2 RCTs.<sup>131,136</sup> This delivered 13 RCTs, of which 7 were assigned to PICO 5.

For PICO 5, we ordered the text according to agent. We found two studies on intravenous Magnesium. Due to the heterogeneity of outcomes, the data were not suitable for pooling. We found one study on cilostazol, two studies on anticoagulation, one on glyceryl trinitrate and one on Xueshuantong (Chinese medicinal herb). These are summarised in Supplemental Table 9.

**Magnesium.** Magnesium has been studied as a neuroprotective agent, although the exact mechanism remains uncertain and may be multimodal.<sup>137</sup> Amongst others, magnesium acts as an NMDA glutamate receptor antagonist, blocks calcium cell entry and exhibits cardiovascular effects.

One randomised placebo-controlled, double-blinded trial (IMAGES, 2004) included 2386 previously independent patients with acute ischaemic stroke, in which study treatment could be started within 12h of stroke onset.<sup>138</sup> Of these, 765 patients (32%) had a clinical lacunar stroke syndrome. Patients received intravenous magnesium (4g bolus followed by 16g over 24h) or placebo. The primary outcome was a joint binary outcome of death and disability at 90days, in which Barthel score and mRS were combined. In the whole cohort, the primary outcome was not improved by magnesium (OR 0.95, 95% CI 0.80, 1.13, *p*=0.59). A post-hoc analysis identified patients with lacunar syndrome as a potential subgroup that could benefit from magnesium (common OR 0.70, 95% CI 0.53, 0.92). However, the study was performed between 1997 and 2003 and major changes in acute stroke management occurred since then, like iv-thrombolysis (proportion in the trial not mentioned), stroke unit care and early start of antiplatelet therapy. Furthermore, although the trial aimed at including ischaemic stroke, imaging was not required before trial entry resulting in 8.9% primary haemorrhage among the lacunar stroke syndrome subjects.<sup>139</sup> Therefore, we think the results of this study are hardly generalisable to the lacunar stroke population in current clinical practice.
A smaller trial with similar design (2013) included 107 patients with acute ischaemic stroke and symptoms less than 12h, of which 41 (38%) had a lacunar syndrome.¹⁴⁰ Patients were randomised between intravenous magnesium or placebo. Primary outcome was the NIHSS score at 90 days, which was different between the two groups (magnesium 4.7 ± 5.0 vs placebo 7.2 ± 5.7; *p*=0.032). In patients with lacunar syndrome, NIHSS was 1.6 ± 1.4 in the Mg group versus 3.3 ± 1.9 in the placebo group (*p*=0.003). The clinical relevance of this difference is uncertain. Secondary outcomes (mRS and mortality at 90 days) were not reported for the subgroup of lacunar stroke.

**Cilostazol.** We identified no cilostazol trials with relevant clinical outcomes that reported specific results for patients with acute lacunar ischaemic stroke. The ECLIPse trial¹³⁶ randomised 103 patients with acute lacunar stroke to either cilostazol plus aspirin or placebo plus aspirin for a duration of 90 days.¹³⁶ The median time from symptom onset to randomisation was 5 days, and 78% of patients were randomised within 7 days. The primary outcome was pulsatility index on Doppler ultrasound, a non-clinical measure, but recurrent ischaemic stroke within 90 days was reported as a secondary outcome: it occurred in one patient in both groups.

**Glyceryl trinitrate.** Nitric oxide (NO) donors such as Glyceryl trinitrate (GTN) are candidate treatments for acute lacunar stroke because of several effects. NO is a cerebral and systemic vasodilator that lowers blood pressure, and has antiplatelet and neuroprotective properties.¹⁴¹

The Efficacy of Nitric Oxide in Stroke (ENOS) trial randomised 4011 patients with acute ischaemic or haemorrhagic stroke within 48h of onset between transdermal GTN 5mg or placebo during 7 days.⁷⁴,¹⁴² The recruitment took over 12 years (2001–2013). 623 (15%) patients had a clinical lacunar stroke syndrome with a compatible CT or MRI scan (acute lacunar infarct or no visible lesion), and 143 had an imaging confirmed lacunar infarct. GTN had no effect on mRS score at 90 days in patients with clinical lacunar stroke syndrome and compatible scan (OR 1.09, 95% CI 0.82, 1.45) nor in those with confirmed lacunar infarction (OR 1.00, 95% CI 0.53, 1.87). The effect on cognition and mood was neutral (not published; personal communication). Of note, the ENOS trial was also included in the analysis of PICO 3 on immediate antihypertensive treatment in acute lacunar stroke.

Based on this one trial, with low risk of bias, which could not show a positive effect on functional outcome, we suggest against the use of GTN in patients with suspected acute lacunar stroke.

**Anticoagulation.** We found two trials on low molecular weight (LMW) heparin or heparinoid, conducted between

1990 and 2000, which presented prespecified results on acute lacunar stroke subgroups. TOAST was a randomised placebo-controlled trial of danaparoid, an LMW heparinoid given in a 7-day course, in acute ischaemic stroke of which 24% were reported to be of lacunar subtype.¹³³ Treatment with danaparoid was not associated with improvement in favourable functional outcome at 90 days in the total group, nor the lacunar subtype. TAIST was a randomised aspirin-controlled trial testing medium or high dose tinzaparin, an LMW heparin, within 48h of acute ischaemic stroke and given for up to 10 days. It included 40% lacunar stroke sub-types.¹³⁴ Tinzaparin in medium or high dose did not improve functional outcome at 180 days compared with aspirin in the whole group, and this result was not different in the lacunar stroke subtype.

Nowadays, there is ample evidence to start antiplatelet therapy as soon as possible after acute ischaemic stroke, and, referring to PICO 2, consensus that this also applies to acute lacunar stroke, resulting in a recommendation against the use of therapeutic LMW heparin or heparinoid in patients with acute lacunar stroke.

**Xueshuantong.** Xueshuantong is an extraction from a Chinese medicinal herb with an anti-inflammatory effect, administered intravenously. One small randomised non-placebo controlled trial in elderly Chinese patients with acute lacunar stroke reported significant more reduction in NIHSS score between admission and discharge after 4 weeks of treatment with Xueshuantong compared to no treatment.¹³⁵ Exact results were not reported, but reading from the figures, the difference in NIHSS score reduction between both groups seemed less than 1. The quality of the study was low, and we found no confirmatory trials.

We found no trials on acute treatment with any other agents reporting on death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, or mood.

## Additional information

**Cilostazol.** In addition to the earlier mentioned ECLIPse trial, that studied the effect of cilostazol in lacunar stroke patients, there were several randomised trials on cilostazol in acute non-cardioembolic stroke, including a substantial proportion of lacunar stroke patients.¹⁰⁹,¹⁴³⁻¹⁴⁵ In these trials cilostazol was started within 24–48h of stroke onset. The smallest study (76 patients, 47% small vessel occlusion) showed that neurological deterioration or stroke recurrence within 14 days was significantly lower in the cilostazol+aspirin group than in the control group (aspirin only) (6%vs 28%, RR 0.21, 95% CI 0.05, 0.87, *p*=0.013).¹⁴³ However, this positive effect was not found in the other trials, although it must be noted that the comparator groups were different. In CAIST, 458 acute ischaemic stroke patients (57% lacunar) were randomly assigned
A smaller trial with similar design (2013) included 107 patients with acute ischaemic stroke and symptoms less than 12h, of which 41 (38%) had a lacunar syndrome.¹⁴⁰ Patients were randomised between intravenous magnesium or placebo. Primary outcome was the NIHSS score at 90 days, which was different between the two groups (magnesium 4.7 ± 5.0 vs placebo 7.2 ± 5.7; *p*=0.032). In patients with lacunar syndrome, NIHSS was 1.6 ± 1.4 in the Mg group versus 3.3 ± 1.9 in the placebo group (*p*=0.003). The clinical relevance of this difference is uncertain. Secondary outcomes (mRS and mortality at 90 days) were not reported for the subgroup of lacunar stroke.

**Cilostazol.** We identified no cilostazol trials with relevant clinical outcomes that reported specific results for patients with acute lacunar ischaemic stroke. The ECLIPse trial¹³⁶ randomised 103 patients with acute lacunar stroke to either cilostazol plus aspirin or placebo plus aspirin for a duration of 90 days.¹³⁶ The median time from symptom onset to randomisation was 5 days, and 78% of patients were randomised within 7 days. The primary outcome was pulsatility index on Doppler ultrasound, a non-clinical measure, but recurrent ischaemic stroke within 90 days was reported as a secondary outcome: it occurred in one patient in both groups.

**Glyceryl trinitrate.** Nitric oxide (NO) donors such as Glyceryl trinitrate (GTN) are candidate treatments for acute lacunar stroke because of several effects. NO is a cerebral and systemic vasodilator that lowers blood pressure, and has antiplatelet and neuroprotective properties.¹⁴¹

The Efficacy of Nitric Oxide in Stroke (ENOS) trial randomised 4011 patients with acute ischaemic or haemorrhagic stroke within 48h of onset between transdermal GTN 5mg or placebo during 7 days.⁷⁴,¹⁴² The recruitment took over 12 years (2001–2013). 623 (15%) patients had a clinical lacunar stroke syndrome with a compatible CT or MRI scan (acute lacunar infarct or no visible lesion), and 143 had an imaging confirmed lacunar infarct. GTN had no effect on mRS score at 90 days in patients with clinical lacunar stroke syndrome and compatible scan (OR 1.09, 95% CI 0.82, 1.45) nor in those with confirmed lacunar infarction (OR 1.00, 95% CI 0.53, 1.87). The effect on cognition and mood was neutral (not published; personal communication). Of note, the ENOS trial was also included in the analysis of PICO 3 on immediate antihypertensive treatment in acute lacunar stroke.

Based on this one trial, with low risk of bias, which could not show a positive effect on functional outcome, we suggest against the use of GTN in patients with suspected acute lacunar stroke.

**Anticoagulation.** We found two trials on low molecular weight (LMW) heparin or heparinoid, conducted between

1990 and 2000, which presented prespecified results on acute lacunar stroke subgroups. TOAST was a randomised placebo-controlled trial of danaparoid, an LMW heparinoid given in a 7-day course, in acute ischaemic stroke of which 24% were reported to be of lacunar subtype.¹³³ Treatment with danaparoid was not associated with improvement in favourable functional outcome at 90 days in the total group, nor the lacunar subtype. TAIST was a randomised aspirin-controlled trial testing medium or high dose tinzaparin, an LMW heparin, within 48h of acute ischaemic stroke and given for up to 10 days. It included 40% lacunar stroke sub-types.¹³⁴ Tinzaparin in medium or high dose did not improve functional outcome at 180 days compared with aspirin in the whole group, and this result was not different in the lacunar stroke subtype.

Nowadays, there is ample evidence to start antiplatelet therapy as soon as possible after acute ischaemic stroke, and, referring to PICO 2, consensus that this also applies to acute lacunar stroke, resulting in a recommendation against the use of therapeutic LMW heparin or heparinoid in patients with acute lacunar stroke.

**Xueshuantong.** Xueshuantong is an extraction from a Chinese medicinal herb with an anti-inflammatory effect, administered intravenously. One small randomised non-placebo controlled trial in elderly Chinese patients with acute lacunar stroke reported significant more reduction in NIHSS score between admission and discharge after 4 weeks of treatment with Xueshuantong compared to no treatment.¹³⁵ Exact results were not reported, but reading from the figures, the difference in NIHSS score reduction between both groups seemed less than 1. The quality of the study was low, and we found no confirmatory trials.

We found no trials on acute treatment with any other agents reporting on death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, or mood.

## Additional information

**Cilostazol.** In addition to the earlier mentioned ECLIPse trial, that studied the effect of cilostazol in lacunar stroke patients, there were several randomised trials on cilostazol in acute non-cardioembolic stroke, including a substantial proportion of lacunar stroke patients.¹⁰⁹,¹⁴³⁻¹⁴⁵ In these trials cilostazol was started within 24–48h of stroke onset. The smallest study (76 patients, 47% small vessel occlusion) showed that neurological deterioration or stroke recurrence within 14 days was significantly lower in the cilostazol+aspirin group than in the control group (aspirin only) (6%vs 28%, RR 0.21, 95% CI 0.05, 0.87, *p*=0.013).¹⁴³ However, this positive effect was not found in the other trials, although it must be noted that the comparator groups were different. In CAIST, 458 acute ischaemic stroke patients (57% lacunar) were randomly assigned
to cilostazol or aspirin.¹⁴⁴ Functional independency (mRS 0–2) was not different between the groups at 90 days. In the study of Shimizu et al. (507 patients, two-thirds lacunar), the rate of progressive stroke on days 3 and/or 5 did not differ between the cilostazol and control (optimal medical treatment only) group, nor did mRS score 0–1 at 90 days.¹⁰⁹ Of note, the use of antiplatelet agents other than cilostazol was more common in the control group than in the cilostazol group (89.8% vs 30.7%). The study of Aoki et al. included 1201 patients with acute ischaemic stroke (44% lacunar stroke), randomising between dual therapy with cilostazol + aspirin versus cilostazol alone.¹⁴⁵ Dual therapy did not decrease the combined occurrence of neurological deterioration, stroke recurrence, and TIA events within 14 days, nor was there a difference in mRS 0–1 at 90 days.

The ECLIPse trial was not powered to find a difference in clinical outcome. Although a substantial proportion of the included patients in the abovementioned trials were of the lacunar subtype, separate results on stroke subtypes were not reported. Furthermore, the comparator groups differed between the studies, and we note some quality concerns (3 of 4 studies were non-blinded). Cilostazol has not been studied against, or on top of, clopidogrel or dual therapy with aspirin + clopidogrel. Reflecting the Asian origin of the abovementioned studies, cilostazol is included in Asian stroke guidelines: in the Japan stroke society guideline, cilostazol ‘may be considered as single anti-platelet therapy or with aspirin in patients with non-cardioembolic stroke within 48h of onset’.³⁰ The guideline of the Chinese stroke association gives cilostazol as an alternative if aspirin or clopidogrel is not available.²⁸ ESO stroke guidelines, the AHA guideline for the early management of patients with acute ischaemic stroke, the Canadian and the Australian and New Zealand stroke guidelines have no recommendation on the use of cilostazol in the acute stroke phase.²⁴,²⁷,⁷¹,¹⁰⁰

Taken together, we feel we cannot recommend on the use of cilostazol for acute treatment in patients with lacunar stroke.

*Ongoing trials.* We are not aware of ongoing trials on acute treatments with other agents in acute lacunar stroke. Agents such as cilostazol, phosphodiesterase inhibitors and anti-inflammatory drugs are currently being investigated in secondary prevention trials but might also be interesting in the acute phase.

**Evidence-based Recommendation 1**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of magnesium for acute treatment.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Evidence-based Recommendation 2**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of cilostazol for acute treatment.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Evidence-based Recommendation 3**

In patients with acute lacunar ischaemic stroke, we suggest against the use of glyceryl trinitrate to reduce dependency.

Quality of evidence: Moderate ⊕⊕⊕

Strength of recommendation: **Weak against intervention ↓?**

**Evidence-based Recommendation 4**

In patients with acute lacunar ischaemic stroke, we recommend against the use of therapeutic LMW heparin/heparinoid to reduce dependency.

Quality of evidence: Moderate ⊕⊕⊕

Strength of recommendation: **Strong against intervention ↓↓**

**Evidence-based Recommendation 5**

In patients with acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of Xueshuantong to reduce dependency.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Evidence-based Recommendation 6**

In the absence of RCTs, we cannot make recommendations on the use of any other agents, such as phosphodiesterase-3, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO I-4, for acute treatment in patients with lacunar ischaemic stroke, to reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder and mood disorder.

Quality of evidence: -

Strength of recommendation: -

## PICO 6:

In patients with lacunar ischaemic stroke, does long term treatment with antiplatelets (single or dual, duration and whether any particular antiplatelet or combination of anti-platelets is better), compared to avoiding/less of/alternative antiplatelet intervention reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorders, and mood disorders?

## Analysis of current evidence:

We identified 22 trials⁹,⁴⁶,¹²⁷,¹³⁰,¹³¹,¹³⁶,¹⁴⁶⁻¹⁶² (Supplemental Table 10; Supplement PRISMA diagrams), with a follow-up of clinical outcomes exceeding 4 weeks from randomisation.
to cilostazol or aspirin.¹⁴⁴ Functional independency (mRS 0–2) was not different between the groups at 90 days. In the study of Shimizu et al. (507 patients, two-thirds lacunar), the rate of progressive stroke on days 3 and/or 5 did not differ between the cilostazol and control (optimal medical treatment only) group, nor did mRS score 0–1 at 90 days.¹⁰⁹ Of note, the use of antiplatelet agents other than cilostazol was more common in the control group than in the cilostazol group (89.8% vs 30.7%). The study of Aoki et al. included 1201 patients with acute ischaemic stroke (44% lacunar stroke), randomising between dual therapy with cilostazol + aspirin versus cilostazol alone.¹⁴⁵ Dual therapy did not decrease the combined occurrence of neurological deterioration, stroke recurrence, and TIA events within 14 days, nor was there a difference in mRS 0–1 at 90 days.

The ECLIPse trial was not powered to find a difference in clinical outcome. Although a substantial proportion of the included patients in the abovementioned trials were of the lacunar subtype, separate results on stroke subtypes were not reported. Furthermore, the comparator groups differed between the studies, and we note some quality concerns (3 of 4 studies were non-blinded). Cilostazol has not been studied against, or on top of, clopidogrel or dual therapy with aspirin + clopidogrel. Reflecting the Asian origin of the abovementioned studies, cilostazol is included in Asian stroke guidelines: in the Japan stroke society guideline, cilostazol ‘may be considered as single anti-platelet therapy or with aspirin in patients with non-cardioembolic stroke within 48h of onset’.³⁰ The guideline of the Chinese stroke association gives cilostazol as an alternative if aspirin or clopidogrel is not available.²⁸ ESO stroke guidelines, the AHA guideline for the early management of patients with acute ischaemic stroke, the Canadian and the Australian and New Zealand stroke guidelines have no recommendation on the use of cilostazol in the acute stroke phase.²⁴,²⁷,⁷¹,¹⁰⁰

Taken together, we feel we cannot recommend on the use of cilostazol for acute treatment in patients with lacunar stroke.

*Ongoing trials.* We are not aware of ongoing trials on acute treatments with other agents in acute lacunar stroke. Agents such as cilostazol, phosphodiesterase inhibitors and anti-inflammatory drugs are currently being investigated in secondary prevention trials but might also be interesting in the acute phase.

**Evidence-based Recommendation 1**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of magnesium for acute treatment.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Evidence-based Recommendation 2**

In patients with suspected acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of cilostazol for acute treatment.

Quality of evidence: Low ⊕⊕

Strength of recommendation: -

**Evidence-based Recommendation 3**

In patients with acute lacunar ischaemic stroke, we suggest against the use of glyceryl trinitrate to reduce dependency.

Quality of evidence: Moderate ⊕⊕⊕

Strength of recommendation: **Weak against intervention ↓?**

**Evidence-based Recommendation 4**

In patients with acute lacunar ischaemic stroke, we recommend against the use of therapeutic LMW heparin/heparinoid to reduce dependency.

Quality of evidence: Moderate ⊕⊕⊕

Strength of recommendation: **Strong against intervention ↓↓**

**Evidence-based Recommendation 5**

In patients with acute lacunar ischaemic stroke, there is continued uncertainty over the benefits and risks of Xueshuantong to reduce dependency.

Quality of evidence: Very low ⊕

Strength of recommendation: -

**Evidence-based Recommendation 6**

In the absence of RCTs, we cannot make recommendations on the use of any other agents, such as phosphodiesterase-3, anti-inflammatory agents, anticoagulants, nitric oxide donors, phosphodiesterase-5 inhibitors or otherwise not mentioned in PICO I-4, for acute treatment in patients with lacunar ischaemic stroke, to reduce any recurrent stroke, recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder and mood disorder.

Quality of evidence: -

Strength of recommendation: -

## PICO 6:

In patients with lacunar ischaemic stroke, does long term treatment with antiplatelets (single or dual, duration and whether any particular antiplatelet or combination of anti-platelets is better), compared to avoiding/less of/alternative antiplatelet intervention reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorders, and mood disorders?

## Analysis of current evidence:

We identified 22 trials⁹,⁴⁶,¹²⁷,¹³⁰,¹³¹,¹³⁶,¹⁴⁶⁻¹⁶² (Supplemental Table 10; Supplement PRISMA diagrams), with a follow-up of clinical outcomes exceeding 4 weeks from randomisation.
For shorter periods with focus on acute phase trials – we identified 3 trials - please see PICO 2 section.

The trials examined different treatments and had various outcomes (Supplemental Table 10; Table 5). This results in a complex situation (illustrated in Figures 6–11) where it is usually not possible to compare studies directly between each other. For example, Prasugrel, Triflusal and Vorapaxar were only included in one trial each.<sup>149,159,163</sup> Six trials included groups receiving placebo. Several other trials were non-blinded where subjects receiving treatment with the study drug were compared with subjects not receiving the study drug. The results of the individual trials are described below. Because cilostazol was studied as an add-on to usual antiplatelet treatment in most trials, and important additional non-antiplatelet effects of cilostazol have been suggested, the cilostazol trials are described in a separate section. Regarding the effect of combining cilostazol and isosorbide mononitrate – please see PICO 10.

Many trials included ‘any stroke’, ‘ischaemic stroke’, or ‘major adverse cardiovascular event (MACE)’ among outcomes. We meta-analysed each of these three outcomes where appropriate (Figures 6–8, Table 5). Because fewer trials included cognitive impairment or dementia, haemorrhagic stroke, mobility or gait disorder or mood disorders, we did not perform meta-analyses for these outcomes.

As an exploratory analysis we also performed network meta-analyses (NMA)<sup>38</sup> where we made indirect comparisons (also see Supplement). In the context of multiple agents for the same indication, a network meta-analysis can be a useful synthesis. We consider NMA as an exploratory rather than definitive analysis, and would urge great caution in the interpretation of these indirect network meta-analyses results as the included trials had substantial heterogeneity and there was no common comparator.

## Antiplatelet trials except for Cilostazol

### Antiplatelets versus placebo

**Aspirin versus placebo.** This was studied in two trials.<sup>57,58,146,147</sup> The Accidents Ischémiques Cérébraux Liés a l'Atherosclerose (AICLA) trial, included 604 patients with atherothrombotic ischaemic strokes or TIA within 1 year from the index event. Patients were randomised in a double-blind fashion to three times daily receive either aspirin 330 mg, aspirin 330 mg plus dipyridamole 75 mg, or placebo, with evaluation at least every 4 months for 3 years. The trial included 16% of patients with lacunar stroke defined as ‘probable lacune’. The combination of aspirin + dipyridamole was superior to placebo in the prevention of recurrent ischaemic stroke (RR 0.22, 95% CI 0.05, 0.95); aspirin was not superior to placebo (RR 0.38, 95% CI 0.11, 1.27) and aspirin + dipyridamole was not superior to aspirin alone (RR 0.59, 95% CI 0.11, 3.29).<sup>146</sup> Data from the AICLA study should be taken with caution as they are

based on very low numbers. Additionally, the trial did not report safety outcomes.

The second European Stroke Prevention Study (ESP-2) trial included 6602 patients with previous minor ischaemic stroke or TIA that were randomised to aspirin (25 mg twice daily) + modified-release dipyridamole (200 mg twice daily), aspirin alone, dipyridamole alone, or placebo.<sup>58,147</sup> There were 2600/6602 subjects with small vessel disease, defined as having one of the classical clinical lacunar syndromes. For these subjects, the combination of aspirin + dipyridamole was superior to placebo and to aspirin alone in prevention of any stroke (HR 0.56, 95% CI 0.40, 0.78, and HR 0.68, 95% CI 0.48, 0.97, respectively) and MACE (HR 0.64, 95% CI 0.48, 0.84, and HR 0.74, 95% CI 0.55, 0.99, respectively), while aspirin alone versus placebo and dipyridamole alone versus placebo were not significant.

We did not perform a meta-analysis of the AICLA and ESP-2 trials because they reported different outcomes.

The Chinese Acute Stroke Trial (CAST) included patients within 48 h after stroke onset and compared aspirin with placebo.<sup>57</sup> We did not include the CAST trial into PICO 6 because the trial did not report outcome results after more than 4 weeks. Please see PICO 2 section for more information.

**Ticlopidine versus placebo.** The Canadian American Ticlopidine Study (CATS) randomised 1072 patients to receive 250 mg Ticlopidine twice daily or placebo entering the study 1 week - 4 months after stroke onset. Patients were followed up for a mean of 24 months.<sup>150</sup> The event rate for stroke, myocardial infarction or vascular death, taken together was significantly lower in the Ticlopidine group.<sup>150</sup> In a subgroup analysis of 274 patients with lacunar stroke reported by Kwok et al.<sup>58</sup> there was a lower proportion of recurrent stroke among those treated with Ticlopidine (HR 0.52, 95% CI 0.28, 0.95).<sup>58</sup>

### Comparisons between different antiplatelet treatments

**Aspirin versus clopidogrel.** The Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com)<sup>130</sup> mainly focused on cilostazol treatment and included 925 subjects with symptomatic lacunar stroke.<sup>131</sup> However, among these subjects not receiving cilostazol, a comparison between aspirin only versus clopidogrel only treatment was possible where 9 of 195 (4.6%) patients assigned aspirin and 22 of 265 (8.3%) patients assigned clopidogrel had primary outcome defined as first recurrence of an ischaemic stroke (RR 0.56, 95% CI 0.26, 1.18).<sup>131</sup>

**Prasugrel versus clopidogrel.** The comparison of PRAsugrel and clopidogrel in Japanese patients with ischaemic STROke (PRASTRO-I) trial was a phase III randomised
For shorter periods with focus on acute phase trials – we identified 3 trials - please see PICO 2 section.

The trials examined different treatments and had various outcomes (Supplemental Table 10; Table 5). This results in a complex situation (illustrated in Figures 6–11) where it is usually not possible to compare studies directly between each other. For example, Prasugrel, Triflusal and Vorapaxar were only included in one trial each.<sup>149,159,163</sup> Six trials included groups receiving placebo. Several other trials were non-blinded where subjects receiving treatment with the study drug were compared with subjects not receiving the study drug. The results of the individual trials are described below. Because cilostazol was studied as an add-on to usual antiplatelet treatment in most trials, and important additional non-antiplatelet effects of cilostazol have been suggested, the cilostazol trials are described in a separate section. Regarding the effect of combining cilostazol and isosorbide mononitrate – please see PICO 10.

Many trials included ‘any stroke’, ‘ischaemic stroke’, or ‘major adverse cardiovascular event (MACE)’ among outcomes. We meta-analysed each of these three outcomes where appropriate (Figures 6–8, Table 5). Because fewer trials included cognitive impairment or dementia, haemorrhagic stroke, mobility or gait disorder or mood disorders, we did not perform meta-analyses for these outcomes.

As an exploratory analysis we also performed network meta-analyses (NMA)<sup>38</sup> where we made indirect comparisons (also see Supplement). In the context of multiple agents for the same indication, a network meta-analysis can be a useful synthesis. We consider NMA as an exploratory rather than definitive analysis, and would urge great caution in the interpretation of these indirect network meta-analyses results as the included trials had substantial heterogeneity and there was no common comparator.

## Antiplatelet trials except for Cilostazol

### Antiplatelets versus placebo

**Aspirin versus placebo.** This was studied in two trials.<sup>57,58,146,147</sup> The Accidents Ischémiques Cérébraux Liés a l'Atherosclerose (AICLA) trial, included 604 patients with atherothrombotic ischaemic strokes or TIA within 1 year from the index event. Patients were randomised in a double-blind fashion to three times daily receive either aspirin 330 mg, aspirin 330 mg plus dipyridamole 75 mg, or placebo, with evaluation at least every 4 months for 3 years. The trial included 16% of patients with lacunar stroke defined as ‘probable lacune’. The combination of aspirin + dipyridamole was superior to placebo in the prevention of recurrent ischaemic stroke (RR 0.22, 95% CI 0.05, 0.95); aspirin was not superior to placebo (RR 0.38, 95% CI 0.11, 1.27) and aspirin + dipyridamole was not superior to aspirin alone (RR 0.59, 95% CI 0.11, 3.29).<sup>146</sup> Data from the AICLA study should be taken with caution as they are

based on very low numbers. Additionally, the trial did not report safety outcomes.

The second European Stroke Prevention Study (ESP-2) trial included 6602 patients with previous minor ischaemic stroke or TIA that were randomised to aspirin (25 mg twice daily) + modified-release dipyridamole (200 mg twice daily), aspirin alone, dipyridamole alone, or placebo.<sup>58,147</sup> There were 2600/6602 subjects with small vessel disease, defined as having one of the classical clinical lacunar syndromes. For these subjects, the combination of aspirin + dipyridamole was superior to placebo and to aspirin alone in prevention of any stroke (HR 0.56, 95% CI 0.40, 0.78, and HR 0.68, 95% CI 0.48, 0.97, respectively) and MACE (HR 0.64, 95% CI 0.48, 0.84, and HR 0.74, 95% CI 0.55, 0.99, respectively), while aspirin alone versus placebo and dipyridamole alone versus placebo were not significant.

We did not perform a meta-analysis of the AICLA and ESP-2 trials because they reported different outcomes.

The Chinese Acute Stroke Trial (CAST) included patients within 48 h after stroke onset and compared aspirin with placebo.<sup>57</sup> We did not include the CAST trial into PICO 6 because the trial did not report outcome results after more than 4 weeks. Please see PICO 2 section for more information.

**Ticlopidine versus placebo.** The Canadian American Ticlopidine Study (CATS) randomised 1072 patients to receive 250 mg Ticlopidine twice daily or placebo entering the study 1 week - 4 months after stroke onset. Patients were followed up for a mean of 24 months.<sup>150</sup> The event rate for stroke, myocardial infarction or vascular death, taken together was significantly lower in the Ticlopidine group.<sup>150</sup> In a subgroup analysis of 274 patients with lacunar stroke reported by Kwok et al.<sup>58</sup> there was a lower proportion of recurrent stroke among those treated with Ticlopidine (HR 0.52, 95% CI 0.28, 0.95).<sup>58</sup>

### Comparisons between different antiplatelet treatments

**Aspirin versus clopidogrel.** The Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com)<sup>130</sup> mainly focused on cilostazol treatment and included 925 subjects with symptomatic lacunar stroke.<sup>131</sup> However, among these subjects not receiving cilostazol, a comparison between aspirin only versus clopidogrel only treatment was possible where 9 of 195 (4.6%) patients assigned aspirin and 22 of 265 (8.3%) patients assigned clopidogrel had primary outcome defined as first recurrence of an ischaemic stroke (RR 0.56, 95% CI 0.26, 1.18).<sup>131</sup>

**Prasugrel versus clopidogrel.** The comparison of PRAsugrel and clopidogrel in Japanese patients with ischaemic STROke (PRASTRO-I) trial was a phase III randomised
## 6a. Antiplatelets vs Placebo

<figure><img src="image_13.png" /></figure>

## 6b. Cilostazol vs placebo

<figure><img src="image_14.png" /></figure>

## 6a.+6b. (combined)

<figure><img src="image_15.png" /></figure>

## 6c. Cilostazol added to other antiplatelets

<figure><img src="image_16.png" /><figcaption>**Figure 6.** PICO 6 Antiplatelet drugs in secondary prevention of any recurrent stroke in patients with lacunar ischaemic stroke: (6a.) Antiplatelets versus Placebo. (6b.) Cilostazol versus placebo. (6a. + 6b.) combined. (6c.) Cilostazol added to other antiplatelets.</figcaption></figure>
## 6a. Antiplatelets vs Placebo

<figure><img src="image_13.png" /></figure>

## 6b. Cilostazol vs placebo

<figure><img src="image_14.png" /></figure>

## 6a.+6b. (combined)

<figure><img src="image_15.png" /></figure>

## 6c. Cilostazol added to other antiplatelets

<figure><img src="image_16.png" /><figcaption>**Figure 6.** PICO 6 Antiplatelet drugs in secondary prevention of any recurrent stroke in patients with lacunar ischaemic stroke: (6a.) Antiplatelets versus Placebo. (6b.) Cilostazol versus placebo. (6a. + 6b.) combined. (6c.) Cilostazol added to other antiplatelets.</figcaption></figure>
7a.

<table><thead><tr><th rowspan="2">Study or Subgroup</th><th colspan="2">Antiplatelets</th><th colspan="2">Placebo</th><th rowspan="2">Total</th><th rowspan="2">Weight</th><th colspan="2">Risk Ratio</th><th rowspan="2">Risk Ratio</th></tr><tr><th>Events</th><th>Total</th><th>Events</th><th>Total</th><th>M-H, Random, 95% CI</th><th>M-H, Random, 95% CI</th></tr></thead><tbody><tr><td colspan="10"><strong>2.1.1 Aspirin+dipyridamole vs placebo</strong></td></tr><tr><td>Bousser 1983</td><td>2</td><td>34</td><td>9</td><td>34</td><td>14.4%</td><td>0.22 [0.05, 0.95]</td><td></td><td></td><td></td></tr><tr><td>Subtotal (95% CI)</td><td></td><td>34</td><td></td><td>34</td><td>14.4%</td><td>0.22 [0.05, 0.95]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>2</td><td></td><td>9</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Not applicable</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.02 (P = 0.04)</td></tr><tr><td colspan="10"><strong>2.1.2 Cilostazol vs placebo</strong></td></tr><tr><td>Gotoh 2000</td><td>20</td><td>400</td><td>39</td><td>394</td><td>85.6%</td><td>0.51 [0.30, 0.85]</td><td></td><td></td><td></td></tr><tr><td>Subtotal (95% CI)</td><td></td><td>400</td><td></td><td>394</td><td>85.6%</td><td>0.51 [0.30, 0.85]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>20</td><td></td><td>39</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Not applicable</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.57 (P = 0.01)</td></tr><tr><td>Total (95% CI)</td><td></td><td>434</td><td></td><td>428</td><td>100.0%</td><td>0.45 [0.25, 0.79]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>22</td><td></td><td>48</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Tau<sup>2</sup> = 0.03; Chi<sup>2</sup> = 1.09, df = 1 (P = 0.30); I<sup>2</sup> = 8%</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.77 (P = 0.006)</td></tr><tr><td colspan="10">Test for subgroup differences: Chi<sup>2</sup> = 1.08, df = 1 (P = 0.30), I<sup>2</sup> = 7.6%</td></tr></tbody></table>

7b.

<table><caption>**Figure 7.** PICO 6 Antiplatelet drugs in secondary prevention of recurrent ischaemic stroke in patients with lacunar ischaemic stroke: (7a.) Antiplatelets versus Placebo. (7b.) Cilostazol added to other antiplatelets.</caption><thead><tr><th rowspan="2">Study or Subgroup</th><th colspan="2">Cilostazol + Clopidogrel or Aspirin</th><th colspan="2">Clopidogrel or Aspirin</th><th rowspan="2">Total</th><th rowspan="2">Weight</th><th colspan="2">Risk Ratio</th><th rowspan="2">Risk Ratio</th></tr><tr><th>Events</th><th>Total</th><th>Events</th><th>Total</th><th>M-H, Random, 95% CI</th><th>M-H, Random, 95% CI</th></tr></thead><tbody><tr><td>Blair 2019</td><td>1</td><td>42</td><td>0</td><td>15</td><td>7.0%</td><td>1.12 [0.05, 26.02]</td><td></td><td></td><td></td></tr><tr><td>Han 2013</td><td>1</td><td>100</td><td>1</td><td>103</td><td>8.8%</td><td>1.03 [0.07, 16.24]</td><td></td><td></td><td></td></tr><tr><td>Nishiyama 2023</td><td>12</td><td>464</td><td>31</td><td>461</td><td>46.2%</td><td>0.38 [0.20, 0.74]</td><td></td><td></td><td></td></tr><tr><td>Wardlaw 2023</td><td>11</td><td>178</td><td>8</td><td>180</td><td>38.1%</td><td>1.39 [0.57, 3.38]</td><td></td><td></td><td></td></tr><tr><td>Total (95% CI)</td><td></td><td>784</td><td></td><td>759</td><td>100.0%</td><td>0.74 [0.30, 1.78]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>25</td><td></td><td>40</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Tau<sup>2</sup> = 0.33; Chi<sup>2</sup> = 5.51, df = 3 (P = 0.14); I<sup>2</sup> = 46%</td></tr><tr><td colspan="10">Test for overall effect: Z = 0.68 (P = 0.50)</td></tr></tbody></table>

controlled trial which included patients with non-cardioembolic ischaemic stroke within 1–26 weeks from informed consent.¹⁴⁹ Patients were randomised to either prasugrel 3.75 mg daily or clopidogrel 75 mg daily. Patients were followed-up for 96 weeks. A subgroup analysis of the PRAS-TRO-I trial stratified the trial results according to stroke aetiology where lacunar stroke was defined according to the TOAST classification criteria. Among patients with lacunar stroke, the risks of recurrent ischaemic stroke (HR 0.81, 95% CI 0.43, 1.51), any stroke (HR 0.86, 95% CI 0.47, 1.56), or MACE (HR 0.82, 95% CI 0.45, 1.50) were not different between the prasugrel and the clopidogrel group.

**Terutroban versus aspirin.** The Prevention of cerebrovascular and cardiovascular Events of ischaemic origin with teRutroban in patients with a history of ischaemic stroke or transient ischaemic attack (PERFORM) trial¹⁵⁶ randomised patients with ischaemic stroke in the previous 3 months or a TIA in the previous 8 days to terutroban 30 mg daily or aspirin 100 mg daily. Among the 1733 patients with lacunar stroke in the trial, no difference between the treatment arms regarding fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (except haemorrhagic death) was seen, with these events occurring in 54 of 856 assigned terutroban and 61 of 877 assigned aspirin (HR 0.90 (95% CI 0.62, 1.31)).¹⁵⁶

**Ticlopidine versus aspirin.** The African American Antiplatelet Stroke Prevention Study (AAASPS) trial randomised patients with ischaemic stroke occurred within 7–90 days to ticlopidine 500 mg daily versus aspirin 650 mg daily.¹⁵¹,¹⁶⁴ Patients were followed up for up to 2 years. The trial found that in patients with lacunar stroke, ticlopidine was not superior to aspirin for secondary prevention of any stroke (HR 0.98, 95% CI 0.64, 1.51).

**Ticlopidine versus clopidogrel.** A pooled analysis of one phase IIIa trial¹⁵⁷ and one phase IIIB trial¹⁵⁷,¹⁵⁸ (no acronyms for these two trials were found) included patients with ischaemic stroke occurring >8 days before treatment who were randomised to receive either ticlopidine (200 mg once daily) or clopidogrel (75 mg once daily).¹⁵⁷ Patients were followed up to 52 weeks. In patients with lacunar stroke, ticlopidine was not superior to clopidogrel in the prevention of a composite of ischaemic stroke, myocardial infarction and death (RR 0.85, 95% CI 0.46, 1.55).

**Triflusal versus clopidogrel.** The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of stroke based on cytochrome P450 2C19 genotyping (MAESTRO) trial included patients with ischaemic stroke within 90 days that were randomised to triflusal (300 mg twice daily) or clopidogrel (75 mg daily).¹⁵² Patients were followed up for
7a.

<table><thead><tr><th rowspan="2">Study or Subgroup</th><th colspan="2">Antiplatelets</th><th colspan="2">Placebo</th><th rowspan="2">Total</th><th rowspan="2">Weight</th><th colspan="2">Risk Ratio</th><th rowspan="2">Risk Ratio</th></tr><tr><th>Events</th><th>Total</th><th>Events</th><th>Total</th><th>M-H, Random, 95% CI</th><th>M-H, Random, 95% CI</th></tr></thead><tbody><tr><td colspan="10"><strong>2.1.1 Aspirin+dipyridamole vs placebo</strong></td></tr><tr><td>Bousser 1983</td><td>2</td><td>34</td><td>9</td><td>34</td><td>14.4%</td><td>0.22 [0.05, 0.95]</td><td></td><td></td><td></td></tr><tr><td>Subtotal (95% CI)</td><td></td><td>34</td><td></td><td>34</td><td>14.4%</td><td>0.22 [0.05, 0.95]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>2</td><td></td><td>9</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Not applicable</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.02 (P = 0.04)</td></tr><tr><td colspan="10"><strong>2.1.2 Cilostazol vs placebo</strong></td></tr><tr><td>Gotoh 2000</td><td>20</td><td>400</td><td>39</td><td>394</td><td>85.6%</td><td>0.51 [0.30, 0.85]</td><td></td><td></td><td></td></tr><tr><td>Subtotal (95% CI)</td><td></td><td>400</td><td></td><td>394</td><td>85.6%</td><td>0.51 [0.30, 0.85]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>20</td><td></td><td>39</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Not applicable</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.57 (P = 0.01)</td></tr><tr><td>Total (95% CI)</td><td></td><td>434</td><td></td><td>428</td><td>100.0%</td><td>0.45 [0.25, 0.79]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>22</td><td></td><td>48</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Tau<sup>2</sup> = 0.03; Chi<sup>2</sup> = 1.09, df = 1 (P = 0.30); I<sup>2</sup> = 8%</td></tr><tr><td colspan="10">Test for overall effect: Z = 2.77 (P = 0.006)</td></tr><tr><td colspan="10">Test for subgroup differences: Chi<sup>2</sup> = 1.08, df = 1 (P = 0.30), I<sup>2</sup> = 7.6%</td></tr></tbody></table>

7b.

<table><caption>**Figure 7.** PICO 6 Antiplatelet drugs in secondary prevention of recurrent ischaemic stroke in patients with lacunar ischaemic stroke: (7a.) Antiplatelets versus Placebo. (7b.) Cilostazol added to other antiplatelets.</caption><thead><tr><th rowspan="2">Study or Subgroup</th><th colspan="2">Cilostazol + Clopidogrel or Aspirin</th><th colspan="2">Clopidogrel or Aspirin</th><th rowspan="2">Total</th><th rowspan="2">Weight</th><th colspan="2">Risk Ratio</th><th rowspan="2">Risk Ratio</th></tr><tr><th>Events</th><th>Total</th><th>Events</th><th>Total</th><th>M-H, Random, 95% CI</th><th>M-H, Random, 95% CI</th></tr></thead><tbody><tr><td>Blair 2019</td><td>1</td><td>42</td><td>0</td><td>15</td><td>7.0%</td><td>1.12 [0.05, 26.02]</td><td></td><td></td><td></td></tr><tr><td>Han 2013</td><td>1</td><td>100</td><td>1</td><td>103</td><td>8.8%</td><td>1.03 [0.07, 16.24]</td><td></td><td></td><td></td></tr><tr><td>Nishiyama 2023</td><td>12</td><td>464</td><td>31</td><td>461</td><td>46.2%</td><td>0.38 [0.20, 0.74]</td><td></td><td></td><td></td></tr><tr><td>Wardlaw 2023</td><td>11</td><td>178</td><td>8</td><td>180</td><td>38.1%</td><td>1.39 [0.57, 3.38]</td><td></td><td></td><td></td></tr><tr><td>Total (95% CI)</td><td></td><td>784</td><td></td><td>759</td><td>100.0%</td><td>0.74 [0.30, 1.78]</td><td></td><td></td><td></td></tr><tr><td>Total events</td><td>25</td><td></td><td>40</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10">Heterogeneity: Tau<sup>2</sup> = 0.33; Chi<sup>2</sup> = 5.51, df = 3 (P = 0.14); I<sup>2</sup> = 46%</td></tr><tr><td colspan="10">Test for overall effect: Z = 0.68 (P = 0.50)</td></tr></tbody></table>

controlled trial which included patients with non-cardioembolic ischaemic stroke within 1–26 weeks from informed consent.¹⁴⁹ Patients were randomised to either prasugrel 3.75 mg daily or clopidogrel 75 mg daily. Patients were followed-up for 96 weeks. A subgroup analysis of the PRAS-TRO-I trial stratified the trial results according to stroke aetiology where lacunar stroke was defined according to the TOAST classification criteria. Among patients with lacunar stroke, the risks of recurrent ischaemic stroke (HR 0.81, 95% CI 0.43, 1.51), any stroke (HR 0.86, 95% CI 0.47, 1.56), or MACE (HR 0.82, 95% CI 0.45, 1.50) were not different between the prasugrel and the clopidogrel group.

**Terutroban versus aspirin.** The Prevention of cerebrovascular and cardiovascular Events of ischaemic origin with teRutroban in patients with a history of ischaemic stroke or transient ischaemic attack (PERFORM) trial¹⁵⁶ randomised patients with ischaemic stroke in the previous 3 months or a TIA in the previous 8 days to terutroban 30 mg daily or aspirin 100 mg daily. Among the 1733 patients with lacunar stroke in the trial, no difference between the treatment arms regarding fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (except haemorrhagic death) was seen, with these events occurring in 54 of 856 assigned terutroban and 61 of 877 assigned aspirin (HR 0.90 (95% CI 0.62, 1.31)).¹⁵⁶

**Ticlopidine versus aspirin.** The African American Antiplatelet Stroke Prevention Study (AAASPS) trial randomised patients with ischaemic stroke occurred within 7–90 days to ticlopidine 500 mg daily versus aspirin 650 mg daily.¹⁵¹,¹⁶⁴ Patients were followed up for up to 2 years. The trial found that in patients with lacunar stroke, ticlopidine was not superior to aspirin for secondary prevention of any stroke (HR 0.98, 95% CI 0.64, 1.51).

**Ticlopidine versus clopidogrel.** A pooled analysis of one phase IIIa trial¹⁵⁷ and one phase IIIB trial¹⁵⁷,¹⁵⁸ (no acronyms for these two trials were found) included patients with ischaemic stroke occurring >8 days before treatment who were randomised to receive either ticlopidine (200 mg once daily) or clopidogrel (75 mg once daily).¹⁵⁷ Patients were followed up to 52 weeks. In patients with lacunar stroke, ticlopidine was not superior to clopidogrel in the prevention of a composite of ischaemic stroke, myocardial infarction and death (RR 0.85, 95% CI 0.46, 1.55).

**Triflusal versus clopidogrel.** The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of stroke based on cytochrome P450 2C19 genotyping (MAESTRO) trial included patients with ischaemic stroke within 90 days that were randomised to triflusal (300 mg twice daily) or clopidogrel (75 mg daily).¹⁵² Patients were followed up for
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>**Figure 8.** PICO 6 Antiplatelet drugs in secondary prevention of MACE in patients with lacunar ischaemic stroke: (8a.) Antiplatelets versus Placebo. (8b.) Aspirin + Dipyridamole versus Aspirin. (8c.) Cilostazol added to other antiplatelets.</figcaption></figure>

a median of 2.7 years. In patients with lacunar stroke, the trial found no difference between triflusal and clopidogrel in secondary prevention of any stroke (HR 0.68, 95% CI 0.20, 2.32). Notably, these trial results only include information for poor metabolisers of clopidogrel selected via genotyping. Therefore, the results of the MAESTRO trial cannot be directly applied to all patients with lacunar stroke.

**Ticagrelor versus aspirin.** The Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial randomised patients with ischaemic stroke, recruited within 24 h of stroke onset, to receive either ticagrelor (90 mg twice daily) or aspirin (100 mg once daily).¹⁶⁰ Patients were treated for 90 days when follow-up occurred. In the subgroup of patients with lacunar stroke – defined according to the ASCOD criteria – ticagrelor was not superior to aspirin in prevention of MACE – defined as a composite of stroke, myocardial infarction, or death (HR 0.91, 95% CI 0.72, 1.14).

**Sarpogrelate versus aspirin.** Sarpogrelate is an antiplatelet compound inhibiting 5-hydroxytryptamine receptors and platelet aggregation.¹⁴⁸ In the Sarpogrelate-Aspirin Comparative Clinical study for Efficacy and Safety in Secondary prevention of cerebral infarction (S-ACCESS) trial, patients were randomised to receive sarpogrelate (100 mg three times per day) or aspirin (81 mg per day). In the subgroup of patients with lacunar infarction, no significant difference regarding the recurrent ischaemic stroke event rates were observed with 5.95% per year in the Sarpogrelate group and 4.53% per year in the aspirin group (HR1.31; 95% CI 0.84, 2.04).¹⁴⁸

**Dual antiplatelet therapy (DAPT) or triple antiplatelet therapy versus single antiplatelet therapy (SAPT) aspirin + clopidogrel versus aspirin.** The Secondary Prevention of Small Subcortical Strokes (SPS3) was specifically designed for the secondary prevention of lacunar stroke.⁹ The trial included 3020 patients with symptomatic lacunar stroke experienced
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>**Figure 8.** PICO 6 Antiplatelet drugs in secondary prevention of MACE in patients with lacunar ischaemic stroke: (8a.) Antiplatelets versus Placebo. (8b.) Aspirin + Dipyridamole versus Aspirin. (8c.) Cilostazol added to other antiplatelets.</figcaption></figure>

a median of 2.7 years. In patients with lacunar stroke, the trial found no difference between triflusal and clopidogrel in secondary prevention of any stroke (HR 0.68, 95% CI 0.20, 2.32). Notably, these trial results only include information for poor metabolisers of clopidogrel selected via genotyping. Therefore, the results of the MAESTRO trial cannot be directly applied to all patients with lacunar stroke.

**Ticagrelor versus aspirin.** The Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial randomised patients with ischaemic stroke, recruited within 24 h of stroke onset, to receive either ticagrelor (90 mg twice daily) or aspirin (100 mg once daily).¹⁶⁰ Patients were treated for 90 days when follow-up occurred. In the subgroup of patients with lacunar stroke – defined according to the ASCOD criteria – ticagrelor was not superior to aspirin in prevention of MACE – defined as a composite of stroke, myocardial infarction, or death (HR 0.91, 95% CI 0.72, 1.14).

**Sarpogrelate versus aspirin.** Sarpogrelate is an antiplatelet compound inhibiting 5-hydroxytryptamine receptors and platelet aggregation.¹⁴⁸ In the Sarpogrelate-Aspirin Comparative Clinical study for Efficacy and Safety in Secondary prevention of cerebral infarction (S-ACCESS) trial, patients were randomised to receive sarpogrelate (100 mg three times per day) or aspirin (81 mg per day). In the subgroup of patients with lacunar infarction, no significant difference regarding the recurrent ischaemic stroke event rates were observed with 5.95% per year in the Sarpogrelate group and 4.53% per year in the aspirin group (HR1.31; 95% CI 0.84, 2.04).¹⁴⁸

**Dual antiplatelet therapy (DAPT) or triple antiplatelet therapy versus single antiplatelet therapy (SAPT) aspirin + clopidogrel versus aspirin.** The Secondary Prevention of Small Subcortical Strokes (SPS3) was specifically designed for the secondary prevention of lacunar stroke.⁹ The trial included 3020 patients with symptomatic lacunar stroke experienced
within 180 days. Patients were randomised after at least 2 weeks from the qualifying stroke to antihypertensive treatment (systolic BP target: <130 mmHg vs 130–149 mmHg) and to antiplatelet treatment (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin alone). Patients were followed up for a mean of 3.4 years. The trial showed that the combination of aspirin and clopidogrel, compared with aspirin alone, was not associated with reduced risk for recurrent ischaemic stroke (HR 0.82, 95% CI 0.63, 1.09), haemorrhagic stroke (HR 1.65, 95% CI 0.83, 3.31), any stroke (HR 0.92, 0.72, 1.16), or MACE (HR 0.89, 95% CI 0.72, 1.11), However, the combination of aspirin and clopidogrel increased the risk of major haemorrhage (HR 1.97, 95% CI 1.41, 2.71) or death (HR 1.52, 95% CI 1.14, 2.04).

**Aspirin + clopidogrel versus clopidogrel alone.** The Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) study included patients with ischaemic stroke within 3 months. Patients were randomised to a combination of clopidogrel 75 mg + aspirin 75 mg daily or clopidogrel alone.¹⁵³ Patients were followed up to 18 months. Overall, the MATCH trial showed that after recent ischaemic stroke or transient ischaemic attack in high-risk patients, the combination of aspirin and clopidogrel did not reduce the risk of recurrent stroke compared with clopidogrel alone but instead increased the risk of life-threatening or major bleeding.¹⁵³ The original report did not present subgroup analyses for lacunar stroke, but this was done in a meta-analysis⁵⁸ that retrieved data from the MATCH trial for the subgroup of patients with lacunar stroke – according to the TOAST definition. This could not show that the combination of aspirin + clopidogrel was superior to clopidogrel alone in preventing recurrent ischaemic stroke in the long term (RR 0.97, 95% CI 0.79, 1.20) in patients with lacunar ischaemic stroke.⁵⁸

**Aspirin + dipyridamole versus aspirin.** The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) trial included patients with minor ischaemic stroke or with TIA within the last 6 months. Patients were randomised to aspirin 30–325 mg daily plus dipyridamole 200 mg daily versus aspirin alone and were followed-up for a maximum of 5 years (mean 3.5 years).¹⁵⁴ In patients with lacunar stroke, whose subgroup results were retrieved from a meta-analysis,⁵⁸ the aspirin + dipyridamole combination was not superior to aspirin alone in the prevention of a composite of any stroke, myocardial infarction, and death (RR 0.91, 95% CI 0.70, 1.17).⁵⁸

**Aspirin + dipyridamole versus clopidogrel.** The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial randomised patients with recent (<90 days) ischaemic stroke to aspirin (25 mg daily) + extended-release dipyridamole (200 mg twice daily) versus clopidogrel (75 mg daily); the trial also randomised patients to telmisartan 80 mg daily versus placebo to study effects of blood pressure treatment.¹⁵⁵ The patients were followed

for a mean of 2.5 years. In the subgroup of patients with lacunar stroke – defined according to the TOAST classification criteria – aspirin + dipyridamole was not superior to clopidogrel for secondary prevention of any stroke (HR 0.96, 95% CI 0.84, 1.09).

**Vorapaxar + standard antiplatelet therapy versus standard antiplatelet therapy.** Vorapaxar is an antiplatelet drug that antagonises protease-activated receptor-1. The TRA 2°P-TIMI 50 trial was a secondary prevention RCT evaluating treatment with vorapaxar, compared with placebo, on top of standard antiplatelet therapy (54%–55% consisting of aspirin alone), among patients with stable atherosclerosis such as myocardial infarction, non-cardioembolic ischaemic stroke or peripheral arterial disease.¹⁵⁹ In a pre-specified analysis of stroke patients, of which 47% had lacunar stroke, no significant difference between vorapaxar and placebo was found in cardiovascular death, myocardial infarction or stroke, while bleeding complications increased. In lacunar stroke HR for MACE was 0.99, 95% CI 0.75, 1.31, while there was an increased risk for bleeding complications (HR 2.85, 95% CI 1.62, 5.06).¹⁵⁹ Vorapaxar is now considered contraindicated in patients with a history of stroke.

## Cilostazol trials

Several trials have been with subjects of Asian ethnicity but trials with subjects with European descent have also been performed. Cilostazol use may sometime be limited by side effects and some patients report to headache, diarrhoea, dizziness, or increased heart rate.¹⁶⁶

### Cilostazol versus placebo

The Cilostazol Stroke Prevention Study (CSPS) included patients with ischaemic stroke within 1–6 months randomised to receive cilostazol 100 mg twice daily or placebo.¹⁶¹,¹⁶² Overall, patients included in the trial were followed up for a mean of 652 days in the cilostazol group and 570 days in the placebo group. No data was reported for the subgroup of patients with lacunar stroke in the initial report,¹⁶¹ but a subsequent report on the subgroup of patients with neuroimaging-confirmed lacunar stroke found that cilostazol was superior to placebo in preventing recurrent ischaemic stroke (RR 0.51, 95% CI 0.30, 0.85).¹⁶²

### Combinations of Cilostazol and other antiplatelets

**Cilostazol versus aspirin.** The second Cilostazol Stroke Prevention Study-2 (CSPS-2) trial randomised patients with a history of ischaemic stroke 1–6 months before treatment start to cilostazol 100 mg twice daily or aspirin 81 mg daily.¹⁶⁷ Patients were followed up to 29 months. In the subgroup of patients with lacunar stroke, cilostazol was not superior to aspirin for secondary prevention of any stroke (HR 0.75, 95% CI 0.54, 1.04).
within 180 days. Patients were randomised after at least 2 weeks from the qualifying stroke to antihypertensive treatment (systolic BP target: <130 mmHg vs 130–149 mmHg) and to antiplatelet treatment (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin alone). Patients were followed up for a mean of 3.4 years. The trial showed that the combination of aspirin and clopidogrel, compared with aspirin alone, was not associated with reduced risk for recurrent ischaemic stroke (HR 0.82, 95% CI 0.63, 1.09), haemorrhagic stroke (HR 1.65, 95% CI 0.83, 3.31), any stroke (HR 0.92, 0.72, 1.16), or MACE (HR 0.89, 95% CI 0.72, 1.11), However, the combination of aspirin and clopidogrel increased the risk of major haemorrhage (HR 1.97, 95% CI 1.41, 2.71) or death (HR 1.52, 95% CI 1.14, 2.04).

**Aspirin + clopidogrel versus clopidogrel alone.** The Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) study included patients with ischaemic stroke within 3 months. Patients were randomised to a combination of clopidogrel 75 mg + aspirin 75 mg daily or clopidogrel alone.¹⁵³ Patients were followed up to 18 months. Overall, the MATCH trial showed that after recent ischaemic stroke or transient ischaemic attack in high-risk patients, the combination of aspirin and clopidogrel did not reduce the risk of recurrent stroke compared with clopidogrel alone but instead increased the risk of life-threatening or major bleeding.¹⁵³ The original report did not present subgroup analyses for lacunar stroke, but this was done in a meta-analysis⁵⁸ that retrieved data from the MATCH trial for the subgroup of patients with lacunar stroke – according to the TOAST definition. This could not show that the combination of aspirin + clopidogrel was superior to clopidogrel alone in preventing recurrent ischaemic stroke in the long term (RR 0.97, 95% CI 0.79, 1.20) in patients with lacunar ischaemic stroke.⁵⁸

**Aspirin + dipyridamole versus aspirin.** The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) trial included patients with minor ischaemic stroke or with TIA within the last 6 months. Patients were randomised to aspirin 30–325 mg daily plus dipyridamole 200 mg daily versus aspirin alone and were followed-up for a maximum of 5 years (mean 3.5 years).¹⁵⁴ In patients with lacunar stroke, whose subgroup results were retrieved from a meta-analysis,⁵⁸ the aspirin + dipyridamole combination was not superior to aspirin alone in the prevention of a composite of any stroke, myocardial infarction, and death (RR 0.91, 95% CI 0.70, 1.17).⁵⁸

**Aspirin + dipyridamole versus clopidogrel.** The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial randomised patients with recent (<90 days) ischaemic stroke to aspirin (25 mg daily) + extended-release dipyridamole (200 mg twice daily) versus clopidogrel (75 mg daily); the trial also randomised patients to telmisartan 80 mg daily versus placebo to study effects of blood pressure treatment.¹⁵⁵ The patients were followed

for a mean of 2.5 years. In the subgroup of patients with lacunar stroke – defined according to the TOAST classification criteria – aspirin + dipyridamole was not superior to clopidogrel for secondary prevention of any stroke (HR 0.96, 95% CI 0.84, 1.09).

**Vorapaxar + standard antiplatelet therapy versus standard antiplatelet therapy.** Vorapaxar is an antiplatelet drug that antagonises protease-activated receptor-1. The TRA 2°P-TIMI 50 trial was a secondary prevention RCT evaluating treatment with vorapaxar, compared with placebo, on top of standard antiplatelet therapy (54%–55% consisting of aspirin alone), among patients with stable atherosclerosis such as myocardial infarction, non-cardioembolic ischaemic stroke or peripheral arterial disease.¹⁵⁹ In a pre-specified analysis of stroke patients, of which 47% had lacunar stroke, no significant difference between vorapaxar and placebo was found in cardiovascular death, myocardial infarction or stroke, while bleeding complications increased. In lacunar stroke HR for MACE was 0.99, 95% CI 0.75, 1.31, while there was an increased risk for bleeding complications (HR 2.85, 95% CI 1.62, 5.06).¹⁵⁹ Vorapaxar is now considered contraindicated in patients with a history of stroke.

## Cilostazol trials

Several trials have been with subjects of Asian ethnicity but trials with subjects with European descent have also been performed. Cilostazol use may sometime be limited by side effects and some patients report to headache, diarrhoea, dizziness, or increased heart rate.¹⁶⁶

### Cilostazol versus placebo

The Cilostazol Stroke Prevention Study (CSPS) included patients with ischaemic stroke within 1–6 months randomised to receive cilostazol 100 mg twice daily or placebo.¹⁶¹,¹⁶² Overall, patients included in the trial were followed up for a mean of 652 days in the cilostazol group and 570 days in the placebo group. No data was reported for the subgroup of patients with lacunar stroke in the initial report,¹⁶¹ but a subsequent report on the subgroup of patients with neuroimaging-confirmed lacunar stroke found that cilostazol was superior to placebo in preventing recurrent ischaemic stroke (RR 0.51, 95% CI 0.30, 0.85).¹⁶²

### Combinations of Cilostazol and other antiplatelets

**Cilostazol versus aspirin.** The second Cilostazol Stroke Prevention Study-2 (CSPS-2) trial randomised patients with a history of ischaemic stroke 1–6 months before treatment start to cilostazol 100 mg twice daily or aspirin 81 mg daily.¹⁶⁷ Patients were followed up to 29 months. In the subgroup of patients with lacunar stroke, cilostazol was not superior to aspirin for secondary prevention of any stroke (HR 0.75, 95% CI 0.54, 1.04).
**Cilostazol + aspirin versus aspirin.** The Effect of Cilostazol in the Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) trial included 203 patients with lacunar stroke – defined according to the TOAST classification – within 7 days from onset.¹³⁶ Patients were randomised to a combination of cilostazol 100 mg twice daily + aspirin 100 mg daily versus aspirin alone and followed up to 90 days. The trial found no superiority of cilostazol + aspirin over aspirin alone in the prevention of recurrent ischaemic stroke (RR 1.03, 95% CI 0.07, 16.24). The data should be interpreted with caution as only one recurrent ischaemic stroke occurred in both the intervention and control group over the short follow-up period of 90 days.

**Cilostazol + aspirin/clopidogrel versus aspirin/clopidogrel.** The Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) trial included patients with lacunar stroke occurring between 8 and 180 days before treatment.¹³¹ Patients were randomised to cilostazol 100 mg twice daily + aspirin (81–100 mg daily) (defined as DAPT) or clopidogrel (50–75 mg daily) versus aspirin or clopidogrel alone and followed up for a median of 1.4 years. The trial found that DAPT with cilostazol was superior to single antiplatelet therapy (SAPT) in preventing recurrent ischaemic stroke (adjusted HR 0.43, 95% CI 0.22, 0.85), any stroke (adjusted HR 0.45, 95% CI 0.24, 0.84) and MACE (adjusted HR 0.42, 95% CI 0.23, 0.77) with no significant increase in haemorrhagic stroke (HR 0.53, 95% 0.10, 2.88) or death (HR 3.20, 95% CI 0.33, 30.8) even though small numbers – only 6 haemorrhagic strokes (2 in the intervention group vs 4 in the comparator group) and 4 deaths (3 in the intervention group vs 1 in the comparator group) during the follow-up might affect the risk estimation.¹³¹

**Cilostazol + aspirin/clopidogrel/no other antiplatelets versus aspirin/clopidogrel/no other antiplatelets.** The LACunar Intervention-1 (LACI-1) trial was a factorial trial in which patients with clinically confirmed lacunar ischaemic stroke in the past 4 years were randomised to isosorbide mononitrate (25 mg daily increased to 25 mg twice daily), cilostazol (50 mg twice daily increased to 100 mg twice daily), both, or none.¹²⁷ There were 55 participants (97%) taking clopidogrel for secondary stroke prevention and two (3%) taking aspirin. Patients were followed up for 11 weeks. During the follow-up period, one recurrent ischaemic stroke occurred in the cilostazol group, versus none in the control group and there were no significant differences regarding cognitive outcomes.

The Lacunar Intervention Trial-2 (LACI-2) recruited 363 subjects with clinical lacunar ischaemic stroke for a 2 × 2 factorial randomisation to cilostazol 200 mg daily, isosorbide mononitrate (ISMN) 40–60 mg daily, both, or neither drug on top of their standard medication that usually included antiplatelet treatment with clopidogrel as in LACI-1.⁴⁶ There were no haemorrhagic strokes registered during the 12 months follow-up period. Cilostazol versus no cilostazol treatment did not differ regarding recurrent ischaemic stroke or any stroke (adjusted OR (aOR) 1.35, 95% CI 0.51, 3.57), cognitive impairment (adjusted mean MoCA difference 0.37, 95% CI–0.37, 1.11), depression (adjusted mean Zung depression scale difference –3.34, 95% CI–6.81, 0.14, or death (aOR 0.90, 95% CI 0.08, 10.26). However, dependency was less common in the cilostazol treatment group (aOR 0.46, 95% CI 0.22, 0.95, for mRS>2).⁴⁶ For discussion on ISMN treatment results, please see PICO 10 section.

PICO 6 Risk of bias assessment of included studies using RoB 2.0 tool (outcome: Any stroke, Ischaemic stroke, MACE)

<figure><img src="image_20.png" /></figure>
**Cilostazol + aspirin versus aspirin.** The Effect of Cilostazol in the Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) trial included 203 patients with lacunar stroke – defined according to the TOAST classification – within 7 days from onset.¹³⁶ Patients were randomised to a combination of cilostazol 100 mg twice daily + aspirin 100 mg daily versus aspirin alone and followed up to 90 days. The trial found no superiority of cilostazol + aspirin over aspirin alone in the prevention of recurrent ischaemic stroke (RR 1.03, 95% CI 0.07, 16.24). The data should be interpreted with caution as only one recurrent ischaemic stroke occurred in both the intervention and control group over the short follow-up period of 90 days.

**Cilostazol + aspirin/clopidogrel versus aspirin/clopidogrel.** The Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) trial included patients with lacunar stroke occurring between 8 and 180 days before treatment.¹³¹ Patients were randomised to cilostazol 100 mg twice daily + aspirin (81–100 mg daily) (defined as DAPT) or clopidogrel (50–75 mg daily) versus aspirin or clopidogrel alone and followed up for a median of 1.4 years. The trial found that DAPT with cilostazol was superior to single antiplatelet therapy (SAPT) in preventing recurrent ischaemic stroke (adjusted HR 0.43, 95% CI 0.22, 0.85), any stroke (adjusted HR 0.45, 95% CI 0.24, 0.84) and MACE (adjusted HR 0.42, 95% CI 0.23, 0.77) with no significant increase in haemorrhagic stroke (HR 0.53, 95% 0.10, 2.88) or death (HR 3.20, 95% CI 0.33, 30.8) even though small numbers – only 6 haemorrhagic strokes (2 in the intervention group vs 4 in the comparator group) and 4 deaths (3 in the intervention group vs 1 in the comparator group) during the follow-up might affect the risk estimation.¹³¹

**Cilostazol + aspirin/clopidogrel/no other antiplatelets versus aspirin/clopidogrel/no other antiplatelets.** The LACunar Intervention-1 (LACI-1) trial was a factorial trial in which patients with clinically confirmed lacunar ischaemic stroke in the past 4 years were randomised to isosorbide mononitrate (25 mg daily increased to 25 mg twice daily), cilostazol (50 mg twice daily increased to 100 mg twice daily), both, or none.¹²⁷ There were 55 participants (97%) taking clopidogrel for secondary stroke prevention and two (3%) taking aspirin. Patients were followed up for 11 weeks. During the follow-up period, one recurrent ischaemic stroke occurred in the cilostazol group, versus none in the control group and there were no significant differences regarding cognitive outcomes.

The Lacunar Intervention Trial-2 (LACI-2) recruited 363 subjects with clinical lacunar ischaemic stroke for a 2 × 2 factorial randomisation to cilostazol 200 mg daily, isosorbide mononitrate (ISMN) 40–60 mg daily, both, or neither drug on top of their standard medication that usually included antiplatelet treatment with clopidogrel as in LACI-1.⁴⁶ There were no haemorrhagic strokes registered during the 12 months follow-up period. Cilostazol versus no cilostazol treatment did not differ regarding recurrent ischaemic stroke or any stroke (adjusted OR (aOR) 1.35, 95% CI 0.51, 3.57), cognitive impairment (adjusted mean MoCA difference 0.37, 95% CI–0.37, 1.11), depression (adjusted mean Zung depression scale difference –3.34, 95% CI–6.81, 0.14, or death (aOR 0.90, 95% CI 0.08, 10.26). However, dependency was less common in the cilostazol treatment group (aOR 0.46, 95% CI 0.22, 0.95, for mRS>2).⁴⁶ For discussion on ISMN treatment results, please see PICO 10 section.

PICO 6 Risk of bias assessment of included studies using RoB 2.0 tool (outcome: Any stroke, Ischaemic stroke, MACE)

<figure><img src="image_20.png" /></figure>
<table><caption>**Table 5.** GRADE evidence profile for PICO 6: long-term antiplatelet treatment (single or dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, to reduce recurrent ischaemic stroke, any stroke and MACE in patients with lacunar ischaemic stroke. Please compare with Figures 6-8.</caption><thead><tr><th rowspan="2">Certainty assessment</th><th colspan="4">No of patients</th><th colspan="2">Effect</th><th colspan="2">Certainty</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirectness</th><th>Imprecision</th><th>Other considerations</th><th>Intervention</th><th>Comparator</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th><th>Importance</th></tr></thead><tbody><tr><td>Any stroke (Antiplatelets vs placebo – other than Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>195/1919 (10.2%)</td><td>93/681 (13.7%)</td><td>RR 0.74 (0.59, 0.94)</td><td>36 fewer per 1000 (from 56 fewer to 8 fewer)</td><td>⊕⊕⊕ High</td><td>CRITICAL</td></tr><tr><td>Any stroke (Cilostazol vs placebo)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>20/400 (5.0%)</td><td>39/394 (9.9%)</td><td>RR 0.51 (0.30, 0.85)</td><td>49 fewer per 1000 (from 69 fewer to 39 more)</td><td>⊕⊕○○ Low</td><td>CRITICAL</td></tr><tr><td>Any stroke (Antiplatelets vs Placebo – including Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>not serious</td><td>not serious</td><td>serious<sup>b</sup></td><td>not serious</td><td>none</td><td>none</td><td>215/2319 (9.3%)</td><td>132/1075 (12.3%)</td><td>RR 0.69 (0.55, 0.88)</td><td>38 fewer per 1000 (from 55 fewer to 15 fewer)</td><td>⊕⊕⊕○ Moderate</td><td>CRITICAL</td></tr><tr><td>Any stroke (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>4 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>serious<sup>c</sup></td><td>None</td><td>None</td><td>27/784 (3.4%)</td><td>44/759 (5.8%)</td><td>RR 0.74 (0.31, 1.75)</td><td>15 fewer per 1000 (from 40 fewer to 43 more)</td><td>⊕⊕⊕○ Moderate</td><td>CRITICAL</td></tr><tr><td>Ischaemic stroke (Antiplatelets vs Placebo – including Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>serious<sup>d</sup></td><td>Not serious</td><td> serious</td><td> serious</td><td> serious</td><td>None</td><td>22/434 (5.1%)</td><td>48/428 (11.2%)</td><td>RR 0.45 (0.25, 0.79)</td><td>62 fewer per 1000 (from 84 fewer to 24 fewer)</td><td>⊕⊕○○ Low</td><td>CRITICAL</td></tr><tr><td>Ischaemic stroke (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>4 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td> serious<sup>c</sup></td><td> serious</td><td>None</td><td>25/784 (3.2%)</td><td>40/759 (5.3%)</td><td>RR 0.74 (0.30, 1.78)</td><td>14 fewer per 1000 (from 37 fewer to 41 more)</td><td>⊕⊕⊕○ Moderate</td><td>CRITICAL</td></tr><tr><td>MACE Outcome (Antiplatelets vs placebo – other than Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>291/1919 (15.2%)</td><td>128/681 (18.8%)</td><td>RR 0.81 (0.66, 0.98)</td><td>38 fewer per 1000 (from 64 fewer to 4 fewer)</td><td>⊕⊕⊕ High</td><td>CRITICAL</td></tr><tr><td>MACE Outcome (Aspirin + Dipyridamole vs Aspirin)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>not serious</td><td>not serious</td><td>not serious</td><td> serious<sup>e</sup></td><td> serious</td><td>none</td><td>178/1346 (13.2%)</td><td>207/1299 (15.9%)</td><td>RR 0.83 (0.69, 1.00)</td><td>27 fewer per 1000 (from 49 fewer to 0 fewer)</td><td>⊕⊕○○ Moderate</td><td>CRITICAL</td></tr><tr><td>MACE Outcome (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td> serious<sup>f</sup></td><td> serious</td><td>None</td><td>30/642 (4.7%)</td><td>50/641 (7.8%)</td><td>RR 0.71 (0.20, 2.50)</td><td>23 fewer per 1000 (from 62 fewer to 117 more)</td><td>⊕⊕○○ Low</td><td>CRITICAL</td></tr></tbody></table>

CI: confidence interval; RR: risk ratio.

Explanations

<sup>a</sup>Optimal information size not met (less event and small sample size).

<sup>b</sup>Variation in interventions.

<sup>c</sup>Wide confidence interval and clinical decision threshold crosses the line of no effect.

<sup>d</sup>Included studies had some concern to high concern/high risk of bias.

<sup>e</sup>Clinical decision threshold touches the line of no effect.

Wide confidence interval and clinical decision threshold crosses the line of no effect.
<table><caption>**Table 5.** GRADE evidence profile for PICO 6: long-term antiplatelet treatment (single or dual, duration, and whether any particular antiplatelet or combination of antiplatelets is better), compared to avoiding/less of/alternative antiplatelet intervention, to reduce recurrent ischaemic stroke, any stroke and MACE in patients with lacunar ischaemic stroke. Please compare with Figures 6-8.</caption><thead><tr><th rowspan="2">Certainty assessment</th><th colspan="4">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirectness</th><th>Imprecision</th><th>Other considerations</th><th>Intervention</th><th>Comparator</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td>Any stroke (Antiplatelets vs placebo – other than Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>None</td><td>195/1919 (10.2%)</td><td>93/681 (13.7%)</td><td>RR 0.74 (0.59, 0.94)</td><td>36 fewer per 1000 (from 56 fewer to 8 fewer)</td><td>⊕⊕⊕ High</td></tr><tr><td>Any stroke (Cilostazol vs placebo)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>20/400 (5.0%)</td><td>39/394 (9.9%)</td><td>RR 0.51 (0.30, 0.85)</td><td>49 fewer per 1000 (from 69 fewer to 39 more)</td><td>⊕⊕○○ Low</td></tr><tr><td>Any stroke (Antiplatelets vs Placebo – including Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>not serious</td><td>not serious</td><td>serious<sup>b</sup></td><td>not serious</td><td>none</td><td>215/2319 (9.3%)</td><td>132/1075 (12.3%)</td><td>RR 0.69 (0.55, 0.88)</td><td>38 fewer per 1000 (from 55 fewer to 15 fewer)</td><td>⊕⊕⊕○ Moderate</td></tr><tr><td>Any stroke (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>4 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td> serious<sup>c</sup></td><td>None</td><td>27/784 (3.4%)</td><td>44/759 (5.8%)</td><td>RR 0.74 (0.31, 1.75)</td><td>15 fewer per 1000 (from 40 fewer to 43 more)</td><td>⊕⊕⊕○ Moderate</td></tr><tr><td>Ischaemic stroke (Antiplatelets vs Placebo – including Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td> serious<sup>d</sup></td><td>Not serious</td><td> serious</td><td> serious<sup>c</sup></td><td>None</td><td>22/434 (5.1%)</td><td>48/428 (11.2%)</td><td>RR 0.45 (0.25, 0.79)</td><td>62 fewer per 1000 (from 84 fewer to 24 fewer)</td><td>⊕⊕○○ Low</td></tr><tr><td>Ischaemic stroke (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>4 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td> serious<sup>c</sup></td><td>None</td><td>25/784 (3.2%)</td><td>40/759 (5.3%)</td><td>RR 0.74 (0.30, 1.78)</td><td>14 fewer per 1000 (from 37 fewer to 41 more)</td><td>⊕⊕⊕○ Moderate</td></tr><tr><td>MACE Outcome (Antiplatelets vs placebo – other than Cilostazol)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td>None</td><td>291/1919 (15.2%)</td><td>128/681 (18.8%)</td><td>RR 0.81 (0.66, 0.98)</td><td>38 fewer per 1000 (from 64 fewer to 4 fewer)</td><td>⊕⊕⊕ High</td></tr><tr><td>MACE Outcome (Aspirin + Dipyridamole vs Aspirin)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>not serious</td><td>not serious</td><td>not serious</td><td> serious<sup>e</sup></td><td>none</td><td>178/1346 (13.2%)</td><td>207/1299 (15.9%)</td><td>RR 0.83 (0.69, 1.00)</td><td>27 fewer per 1000 (from 49 fewer to 0 fewer)</td><td>⊕⊕○○ Moderate</td></tr><tr><td>MACE Outcome (Cilostazol added to other antiplatelets)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2 Randomised trials</td><td>Not serious</td><td>Not serious</td><td>Not serious</td><td> serious<sup>f</sup></td><td>None</td><td>30/642 (4.7%)</td><td>50/641 (7.8%)</td><td>RR 0.71 (0.20, 2.50)</td><td>23 fewer per 1000 (from 62 fewer to 117 more)</td><td>⊕⊕○○ Low</td></tr></tbody></table>

CI: confidence interval; RR: risk ratio.

Explanations

<sup>a</sup>Optimal information size not met (less event and small sample size).

<sup>b</sup>Variation in interventions.

<sup>c</sup>Wide confidence interval and clinical decision threshold crosses the line of no effect.

<sup>d</sup>Included studies had some concern to high concern/high risk of bias.

<sup>e</sup>Clinical decision threshold touches the line of no effect.

Wide confidence interval and clinical decision threshold crosses the line of no effect.
## Network meta-analyses

A previous network metal-analysis (NMA) of antiplatelet treatment in lacunar stroke with a literature search up to May 2022 has been published.¹⁶⁸ We now performed an updated NMA, with results of indirect comparisons among the different antiplatelet agents – or combination of them – for the prevention of three specific outcomes: ‘Any stroke’ ‘Ischaemic stroke’, or ‘MACE’ are reported in Figures 9 to 11, respectively and only including randomised controlled trials. The NMA was performed with Stata 11.15 according to the methods laid down in Cochrane handbook.³⁸

In these Figures, the size of the dots is proportional to the number of patients included in trials, while the widths of lines are proportional to the number of trials. For the outcome ‘Any stroke’, aspirin was the drug tested in most patients, followed by aspirin + dipyridamole and by clopidogrel; for the outcome ‘Ischaemic stroke’, the most tested drug was again aspirin, followed by the aspirin-clopidogrel combination and by cilostazol. It should be noted that cilostazol was tested in several studies (wide lines) each including few patients (small dots), while the other drugs were usually the object of single trials (narrow lines).

Supplemental tables report the quantitative results of indirect comparisons. The results should be taken with

extreme caution as they derive from indirect comparisons and are therefore less reliable than those of direct comparisons. This is the rationale for why we do not include the results from the network meta-analyses into our recommendations. However, the analyses indicate that there may be a need for further studies on for example, cilostazol treatment or the combination of dipyridamole and aspirin.

### Any stroke

The network diagram for any stroke is presented in Figure 9. We included 9 RCTs in the analysis with 21080 participants. For details regarding detailed numerical values – please see Supplemental Table 11. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.56, 95% CI: 0.41, 0.77, low certainty evidence), Cilostazol (RR 0.55, 95% CI 0.36, 0.84, low certainty evidence) and Clopidogrel (RR 0.59, 95% CI 0.42, 0.83, low certainty evidence) reduces the risk of any stroke in patients with lacunar stroke (Supplemental Table 11).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

<figure><img src="image_21.png" /><figcaption>**Figure 9.** Network Meta-analysis of antiplatelet trials including the outcome ‘Any stroke’.</figcaption></figure>

a. ESPS-2 (Ariesen; 2006)¹⁴⁷

b. AAASPS (Gorelick; 2003)¹⁶⁴

c. CSPS 2 (Shinohara; 2010)¹³⁰

d. ECLIPSE (Han; 2013)¹³⁶

e. SPS3 (Benavente; 2012)¹⁶⁵

f. CATS (Gent; 1989; Kwok; 2015)⁵⁸, ¹⁵⁰

g. PRoFESS (Sacco; 2008)¹⁵⁵

h. PRASTRO-I (Kitazono; 2021)¹⁴⁹

i. MAESTRO (Han; 2017)¹⁶³
## Network meta-analyses

A previous network metal-analysis (NMA) of antiplatelet treatment in lacunar stroke with a literature search up to May 2022 has been published.¹⁶⁸ We now performed an updated NMA, with results of indirect comparisons among the different antiplatelet agents – or combination of them – for the prevention of three specific outcomes: ‘Any stroke’ ‘Ischaemic stroke’, or ‘MACE’ are reported in Figures 9 to 11, respectively and only including randomised controlled trials. The NMA was performed with Stata 11.15 according to the methods laid down in Cochrane handbook.³⁸

In these Figures, the size of the dots is proportional to the number of patients included in trials, while the widths of lines are proportional to the number of trials. For the outcome ‘Any stroke’, aspirin was the drug tested in most patients, followed by aspirin + dipyridamole and by clopidogrel; for the outcome ‘Ischaemic stroke’, the most tested drug was again aspirin, followed by the aspirin-clopidogrel combination and by cilostazol. It should be noted that cilostazol was tested in several studies (wide lines) each including few patients (small dots), while the other drugs were usually the object of single trials (narrow lines).

Supplemental tables report the quantitative results of indirect comparisons. The results should be taken with

extreme caution as they derive from indirect comparisons and are therefore less reliable than those of direct comparisons. This is the rationale for why we do not include the results from the network meta-analyses into our recommendations. However, the analyses indicate that there may be a need for further studies on for example, cilostazol treatment or the combination of dipyridamole and aspirin.

### Any stroke

The network diagram for any stroke is presented in Figure 9. We included 9 RCTs in the analysis with 21080 participants. For details regarding detailed numerical values – please see Supplemental Table 11. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.56, 95% CI: 0.41, 0.77, low certainty evidence), Cilostazol (RR 0.55, 95% CI 0.36, 0.84, low certainty evidence) and Clopidogrel (RR 0.59, 95% CI 0.42, 0.83, low certainty evidence) reduces the risk of any stroke in patients with lacunar stroke (Supplemental Table 11).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

<figure><img src="image_21.png" /><figcaption>**Figure 9.** Network Meta-analysis of antiplatelet trials including the outcome ‘Any stroke’.</figcaption></figure>

a. ESPS-2 (Ariesen; 2006)¹⁴⁷

b. AAASPS (Gorelick; 2003)¹⁶⁴

c. CSPS 2 (Shinohara; 2010)¹³⁰

d. ECLIPSE (Han; 2013)¹³⁶

e. SPS3 (Benavente; 2012)¹⁶⁵

f. CATS (Gent; 1989; Kwok; 2015)⁵⁸, ¹⁵⁰

g. PRoFESS (Sacco; 2008)¹⁵⁵

h. PRASTRO-I (Kitazono; 2021)¹⁴⁹

i. MAESTRO (Han; 2017)¹⁶³
## Ischaemic stroke

The network diagram for ischaemic stroke is presented in Figure 10. We included 8 RCTs in the analysis with 9862 participants. For details regarding detailed numerical values – please see Supplemental Table 12. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.22, 95% CI 0.05, 0.95, low certainty evidence) and Cilostazol (RR 0.51, 95% CI 0.30, 0.85, low certainty evidence) reduces the risk of ischaemic stroke in patients with lacunar stroke (Supplemental Table 12).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

## MACE

The network diagram for major adverse cardiovascular outcome is presented in Figure 11. We included 5 RCTs in the analysis with 12569 participants. For details regarding detailed numerical values – please see Supplemental Table 13. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.70, 95% CI 0.56, 0.88, low certainty evidence) and Clopidogrel + Aspirin (RR 0.74, 95% CI 0.54, 0.99, low certainty evidence) reduces the risk

of MACE in patients with lacunar stroke (Supplemental Table 13).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

## Additional information

Different monotherapy choices are recommended in different countries and are somewhat influenced by the findings for example, in the CAPRIE trial.¹⁶⁹ A subgroup analysis of the SPS3 trial considered the CYP2C19 metaboliser status in patients with lacunar stroke, comparing the CYP2C19*2 with CYP2C19*17 allele; the metaboliser status did not influence the rate of recurrent ischaemic stroke and major bleeding.¹⁷⁰ The recently published subgroup analysis from the CHANCE-2 trial that included patients with minor stroke or transient ischaemic attack within 24h of symptom onset and carring CYP2C19 loss-of-function alleles, for treatment with either ticagrelor + aspirin or clopidogrel + aspirin for 90 days,⁶⁵ showed that for 1750 patients with small vessel occlusion ischaemic stroke, the primary outcome new stroke within 90days occurred among 3.6% of those administered ticagrelor + aspirin versus 7.0% of those administered clopidogrel + aspirin (0.51, 95% CI 0.33, 0.79, *p*=0.002).⁶⁶ This is also discussed in the PICO 2 section of this GL. We did not perform a systematic screen of all relevant literature

<figure><img src="image_22.png" /><figcaption>**Figure 10.** Network Meta-analysis of antiplatelet trials including the outcome 'Ischaemic stroke'.</figcaption></figure>

a. AICLA (Bousser; 1983)¹⁴⁶

b. ECLIPSE (Han; 2013)¹³⁶

c. S-ACCESS (Shinohara; 2008)¹⁴⁸

d. SPS3 (Benavente; 2012)¹⁶⁵

e. CSPS.com (Nishiyama; 2023)¹³¹

f. MATCH (Diener; 2004)¹⁵³

g. PASTRO-I (Kitazono; 2021)¹⁴⁹

h. CSPS (Matsumoto; 2006)¹⁶²
## Ischaemic stroke

The network diagram for ischaemic stroke is presented in Figure 10. We included 8 RCTs in the analysis with 9862 participants. For details regarding detailed numerical values – please see Supplemental Table 12. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.22, 95% CI 0.05, 0.95, low certainty evidence) and Cilostazol (RR 0.51, 95% CI 0.30, 0.85, low certainty evidence) reduces the risk of ischaemic stroke in patients with lacunar stroke (Supplemental Table 12).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

## MACE

The network diagram for major adverse cardiovascular outcome is presented in Figure 11. We included 5 RCTs in the analysis with 12569 participants. For details regarding detailed numerical values – please see Supplemental Table 13. No evidence of global or loop-specific incoherence was found in the network. Compared to placebo, only Aspirin + Dipyridamole (RR 0.70, 95% CI 0.56, 0.88, low certainty evidence) and Clopidogrel + Aspirin (RR 0.74, 95% CI 0.54, 0.99, low certainty evidence) reduces the risk

of MACE in patients with lacunar stroke (Supplemental Table 13).

The size of dots is proportional to the number of patients included in trials, while the widths of the lines are proportional to the number of trials.

## Additional information

Different monotherapy choices are recommended in different countries and are somewhat influenced by the findings for example, in the CAPRIE trial.¹⁶⁹ A subgroup analysis of the SPS3 trial considered the CYP2C19 metaboliser status in patients with lacunar stroke, comparing the CYP2C19*2 with CYP2C19*17 allele; the metaboliser status did not influence the rate of recurrent ischaemic stroke and major bleeding.¹⁷⁰ The recently published subgroup analysis from the CHANCE-2 trial that included patients with minor stroke or transient ischaemic attack within 24h of symptom onset and carring CYP2C19 loss-of-function alleles, for treatment with either ticagrelor + aspirin or clopidogrel + aspirin for 90 days,⁶⁵ showed that for 1750 patients with small vessel occlusion ischaemic stroke, the primary outcome new stroke within 90days occurred among 3.6% of those administered ticagrelor + aspirin versus 7.0% of those administered clopidogrel + aspirin (0.51, 95% CI 0.33, 0.79, *p*=0.002).⁶⁶ This is also discussed in the PICO 2 section of this GL. We did not perform a systematic screen of all relevant literature

<figure><img src="image_22.png" /><figcaption>**Figure 10.** Network Meta-analysis of antiplatelet trials including the outcome 'Ischaemic stroke'.</figcaption></figure>

a. AICLA (Bousser; 1983)¹⁴⁶

b. ECLIPSE (Han; 2013)¹³⁶

c. S-ACCESS (Shinohara; 2008)¹⁴⁸

d. SPS3 (Benavente; 2012)¹⁶⁵

e. CSPS.com (Nishiyama; 2023)¹³¹

f. MATCH (Diener; 2004)¹⁵³

g. PASTRO-I (Kitazono; 2021)¹⁴⁹

h. CSPS (Matsumoto; 2006)¹⁶²
<figure><img src="image_23.png" /><figcaption>**Figure 11.** Network Meta-analysis of antiplatelet trials including the outcome major adverse cardiovascular event (MACE) in patients with lacunar ischaemic stroke.</figcaption></figure>

concerning this topic, therefore we cannot make any specific recommendations. It should be noted that this PICO 6 addresses long term recommendations. The MWG's recommendations on antiplatelet treatment in the acute phase after lacunar stroke are described in PICO 2, which includes an Expert consensus statement that initiation of antiplatelet therapy should be started as soon as possible after stroke onset.

## Previous systematic reviews

A pooled analysis of 17 trials with 42234 subjects with lacunar stroke concluded that a single antiplatelet agent compared with placebo is adequate for secondary stroke prevention, whereas dual antiplatelet therapy should not be used for long-term treatment,⁵⁸ which is in line with our results.

A systematic review and meta-analysis on cilostazol in stroke prevention performed an exploratory sensitivity analysis of 9 trials where more than 40% (on average of the participants had lacunar stroke.)¹⁷¹ Cilostazol treatment was associated with a reduction of recurrent ischaemic stroke (OR 0.64, 95% CI 0.52, 0.79),¹⁷¹ but the authors concluded that more evidence is needed before cilostazol is used more widely in stroke in routine practice.

Another systematic review and meta-analysis of 13 studies with 33011 subjects suggested that cilostazol may be a priority option for secondary prevention in lacunar stroke, but that this needs further study.¹⁶⁸

## Current guidelines

We found no specific recommendations regarding long-term antiplatelet treatment in lacunar ischaemic stroke in guidelines from AHA/ASA 2021,²¹ Canadian Stroke Best Practice 2020,²⁴ ESO 2022,¹⁶ or Australia (https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management and https://app[magicapp.org/#/guideline/8L0RME/section/j1qQXj, accessed on July 7th, 2023) (Table 1).

**Evidence-based Recommendation**

In patients with suspected lacunar ischaemic stroke, for secondary prevention of long-term adverse outcomes, we recommend long term single antiplatelet therapy with aspirin or clopidogrel from 2 to 4 weeks after stroke onset.

Quality of evidence: **Moderate** ⊕⊕⊕

Strength of recommendation: **Weak for intervention** ↑?

**Expert Consensus Statement I**

In patients with suspected lacunar ischaemic stroke twelve of 12 MWG members recommend against the use of long-term,* dual or triple antiplatelet therapy. Instead, single antiplatelet therapy should be used as per the Evidence Based Recommendation above, unless other conditions warrant a combination of these medications.

<footnote>ªPERFORM (Bousser; 2011)¹⁵⁶</footnote>

<footnote>ᵇSOCRATES (Amarenco; 2017)¹⁶⁰</footnote>

<footnote>ᶜESPS-2 (Ariesen; 2006)¹⁴⁷</footnote>

<footnote>ᵈESPRIT (ESPRIT; 2006)¹⁵⁴</footnote>

<footnote>ᵉSPS3 (Benavente 2012)¹⁶⁵</footnote>

<footnote>*Defined as more than 2–4 weeks.</footnote>
<figure><img src="image_23.png" /><figcaption>**Figure 11.** Network Meta-analysis of antiplatelet trials including the outcome major adverse cardiovascular event (MACE) in patients with lacunar ischaemic stroke.</figcaption></figure>

concerning this topic, therefore we cannot make any specific recommendations. It should be noted that this PICO 6 addresses long term recommendations. The MWG's recommendations on antiplatelet treatment in the acute phase after lacunar stroke are described in PICO 2, which includes an Expert consensus statement that initiation of antiplatelet therapy should be started as soon as possible after stroke onset.

## Previous systematic reviews

A pooled analysis of 17 trials with 42234 subjects with lacunar stroke concluded that a single antiplatelet agent compared with placebo is adequate for secondary stroke prevention, whereas dual antiplatelet therapy should not be used for long-term treatment,⁵⁸ which is in line with our results.

A systematic review and meta-analysis on cilostazol in stroke prevention performed an exploratory sensitivity analysis of 9 trials where more than 40% (on average of the participants had lacunar stroke.)¹⁷¹ Cilostazol treatment was associated with a reduction of recurrent ischaemic stroke (OR 0.64, 95% CI 0.52, 0.79),¹⁷¹ but the authors concluded that more evidence is needed before cilostazol is used more widely in stroke in routine practice.

Another systematic review and meta-analysis of 13 studies with 33011 subjects suggested that cilostazol may be a priority option for secondary prevention in lacunar stroke, but that this needs further study.¹⁶⁸

## Current guidelines

We found no specific recommendations regarding long-term antiplatelet treatment in lacunar ischaemic stroke in guidelines from AHA/ASA 2021,²¹ Canadian Stroke Best Practice 2020,²⁴ ESO 2022,¹⁶ or Australia (https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management and https://app[magicapp.org/#/guideline/8L0RME/section/j1qQXj, accessed on July 7th, 2023) (Table 1).

**Evidence-based Recommendation**

In patients with suspected lacunar ischaemic stroke, for secondary prevention of long-term adverse outcomes, we recommend long term single antiplatelet therapy with aspirin or clopidogrel from 2 to 4 weeks after stroke onset.

Quality of evidence: **Moderate** ⊕⊕⊕

Strength of recommendation: **Weak for intervention** ↑?

**Expert Consensus Statement I**

In patients with suspected lacunar ischaemic stroke twelve of 12 MWG members recommend against the use of long-term,* dual or triple antiplatelet therapy. Instead, single antiplatelet therapy should be used as per the Evidence Based Recommendation above, unless other conditions warrant a combination of these medications.

<footnote>ªPERFORM (Bousser; 2011)¹⁵⁶</footnote>

<footnote>ᵇSOCRATES (Amarenco; 2017)¹⁶⁰</footnote>

<footnote>ᶜESPS-2 (Ariesen; 2006)¹⁴⁷</footnote>

<footnote>ᵈESPRIT (ESPRIT; 2006)¹⁵⁴</footnote>

<footnote>ᵉSPS3 (Benavente 2012)¹⁶⁵</footnote>

<footnote>*Defined as more than 2–4 weeks.</footnote>
**Expert Consensus Statement 2**

In patients with suspected lacunar ischaemic stroke, eleven of 12 MWG members agreed that the current evidence was inadequate to recommend routine use of cilostazol to prevent adverse long term outcomes.

**PICO 7:**

In patients with lacunar ischaemic stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention given long term, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder and mood disorders?

**Analysis of current evidence**

Two RCTs have examined the impact of antihypertensive treatment compared to less intense or avoiding this intervention on risk of recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke and MACE in patients with a history of lacunar ischaemic stroke, SPS3 (primary outcomes) and How intensively should we treat blood PRESSure in established cerebral small VEnsel disease? (PRESERVE) trial (secondary outcome),⁹,¹⁷² No data are available on the impact of antihypertensive treatment on mobility, gait disorder or mood disorders in lacunar ischaemic stroke patients. No subgroup analyses in lacunar ischaemic stroke patients are available either in large RCTs on secondary prevention of ischaemic stroke at large. Details of the trials see Supplemental Table 14; PRISMA diagram see Supplement PRISMA diagrams.

*Blood-pressure targets in patients with recent lacunar stroke (SPS3) randomised trial.* The SPS3 trial⁹ is a randomised open-label trial, including patients living in North America, Latin America and Spain who had a recent, MRI-defined symptomatic lacunar ischaemic stroke. Patients were randomly assigned, according to a two-by-two multifactorial design, to a SBP target of 130–149 mmHg or < 130 mmHg. The primary endpoint was reduction in any stroke. Patients were included at least 2 weeks poststroke, with a median of 62 days after the event. In total, 3020 patients were enrolled, 1519 in the higher-target group and 1501 in the lower-target group and followed up for 3.7 ± 2.0 years. After 1 year, the achieved difference in mean SBP was 11 mmHg between the higher-target and the lower-target group.

Non-significant rate reductions were seen for all stroke (HR 0.81, 95% CI 0.64, 1.03, *p*=0.08) and the composite MACE outcome of myocardial infarction or vascular death (HR 0.84, 95% CI 0.68, 1.04, *p*=0.32) with the lower SBP target (Supplemental Table 14). The rate of ICH was significantly reduced (HR 0.37, 95% CI 0.15, 0.95, *p*=0.03)

(Supplemental Table 14). Changes in Cognitive Ability Screening Instrument (CASI) statistical Z scores over time and cumulative incidence of mild cognitive impairment did not differ between assigned BP target groups (*p*=0.520 and *p*=0.555).⁸

*Randomised trial of intensive versus standard blood pressure control in small vessel disease (PRESERVE)*. The PRESERVE trial¹⁷² is a randomised, parallel, multicentre controlled, blinded-outcomes clinical trial where 111 participants with MRI-confirmed lacunar ischaemic stroke and confluent WMH were recruited at least 3 months poststroke and randomised to standard (SBP 130–140 mmHg) (*n*=56) or intensive (SBP < 125 mmHg) (*n*=55) BP targets. The primary endpoint was change in diffusion tensor imaging (DTI) white matter mean diffusivity (MD) peak height between baseline and 24 months and secondary endpoints included change in cognitive performance. Noteworthy, the initial endpoint was a global cognitive score with DTI-MRI as a secondary end point, but following the publication of the SPS3 cognition study, showing that cognitive change could not be detected over 2 years in 2916 participants with lacunar ischaemic stroke, recruitment to the cognitive only arm of PRESERVE was halted and only recruitment to the DTI-MRI arm continued (which had a smaller sample size of 180), with the primary end point of the overall study becoming DTI. Mean BP was reduced by –15.3 and –23.1 mmHg in the standard and intensive groups respectively (*p* < 0.001).

Over 24 months follow-up there was no difference between treatment groups for the primary endpoint of change in MD peak height on DTI (*p*=0.92) or the secondary endpoint of change in cognitive performance (*p* > 0.33, Supplemental Table 14). Of note, in the overall sample there was a significant deterioration in white matter microstructure on multimodal diffusion tensor imaging-magnetic resonance imaging but no detectable decrease in cognition. During follow-up, there were three strokes, and one death in the intensive, and three strokes, and two deaths in the standard arms.

The number of patients with any side effect was 45 in the intensive arm and 36 in the standard arm (OR 2.48, 95% CI 0.96, 6.73, *p*=0.05). There was no difference between groups in the number of falls (intensive 21, standard 14; OR 0.54, 95% CI 0.22, 1.31, *p*=0.16), or postural-related dizziness (intensive 27, standard 22; OR 0.67, 95% CI 0.30, 1.52, *p*=0.34).

**Meta-analysis results**

*Risk of recurrent stroke.* When combining SPS3 and PRESERVE, the lower target group (<130 mmHg) was
**Expert Consensus Statement 2**

In patients with suspected lacunar ischaemic stroke, eleven of 12 MWG members agreed that the current evidence was inadequate to recommend routine use of cilostazol to prevent adverse long term outcomes.

**PICO 7:**

In patients with lacunar ischaemic stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention given long term, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder and mood disorders?

**Analysis of current evidence**

Two RCTs have examined the impact of antihypertensive treatment compared to less intense or avoiding this intervention on risk of recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke and MACE in patients with a history of lacunar ischaemic stroke, SPS3 (primary outcomes) and How intensively should we treat blood PRESSure in established cerebral small VEnsel disease? (PRESERVE) trial (secondary outcome),⁹,¹⁷² No data are available on the impact of antihypertensive treatment on mobility, gait disorder or mood disorders in lacunar ischaemic stroke patients. No subgroup analyses in lacunar ischaemic stroke patients are available either in large RCTs on secondary prevention of ischaemic stroke at large. Details of the trials see Supplemental Table 14; PRISMA diagram see Supplement PRISMA diagrams.

*Blood-pressure targets in patients with recent lacunar stroke (SPS3) randomised trial.* The SPS3 trial⁹ is a randomised open-label trial, including patients living in North America, Latin America and Spain who had a recent, MRI-defined symptomatic lacunar ischaemic stroke. Patients were randomly assigned, according to a two-by-two multifactorial design, to a SBP target of 130–149 mmHg or < 130 mmHg. The primary endpoint was reduction in any stroke. Patients were included at least 2 weeks poststroke, with a median of 62 days after the event. In total, 3020 patients were enrolled, 1519 in the higher-target group and 1501 in the lower-target group and followed up for 3.7 ± 2.0 years. After 1 year, the achieved difference in mean SBP was 11 mmHg between the higher-target and the lower-target group.

Non-significant rate reductions were seen for all stroke (HR 0.81, 95% CI 0.64, 1.03, *p*=0.08) and the composite MACE outcome of myocardial infarction or vascular death (HR 0.84, 95% CI 0.68, 1.04, *p*=0.32) with the lower SBP target (Supplemental Table 14). The rate of ICH was significantly reduced (HR 0.37, 95% CI 0.15, 0.95, *p*=0.03)

(Supplemental Table 14). Changes in Cognitive Ability Screening Instrument (CASI) statistical Z scores over time and cumulative incidence of mild cognitive impairment did not differ between assigned BP target groups (*p*=0.520 and *p*=0.555).⁸

*Randomised trial of intensive versus standard blood pressure control in small vessel disease (PRESERVE)*. The PRESERVE trial¹⁷² is a randomised, parallel, multicentre controlled, blinded-outcomes clinical trial where 111 participants with MRI-confirmed lacunar ischaemic stroke and confluent WMH were recruited at least 3 months poststroke and randomised to standard (SBP 130–140 mmHg) (*n*=56) or intensive (SBP < 125 mmHg) (*n*=55) BP targets. The primary endpoint was change in diffusion tensor imaging (DTI) white matter mean diffusivity (MD) peak height between baseline and 24 months and secondary endpoints included change in cognitive performance. Noteworthy, the initial endpoint was a global cognitive score with DTI-MRI as a secondary end point, but following the publication of the SPS3 cognition study, showing that cognitive change could not be detected over 2 years in 2916 participants with lacunar ischaemic stroke, recruitment to the cognitive only arm of PRESERVE was halted and only recruitment to the DTI-MRI arm continued (which had a smaller sample size of 180), with the primary end point of the overall study becoming DTI. Mean BP was reduced by –15.3 and –23.1 mmHg in the standard and intensive groups respectively (*p* < 0.001).

Over 24 months follow-up there was no difference between treatment groups for the primary endpoint of change in MD peak height on DTI (*p*=0.92) or the secondary endpoint of change in cognitive performance (*p* > 0.33, Supplemental Table 14). Of note, in the overall sample there was a significant deterioration in white matter microstructure on multimodal diffusion tensor imaging-magnetic resonance imaging but no detectable decrease in cognition. During follow-up, there were three strokes, and one death in the intensive, and three strokes, and two deaths in the standard arms.

The number of patients with any side effect was 45 in the intensive arm and 36 in the standard arm (OR 2.48, 95% CI 0.96, 6.73, *p*=0.05). There was no difference between groups in the number of falls (intensive 21, standard 14; OR 0.54, 95% CI 0.22, 1.31, *p*=0.16), or postural-related dizziness (intensive 27, standard 22; OR 0.67, 95% CI 0.30, 1.52, *p*=0.34).

**Meta-analysis results**

*Risk of recurrent stroke.* When combining SPS3 and PRESERVE, the lower target group (<130 mmHg) was
<figure><img src="image_24.png" /><figcaption>**Figure 12.** PICO 7. Long term intensive versus guideline BP reduction to prevent recurrent stroke in patients with lacunar ischaemic stroke.</figcaption></figure>

<figure><img src="image_25.png" /><figcaption>**Figure 13.** PICO 7. Long term intensive versus guideline BP reduction to prevent death in patients with lacunar ischaemic stroke.</figcaption></figure>

found to be non-significantly associated with a relative risk reduction in recurrent stroke of 13% (RR 0.87, 95% CI 0.68, 1.10, *p*=0.25) compared to the higher target group (130–149 mmHg) Table 6, Figure 12.

**Risk of death.** When combining SPS3 and PRESERVE, no significant association was found between the lower and higher target BP group in terms of risk of death (*p*=0.70) Figure 13.

<figure><img src="image_26.png" /><figcaption>PICO 7 Risk of bias of randomised controlled trials (outcome: recurrent stroke, death)</figcaption></figure>

## Additional information

A large number of secondary analyses of the SPS3 trial in subgroup of patients have been conducted (Supplemental Table 14), demonstrating:

*A modifying effect of WMH burden on the risk of recurrent stroke*¹⁷³: Participants with higher WMH burden appeared to experience greater benefit from intensive BP lowering in prevention of recurrent stroke (*p* for interaction 0.04).

*A modifying effect of WMH burden on vascular outcomes amongst older SPS3 participants*¹⁷⁴:

Among 1263 participants aged 65 years and older a lower SBP target (<130 mmHg) appeared more beneficial

among those with worse WMH burden for risk of recurrent stroke (P for interaction 0.01) and MACE (*p* for interaction 0.03). No significant interaction was observed for change in cognitive function.

*No significant modifying effect of cerebral microbleeds on the risk of recurrent stroke and death* 17⁵: Intensive BP lowering significantly reduced risk of stroke recurrence in patients with CMB (HR 0.5, 95% CI 0.3, 0.9) but not patients without CMB (HR 0.7, 95% CI 0.4, 1.3), however, the difference in the magnitude of effect was not significant (*p* for interaction 0.34). No effect on all-cause mortality was detected in patients with (HR 0.9, 95% CI 0.4, 1.8) or without CMB (HR 0.8, 95% CI 0.5, 1.5, *p* for interaction 0.99)
<figure><img src="image_24.png" /><figcaption>**Figure 12.** PICO 7. Long term intensive versus guideline BP reduction to prevent recurrent stroke in patients with lacunar ischaemic stroke.</figcaption></figure>

<figure><img src="image_25.png" /><figcaption>**Figure 13.** PICO 7. Long term intensive versus guideline BP reduction to prevent death in patients with lacunar ischaemic stroke.</figcaption></figure>

found to be non-significantly associated with a relative risk reduction in recurrent stroke of 13% (RR 0.87, 95% CI 0.68, 1.10, *p*=0.25) compared to the higher target group (130–149 mmHg) Table 6, Figure 12.

**Risk of death.** When combining SPS3 and PRESERVE, no significant association was found between the lower and higher target BP group in terms of risk of death (*p*=0.70) Figure 13.

<figure><img src="image_26.png" /><figcaption>PICO 7 Risk of bias of randomised controlled trials (outcome: recurrent stroke, death)</figcaption></figure>

## Additional information

A large number of secondary analyses of the SPS3 trial in subgroup of patients have been conducted (Supplemental Table 14), demonstrating:

*A modifying effect of WMH burden on the risk of recurrent stroke*¹⁷³: Participants with higher WMH burden appeared to experience greater benefit from intensive BP lowering in prevention of recurrent stroke (*p* for interaction 0.04).

*A modifying effect of WMH burden on vascular outcomes amongst older SPS3 participants*¹⁷⁴:

Among 1263 participants aged 65 years and older a lower SBP target (<130 mmHg) appeared more beneficial

among those with worse WMH burden for risk of recurrent stroke (P for interaction 0.01) and MACE (*p* for interaction 0.03). No significant interaction was observed for change in cognitive function.

*No significant modifying effect of cerebral microbleeds on the risk of recurrent stroke and death* 17⁵: Intensive BP lowering significantly reduced risk of stroke recurrence in patients with CMB (HR 0.5, 95% CI 0.3, 0.9) but not patients without CMB (HR 0.7, 95% CI 0.4, 1.3), however, the difference in the magnitude of effect was not significant (*p* for interaction 0.34). No effect on all-cause mortality was detected in patients with (HR 0.9, 95% CI 0.4, 1.8) or without CMB (HR 0.8, 95% CI 0.5, 1.5, *p* for interaction 0.99)
<table><caption>**Table 6.** PICO 7 – GRADE evidence profile table. In patients with lacunar stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention, reduce recurrent stroke and risk of death?</caption><thead><tr><th colspan="3">Certainty assessment</th><th rowspan="2">No of patients<br>Intervention</th><th rowspan="2">Effect<br>Relative<br>(95% CI)</th><th rowspan="2">Certainty<br>Importance</th></tr><tr><th>No of<br>studies</th><th>Study design</th><th>Risk of<br>bias</th><th>Imprecision</th><th>Other<br>considerations</th></tr></thead><tbody><tr><td colspan="6"><strong>Recurrent stroke</strong></td></tr><tr><td rowspan="2">2</td><td rowspan="2">Randomised<br>controlled trials</td><td rowspan="2">serious<sup>a</sup></td><td rowspan="2">not serious</td><td rowspan="2">not serious</td><td rowspan="2">serious<sup>b</sup></td><td rowspan="2">none</td><td rowspan="2">115/1557<br>(7.4%)</td><td rowspan="2">134/1574<br>(8.5%)</td><td rowspan="2">RR 0.87<br>(0.68, 1.10)</td><td rowspan="2">11 fewer per 1000<br>(from 27 fewer to<br>9 more)</td><td rowspan="2">⊕⊕○○<br>Low</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="6"><strong>Death</strong></td></tr><tr><td rowspan="2">2</td><td rowspan="2">Randomised<br>controlled trials</td><td rowspan="2">serious<sup>a</sup></td><td rowspan="2">not serious</td><td rowspan="2">not serious</td><td rowspan="2">serious<sup>b</sup></td><td rowspan="2">none</td><td rowspan="2">107/1540<br>(6.9%)</td><td rowspan="2">103/1561<br>(6.6%)</td><td rowspan="2">RR 1.05<br>(0.81, 1.37)</td><td rowspan="2">3 more per 1000<br>(from 13 fewer to<br>24 more)</td><td rowspan="2">⊕⊕○○<br>Low</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

CI: confidence interval; RR: Relative Risk.

<footnote>aLow to high risk of bias.</footnote>

<footnote>bConfidence interval crosses the clinical decision threshold.</footnote>
<table><caption>**Table 6.** PICO 7 – GRADE evidence profile table. In patients with lacunar stroke, does antihypertensive treatment considering a particular agent or target, compared to less intense or avoiding this intervention, reduce recurrent stroke and risk of death?</caption><thead><tr><th colspan="3">Certainty assessment</th><th rowspan="2">No of patients<br>Intervention</th><th rowspan="2">Effect<br>Relative<br>(95% CI)</th><th rowspan="2">Certainty<br>Importance</th></tr><tr><th>No of<br>studies</th><th>Study design</th><th>Risk of<br>bias</th><th>Imprecision</th><th>Other<br>considerations</th></tr></thead><tbody><tr><td colspan="6"><strong>Recurrent stroke</strong></td></tr><tr><td rowspan="2">2</td><td rowspan="2">Randomised<br>controlled trials</td><td rowspan="2">serious<sup>a</sup></td><td rowspan="2">not serious</td><td rowspan="2">not serious</td><td rowspan="2">serious<sup>b</sup></td><td rowspan="2">none</td><td>115/1557<br>(7.4%)</td><td>134/1574<br>(8.5%)</td><td>RR 0.87<br>(0.68, 1.10)</td><td>11 fewer per 1000<br>(from 27 fewer to<br>9 more)</td><td>⊕⊕○○<br>Low</td></tr><tr><td>107/1540<br>(6.9%)</td><td>103/1561<br>(6.6%)</td><td>RR 1.05<br>(0.81, 1.37)</td><td>3 more per 1000<br>(from 13 fewer to<br>24 more)</td><td>⊕⊕○○<br>Low</td></tr><tr><td colspan="6"><strong>Death</strong></td></tr><tr><td>2</td><td>Randomised<br>controlled trials</td><td>serious<sup>a</sup></td><td>not serious</td><td>not serious</td><td>serious<sup>b</sup></td><td>none</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

CI: confidence interval; RR: Relative Risk.

<footnote>aLow to high risk of bias.</footnote>

<footnote>bConfidence interval crosses the clinical decision threshold.</footnote>
Several secondary analyses have also examined the relation of blood pressure reduction with outcomes, prompting caution:

After a mean follow up of 3.7 years, there was a J-shaped association between achieved blood pressure and outcomes.¹⁷⁶ For example, above a SBP of 124 mmHg, 1 standard deviation higher (11.1 mmHg) was associated with increased mortality (aHR 1.9, 95% CI 1.4, 2.7), whereas below this level, this relationship was inverted (aHR 0.29, 95% CI 0.10, 0.79, *p* < 0.001) for interaction. Above a DBP of 67 mmHg, a 1 standard deviation higher (8.2 mmHg) was associated with an increased risk of stroke (aHR 2.2, 95% CI 1.4, 3.6), whereas below this level, the association was in the opposite direction (aHR 0.34, 95% CI 0.13, 0.89), *p* = 0.02 for interaction. The lowest risk of all events occurred at a nadir of ≈ 120–128 mmHg systolic blood pressure and 65–70 mmHg diastolic blood pressure.

Another study used an unsupervised cluster procedure to identify distinct patterns of BP change during the first 9 months of anti-hypertensive therapy intensification among 1331 SPS3 participants randomised to the lower BP target (SBP<130 mmHg).¹⁷⁷ Compared to mild reducers (mildly elevated baseline SBP and minimal visit-to-visit BP variability) moderate reducers (moderately elevated baseline SBP and moderate visit-to-visit BP variability) had a higher risk of death (aHR 1.6, 95% CI 1.0, 2.7), MACE (aHR 2.1, 95% CI 1.4, 3.2) and stroke (aHR 2.6, 95% CI 1.7, 4.1), while large reducers (very elevated baseline SBP with very large visit-to-visit BP variability) had the highest risk of death (aHR 2.3, 95% CI 1.2, 4.4).¹⁷⁷

## Other guidelines

Few guidelines have addressed the question of BP lowering for secondary stroke prevention in lacunar ischaemic stroke patients specifically (Table 1):

Current US guidelines for the prevention, detection, evaluation and management of high blood pressure in adults suggest that for adults with a lacunar stroke, a target SBP goal of less than 130 mmHg may be reasonable (Class IIb; Level of Evidence B-randomised).¹⁷⁸,¹⁷⁹

A recent Chinese guideline for clinical management of cerebrovascular disorders²⁸ recommends to manage blood pressure in patients with lacunar ischaemic stroke (Class I, level of evidence B). As cSVD leads to a significant decrease in the adaptability of brain tissue to excessive hypertension and hypotension the blood pressure of patients should be closely monitored (Class IIa, level of evidence B). Control of systolic and diastolic pressure is described as the key factor to control the incidence and progression of cSVD (Class IIa, level of evidence B). The guideline also recommends to monitor the 24 h ambulatory blood pressure and, when possible, to detect changes in BP during head upright tilt test (Class I, level of evidence B).

Another, recent Chinese guideline (in Chinese), specifically dedicated to the diagnosis and treatment of cSVD states, first, that an SBP target of below 130 mmHg in patients with cSVD might achieve better outcomes (strength of recommendation: I/level of evidence: A); in the case of co-existing large artery atherosclerosis the magnitude and rate of blood pressure reduction should be relatively small and slow. Second, this guideline states that antihypertensive drugs that reduce blood pressure variability may be more effective in managing cSVD, highlighting that calcium channel blockers and renin angiotensin system inhibitors are more effective in stabilising blood pressure variability (strength of recommendation: II/level of evidence: B).²⁹

Other guidelines focus on BP lowering for secondary stroke prevention in general, with no specific recommendations for lacunar ischaemic stroke:

The latest ESO guideline on secondary stroke prevention¹⁶ recommends BP lowering treatment in people with previous ischaemic stroke or TIA, to reduce the risk of recurrent stroke, aiming for BP <130/80 mmHg. In these people it supports the use of out of office blood pressure measurements wherever feasible, to achieve better long-term control of blood pressure. It supports initiation of a combination of two blood pressure lowering drugs to reduce the risk of recurrent stroke, with consideration of monotherapy where there are potential risks of hypotension, such as in frail, elderly people and people with borderline hypertension. The use of out of office BP measurements is supported wherever feasible.

The AHA/ASA 2021 secondary stroke prevention guideline²¹ recommends an office BP goal of <130/80 mmHg in patients with hypertension who experience a stroke or TIA to reduce the risk of recurrent stroke and vascular events (Class 1; Level of Evidence B-randomised). In these patients, treatment with a thiazide diuretic, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blockers is useful for lowering BP and reducing recurrent stroke risk (Class 1; Level of Evidence A); individualised drug regimens that take into account patient comorbidities, agent pharmacological class and patient preference are recommended to maximise drug efficacy (Class 1; Level of Evidence B-nonrandomised). In patients with no history of hypertension who experience a stroke or TIA and have an average office BP of ≥130/80 mmHg, antihypertensive medication treatment can be beneficial to reduce the risk of recurrent stroke, ICH and other vascular events (Class 2a; Level of Evidence B-randomised).

## Systematic reviews and meta-analyses

The largest most recent meta-analysis exploring the impact of BP-lowering treatment on clinical outcomes in patients with a history of stroke or TIA was conducted as part of the ESO secondary stroke prevention guideline,¹⁶ but did not include any specific subgroup analyses for lacunar ischaemic stroke.
Several secondary analyses have also examined the relation of blood pressure reduction with outcomes, prompting caution:

After a mean follow up of 3.7 years, there was a J-shaped association between achieved blood pressure and outcomes.¹⁷⁶ For example, above a SBP of 124 mmHg, 1 standard deviation higher (11.1 mmHg) was associated with increased mortality (aHR 1.9, 95% CI 1.4, 2.7), whereas below this level, this relationship was inverted (aHR 0.29, 95% CI 0.10, 0.79, *p* < 0.001) for interaction. Above a DBP of 67 mmHg, a 1 standard deviation higher (8.2 mmHg) was associated with an increased risk of stroke (aHR 2.2, 95% CI 1.4, 3.6), whereas below this level, the association was in the opposite direction (aHR 0.34, 95% CI 0.13, 0.89), *p* = 0.02 for interaction. The lowest risk of all events occurred at a nadir of ≈ 120–128 mmHg systolic blood pressure and 65–70 mmHg diastolic blood pressure.

Another study used an unsupervised cluster procedure to identify distinct patterns of BP change during the first 9 months of anti-hypertensive therapy intensification among 1331 SPS3 participants randomised to the lower BP target (SBP<130 mmHg).¹⁷⁷ Compared to mild reducers (mildly elevated baseline SBP and minimal visit-to-visit BP variability) moderate reducers (moderately elevated baseline SBP and moderate visit-to-visit BP variability) had a higher risk of death (aHR 1.6, 95% CI 1.0, 2.7), MACE (aHR 2.1, 95% CI 1.4, 3.2) and stroke (aHR 2.6, 95% CI 1.7, 4.1), while large reducers (very elevated baseline SBP with very large visit-to-visit BP variability) had the highest risk of death (aHR 2.3, 95% CI 1.2, 4.4).¹⁷⁷

## Other guidelines

Few guidelines have addressed the question of BP lowering for secondary stroke prevention in lacunar ischaemic stroke patients specifically (Table 1):

Current US guidelines for the prevention, detection, evaluation and management of high blood pressure in adults suggest that for adults with a lacunar stroke, a target SBP goal of less than 130 mmHg may be reasonable (Class IIb; Level of Evidence B-randomised).¹⁷⁸,¹⁷⁹

A recent Chinese guideline for clinical management of cerebrovascular disorders²⁸ recommends to manage blood pressure in patients with lacunar ischaemic stroke (Class I, level of evidence B). As cSVD leads to a significant decrease in the adaptability of brain tissue to excessive hypertension and hypotension the blood pressure of patients should be closely monitored (Class IIa, level of evidence B). Control of systolic and diastolic pressure is described as the key factor to control the incidence and progression of cSVD (Class IIa, level of evidence B). The guideline also recommends to monitor the 24 h ambulatory blood pressure and, when possible, to detect changes in BP during head upright tilt test (Class I, level of evidence B).

Another, recent Chinese guideline (in Chinese), specifically dedicated to the diagnosis and treatment of cSVD states, first, that an SBP target of below 130 mmHg in patients with cSVD might achieve better outcomes (strength of recommendation: I/level of evidence: A); in the case of co-existing large artery atherosclerosis the magnitude and rate of blood pressure reduction should be relatively small and slow. Second, this guideline states that antihypertensive drugs that reduce blood pressure variability may be more effective in managing cSVD, highlighting that calcium channel blockers and renin angiotensin system inhibitors are more effective in stabilising blood pressure variability (strength of recommendation: II/level of evidence: B).²⁹

Other guidelines focus on BP lowering for secondary stroke prevention in general, with no specific recommendations for lacunar ischaemic stroke:

The latest ESO guideline on secondary stroke prevention¹⁶ recommends BP lowering treatment in people with previous ischaemic stroke or TIA, to reduce the risk of recurrent stroke, aiming for BP <130/80 mmHg. In these people it supports the use of out of office blood pressure measurements wherever feasible, to achieve better long-term control of blood pressure. It supports initiation of a combination of two blood pressure lowering drugs to reduce the risk of recurrent stroke, with consideration of monotherapy where there are potential risks of hypotension, such as in frail, elderly people and people with borderline hypertension. The use of out of office BP measurements is supported wherever feasible.

The AHA/ASA 2021 secondary stroke prevention guideline²¹ recommends an office BP goal of <130/80 mmHg in patients with hypertension who experience a stroke or TIA to reduce the risk of recurrent stroke and vascular events (Class 1; Level of Evidence B-randomised). In these patients, treatment with a thiazide diuretic, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blockers is useful for lowering BP and reducing recurrent stroke risk (Class 1; Level of Evidence A); individualised drug regimens that take into account patient comorbidities, agent pharmacological class and patient preference are recommended to maximise drug efficacy (Class 1; Level of Evidence B-nonrandomised). In patients with no history of hypertension who experience a stroke or TIA and have an average office BP of ≥130/80 mmHg, antihypertensive medication treatment can be beneficial to reduce the risk of recurrent stroke, ICH and other vascular events (Class 2a; Level of Evidence B-randomised).

## Systematic reviews and meta-analyses

The largest most recent meta-analysis exploring the impact of BP-lowering treatment on clinical outcomes in patients with a history of stroke or TIA was conducted as part of the ESO secondary stroke prevention guideline,¹⁶ but did not include any specific subgroup analyses for lacunar ischaemic stroke.
When comparing BP lowering treatment to no intervention, on meta-analysis of data from nine trials,¹⁸⁰⁻¹⁸⁸ there was a significant reduction in the odds of recurrent stroke by almost 20% (OR 0.81, 95% CI 0.71, 0.92, *p*=0.002 non significant for ischaemic and haemorrhagic stroke separately), a significant reduction in MACE (OR 0.80, 95% CI 0.69, 0.94, *p*=0.006), and no significant reduction in all cause death (seven trials,¹⁸⁰,¹⁸²⁻¹⁸⁴,¹⁸⁶,¹⁸⁷ OR 0.97, 95% CI 0.90, 1.05, *p*=0.51). There were insufficient data to allow analysis of the effect of antihypertensive medication on dementia and functional outcome.

When comparing intensive BP treatment with a standard BP reduction strategy, there was a significant reduction in recurrent stroke with (OR 0.79, 95% CI 0.64, 0.98, *p*=0.029), significant for haemorrhagic (*p*=0.033) but not ischaemic stroke (*p*=0.228) and no significant difference between groups for the outcomes of major vascular events, all-cause death on meta-analysis. Functional outcome was only assessed in the SPS3 trial,⁹ with no significant difference between intensive and standard BP reduction groups for poor outcome (mRS 3–6).

Regarding combined versus monotherapy,¹⁶ trials in people with essential hypertension show that the former leads to better control of BP.¹⁸⁹,¹⁹⁰ A large systematic review and meta-analysis shows that the extra BP reduction from combining two drug classes is approximately five times greater than doubling the dose of one drug.¹⁹¹ The European Society of Hypertension and European Society of Cardiology guidelines¹⁹² which recommend initiation of antihypertensive treatment with combination treatment, except in people at increased risk of hypotension and those with mild hypertension and low cardiovascular risk. In the absence of alternative specific evidence for secondary prevention in stroke, and supportive evidence for the potential benefit of combination treatment in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),¹⁸⁰ this European guidance is therefore applicable for most people with prior stroke. No specific data is available for lacunar ischaemic stroke.

Regarding the choice of BP-lowering molecules, in primary prevention trials, calcium channel blockers (CCBs) appear to be slightly more efficacious than other classes in prevention of stroke at large,¹⁹³,¹⁹⁴ and a greater consistency of BP control and lower systolic BP variability¹⁹³ has been observed with CCBs and thiazide-like diuretics. Based on primary prevention guidelines, plus supportive evidence from drug classes used in trials such as PROGRESS,¹⁸⁰,¹⁹⁵ initiation of treatment with a combination of antihypertensive medication, usually containing either a thiazide-like diuretic (such as indapamide) or a CCB (such as amlodipine or felodipine), combined with a RAS inhibitor (ACE inhibitor or angiotensin 2 receptor blocker) was considered reasonable in patients with a history of stroke or TIA.¹⁶ While no trial data is available specifically for patients with lacunar ischaemic stroke, indirect evidence from a

Mendelian randomisation study can be reported.¹⁹⁶ In this study genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischaemic stroke and showed particularly strong associations with small vessel stroke and WMH, an MRI-marker of cSVD.

For patients with prior stroke or TIA, there is concern that a possible lower BP threshold may increase the risk of stroke, or a J-curve effect. In the past, post hoc analyses of RCTs, meta-analyses and population-based studies of patients with cerebrovascular disease have shown an inconsistent relationship between achieved SBP<120mmHg and poor outcomes.¹⁹⁵,¹⁹⁷⁻²⁰⁰ New data from RCTs and large meta-analyses now provide compelling evidence that neurologically stable patients with cerebrovascular disease also benefit from a BP goal of <130/80mmHg and that BP targets for stroke prevention should be more aligned with targets for prevention of other cardiovascular conditions. However, there is insufficient evidence to recommend a lower limit of BP within the normal range for patients with prior stroke.

**Evidence-based Recommendation**

In patients with lacunar ischaemic stroke we recommend the use of antihypertensive treatment to prevent recurrent stroke and MACE.

Quality of evidence: Low ⊕⊕

Strength of recommendation: **Strong for intervention** ↑↑

**Expert Consensus Statement 1**

Twelve of 12 MWG members suggest that: BP should be appropriately monitored and well controlled, when possible through use of out of office blood pressure measurements. We cannot advise any specific antihypertensive treatment.

**Expert Consensus Statement 2**

Eleven of 12 MWG members agree that aiming for BP <130/80 mmHg as generally recommended for patients with previous ischaemic stroke or TIA may be reasonable, but that drastic BP reductions and important BP variability should be avoided, probably targeting SBP between 125 and 130mmHg and DBP between 70 and 80mmHg.

## PICO 8:

In patients with lacunar ischaemic stroke, does treatment with lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

## Analysis of current evidence

We identified two randomised clinical trials relevant to this PICO question,²⁰¹,²⁰² (Supplemental Table 15; Supplement
When comparing BP lowering treatment to no intervention, on meta-analysis of data from nine trials,¹⁸⁰⁻¹⁸⁸ there was a significant reduction in the odds of recurrent stroke by almost 20% (OR 0.81, 95% CI 0.71, 0.92, *p*=0.002 non significant for ischaemic and haemorrhagic stroke separately), a significant reduction in MACE (OR 0.80, 95% CI 0.69, 0.94, *p*=0.006), and no significant reduction in all cause death (seven trials,¹⁸⁰,¹⁸²⁻¹⁸⁴,¹⁸⁶,¹⁸⁷ OR 0.97, 95% CI 0.90, 1.05, *p*=0.51). There were insufficient data to allow analysis of the effect of antihypertensive medication on dementia and functional outcome.

When comparing intensive BP treatment with a standard BP reduction strategy, there was a significant reduction in recurrent stroke with (OR 0.79, 95% CI 0.64, 0.98, *p*=0.029), significant for haemorrhagic (*p*=0.033) but not ischaemic stroke (*p*=0.228) and no significant difference between groups for the outcomes of major vascular events, all-cause death on meta-analysis. Functional outcome was only assessed in the SPS3 trial,⁹ with no significant difference between intensive and standard BP reduction groups for poor outcome (mRS 3–6).

Regarding combined versus monotherapy,¹⁶ trials in people with essential hypertension show that the former leads to better control of BP.¹⁸⁹,¹⁹⁰ A large systematic review and meta-analysis shows that the extra BP reduction from combining two drug classes is approximately five times greater than doubling the dose of one drug.¹⁹¹ The European Society of Hypertension and European Society of Cardiology guidelines¹⁹² which recommend initiation of antihypertensive treatment with combination treatment, except in people at increased risk of hypotension and those with mild hypertension and low cardiovascular risk. In the absence of alternative specific evidence for secondary prevention in stroke, and supportive evidence for the potential benefit of combination treatment in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),¹⁸⁰ this European guidance is therefore applicable for most people with prior stroke. No specific data is available for lacunar ischaemic stroke.

Regarding the choice of BP-lowering molecules, in primary prevention trials, calcium channel blockers (CCBs) appear to be slightly more efficacious than other classes in prevention of stroke at large,¹⁹³,¹⁹⁴ and a greater consistency of BP control and lower systolic BP variability¹⁹³ has been observed with CCBs and thiazide-like diuretics. Based on primary prevention guidelines, plus supportive evidence from drug classes used in trials such as PROGRESS,¹⁸⁰,¹⁹⁵ initiation of treatment with a combination of antihypertensive medication, usually containing either a thiazide-like diuretic (such as indapamide) or a CCB (such as amlodipine or felodipine), combined with a RAS inhibitor (ACE inhibitor or angiotensin 2 receptor blocker) was considered reasonable in patients with a history of stroke or TIA.¹⁶ While no trial data is available specifically for patients with lacunar ischaemic stroke, indirect evidence from a

Mendelian randomisation study can be reported.¹⁹⁶ In this study genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischaemic stroke and showed particularly strong associations with small vessel stroke and WMH, an MRI-marker of cSVD.

For patients with prior stroke or TIA, there is concern that a possible lower BP threshold may increase the risk of stroke, or a J-curve effect. In the past, post hoc analyses of RCTs, meta-analyses and population-based studies of patients with cerebrovascular disease have shown an inconsistent relationship between achieved SBP<120mmHg and poor outcomes.¹⁹⁵,¹⁹⁷⁻²⁰⁰ New data from RCTs and large meta-analyses now provide compelling evidence that neurologically stable patients with cerebrovascular disease also benefit from a BP goal of <130/80mmHg and that BP targets for stroke prevention should be more aligned with targets for prevention of other cardiovascular conditions. However, there is insufficient evidence to recommend a lower limit of BP within the normal range for patients with prior stroke.

**Evidence-based Recommendation**

In patients with lacunar ischaemic stroke we recommend the use of antihypertensive treatment to prevent recurrent stroke and MACE.

Quality of evidence: Low ⊕⊕

Strength of recommendation: **Strong for intervention** ↑↑

**Expert Consensus Statement 1**

Twelve of 12 MWG members suggest that: BP should be appropriately monitored and well controlled, when possible through use of out of office blood pressure measurements. We cannot advise any specific antihypertensive treatment.

**Expert Consensus Statement 2**

Eleven of 12 MWG members agree that aiming for BP <130/80 mmHg as generally recommended for patients with previous ischaemic stroke or TIA may be reasonable, but that drastic BP reductions and important BP variability should be avoided, probably targeting SBP between 125 and 130mmHg and DBP between 70 and 80mmHg.

## PICO 8:

In patients with lacunar ischaemic stroke, does treatment with lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

## Analysis of current evidence

We identified two randomised clinical trials relevant to this PICO question,²⁰¹,²⁰² (Supplemental Table 15; Supplement
PRISMA diagrams). Other RCTS and observational studies did not adequately subtype ischaemic stroke or report outcomes stratified by stroke subtype.

The main SPARCL trial randomised 4731 patients with a history of stroke, TIA 1–6 months previously and with no pre-existing indication for lipid lowering therapy to receive 80 mg atorvastatin versus placebo.²⁰³ Patients with atrial fibrillation, peripheral vascular disease or coronary artery disease were excluded. The main results showed that over a follow up of 4.9 years atorvastatin reduced the overall incidence of stroke and cardiovascular events with no effect on mortality.

A subsequent sub-analysis of the SPARCL trial included here investigated primary end points and outcomes stratified by presenting stroke subtype (large vessel, small vessel, unknown cause and ICH).²⁰¹ There were limited numbers of patients with cardio-embolic stroke as those with AF and other heart disease were excluded. Thirty percent of participants had small vessel (referred to here as lacunar) stroke, 16% large vessel, 22% unknown, 31% TIA and 2% ICH. Of the 1409 patients with lacunar stroke at baseline the primary outcome of any stroke occurred in 93 (13.1%) of the atorvastatin treated group and 109 (15.2%) of the control group with a HR 0.85, 95% CI 0.64, 1.12, *p*=0.249. The HR were similar for secondary outcomes of Stroke/TIA or MACE. The primary end point event rate of fatal or non-fatal stroke for those randomised to atorvastatin versus placebo was 13.1% versus 18.6% for patients with large vessel stroke, 11.2% versus 12.7% for unknown cause and 7.6% versus 8.8% for TIA. The trial did not find a difference in the efficacy of treatment for the primary outcome of stroke (large vessel stroke HR 0.70, 95% CI 0.49, 1.02, TIA HR 0.81, 95% CI 0.57, 1.17, SVD HR 0.85, 95% CI 0.64, 1.12, unknown cause HR 0.87, 95% CI 0.61, 1.24, haemorrhagic stroke HR 3.24, 95% CI 1.01, 10.4; P for heterogeneity=0.421), or MACE (P for heterogeneity=0.360) based on stroke subtype of the index event. It should be noted however that this was a post hoc subgroup analysis.

The J-STARS trial was a randomised multicentre open label parallel group study which randomised 1578 patients with non cardio-embolic ischaemic stroke and total cholesterol levels of 4.65–6.21 mmol/L to receive pravastatin 10 mg once daily versus placebo with a primary outcome of stroke/TIA over a mean follow up period of 4.9 years.²⁰² At baseline 1006 patients had lacunar infarcts, 401 atherothrombotic and 171 unknown aetiology. The main results for the trial showed no significant difference for the primary outcome of stroke/TIA between the groups but the rate of atherothrombotic infarction was lower in the pravastatin group compared to the control group (0.21% vs 0.64%/year, *p*=0.0047, aHR 0.33, 95% CI 0.15, 0.74). Data are presented in the Supplemental material of the publication, providing outcomes stratified by baseline stroke subtype.²⁰² In the 1006 patients with lacunar stroke at baseline there was no significant difference in the primary outcome of TIA/stroke (49 stroke outcomes in the pravastatin arm and 47 stroke outcomes in the control arm) but the authors report a trend in reduction of incident atherothrombotic infarcts for patients with lacunar stroke at baseline albeit limited by small event rates (0 in case group, 10 in control).

A meta-analysis was performed using the data from the subgroup analysis of the SPARCL trial and the J-STARS trial to evaluate whether statins would be effective in reducing the risk of stroke/TIA in patients with lacunar ischaemic stroke.²⁰¹,²⁰² Neither Pravastatin 10 mg nor Atorvastatin 80 mg was found to be effective in reducing the risk of stroke/TIA in patients with lacunar ischaemic stroke (Figure 14). Furthermore, combining the results of the 2 trials, statin use was not associated with a significant reduction of the risk of stroke/TIA (RR 0.93, 95% CI 0.77, 1.12) (Figure 14). Taken together, since neither trial focused on lacunar ischaemic stroke and the meta-analysis was inconclusive, we feel that the evidence is insufficient to make a recommendation (Table 7) and therefore the Evidence-based Recommendation reflects the continued uncertainty over lipid lowering specifically in lacunar ischaemic stroke.

<figure><img src="image_27.png" /><figcaption>PICO 8 Risk of bias of randomised controlled trials (outcome: recurrent stroke)</figcaption></figure>
PRISMA diagrams). Other RCTS and observational studies did not adequately subtype ischaemic stroke or report outcomes stratified by stroke subtype.

The main SPARCL trial randomised 4731 patients with a history of stroke, TIA 1–6 months previously and with no pre-existing indication for lipid lowering therapy to receive 80 mg atorvastatin versus placebo.²⁰³ Patients with atrial fibrillation, peripheral vascular disease or coronary artery disease were excluded. The main results showed that over a follow up of 4.9 years atorvastatin reduced the overall incidence of stroke and cardiovascular events with no effect on mortality.

A subsequent sub-analysis of the SPARCL trial included here investigated primary end points and outcomes stratified by presenting stroke subtype (large vessel, small vessel, unknown cause and ICH).²⁰¹ There were limited numbers of patients with cardio-embolic stroke as those with AF and other heart disease were excluded. Thirty percent of participants had small vessel (referred to here as lacunar) stroke, 16% large vessel, 22% unknown, 31% TIA and 2% ICH. Of the 1409 patients with lacunar stroke at baseline the primary outcome of any stroke occurred in 93 (13.1%) of the atorvastatin treated group and 109 (15.2%) of the control group with a HR 0.85, 95% CI 0.64, 1.12, *p*=0.249. The HR were similar for secondary outcomes of Stroke/TIA or MACE. The primary end point event rate of fatal or non-fatal stroke for those randomised to atorvastatin versus placebo was 13.1% versus 18.6% for patients with large vessel stroke, 11.2% versus 12.7% for unknown cause and 7.6% versus 8.8% for TIA. The trial did not find a difference in the efficacy of treatment for the primary outcome of stroke (large vessel stroke HR 0.70, 95% CI 0.49, 1.02, TIA HR 0.81, 95% CI 0.57, 1.17, SVD HR 0.85, 95% CI 0.64, 1.12, unknown cause HR 0.87, 95% CI 0.61, 1.24, haemorrhagic stroke HR 3.24, 95% CI 1.01, 10.4; P for heterogeneity=0.421), or MACE (P for heterogeneity=0.360) based on stroke subtype of the index event. It should be noted however that this was a post hoc subgroup analysis.

The J-STARS trial was a randomised multicentre open label parallel group study which randomised 1578 patients with non cardio-embolic ischaemic stroke and total cholesterol levels of 4.65–6.21 mmol/L to receive pravastatin 10 mg once daily versus placebo with a primary outcome of stroke/TIA over a mean follow up period of 4.9 years.²⁰² At baseline 1006 patients had lacunar infarcts, 401 atherothrombotic and 171 unknown aetiology. The main results for the trial showed no significant difference for the primary outcome of stroke/TIA between the groups but the rate of atherothrombotic infarction was lower in the pravastatin group compared to the control group (0.21% vs 0.64%/year, *p*=0.0047, aHR 0.33, 95% CI 0.15, 0.74). Data are presented in the Supplemental material of the publication, providing outcomes stratified by baseline stroke subtype.²⁰² In the 1006 patients with lacunar stroke at baseline there was no significant difference in the primary outcome of TIA/stroke (49 stroke outcomes in the pravastatin arm and 47 stroke outcomes in the control arm) but the authors report a trend in reduction of incident atherothrombotic infarcts for patients with lacunar stroke at baseline albeit limited by small event rates (0 in case group, 10 in control).

A meta-analysis was performed using the data from the subgroup analysis of the SPARCL trial and the J-STARS trial to evaluate whether statins would be effective in reducing the risk of stroke/TIA in patients with lacunar ischaemic stroke.²⁰¹,²⁰² Neither Pravastatin 10 mg nor Atorvastatin 80 mg was found to be effective in reducing the risk of stroke/TIA in patients with lacunar ischaemic stroke (Figure 14). Furthermore, combining the results of the 2 trials, statin use was not associated with a significant reduction of the risk of stroke/TIA (RR 0.93, 95% CI 0.77, 1.12) (Figure 14). Taken together, since neither trial focused on lacunar ischaemic stroke and the meta-analysis was inconclusive, we feel that the evidence is insufficient to make a recommendation (Table 7) and therefore the Evidence-based Recommendation reflects the continued uncertainty over lipid lowering specifically in lacunar ischaemic stroke.

<figure><img src="image_27.png" /><figcaption>PICO 8 Risk of bias of randomised controlled trials (outcome: recurrent stroke)</figcaption></figure>
<figure><img src="image_28.png" /><figcaption>**Figure 14.** PICO 8. Effect of lipid lowering on recurrent stroke or TIA in patients with lacunar ischaemic stroke.</figcaption></figure>

## Additional information

The Heart Protection Study included 3280 patients with cerebrovascular disease (defined as non-disabling stroke, TIA or having had a carotid endarterectomy) in whom treatments with simvastatin 40 mg versus placebo reduced subsequent major vascular events over 5 years follow up *n*=406 (24.7%) versus 488 (29.8%); *p*=0.001.²⁰⁴ Although patients with lacunar stroke are likely to have been recruited to this study there is no mention of the proportion with lacunar stroke.

Similarly, in the Treat Stroke to Target Trial 2860 patients with recent stroke or TIA and ‘atherosclerotic disease’ were randomised in France and South Korea to receive lipid lowering medication (statin, ezetimibe or both) with a lower target (LDL-C<1.8 mmol/L (<70 mg/dL)) or higher target (2.3–2.8 mmol/L (90–110 mg/dL)).²⁰⁵ The composite primary end point (MACE) occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (aHR 0.78, 95% CI 0.61, 0.98; *p*=0.04) suggesting benefit to a lower target. Again, stroke was not subtyped.

International US,²¹ European¹⁶,²⁰⁶ and local guidelines (UK/Ireland https://www.strokeguideline.org/ Sweden https://www.socialstyrelsen.se/globalassets/share-point-dokument/artikelkatalog/nationella-riktlinjer/2020-1-6545-kunskapsunderlag-2020.pdf) recommend

### Evidence-based Recommendation

There is continued uncertainty regarding the effect of lipid lowering specific to lacunar stroke. However we recognise that lipid lowering is effective in reducing clinically adverse outcomes in patients with undifferentiated ischaemic stroke.
Quality of evidence: Low ⊕⊕
Strength of recommendation: -

### Expert Consensus Statement

Twelve of 12 MWG members agreed that patients with lacunar ischaemic stroke should receive lipid lowering therapy given there is some evidence of benefit and no clear evidence of harm.

intensive LDL-C lowering therapy in patients following ischaemic stroke with the AHA and UK guidance specifying atorvastatin 80 mg od and to consider other agents based upon co-morbidities with the AHA recommending a target level of LDL-C<1.8 mmol/L (<70 mg/dL) (Table 1). Where documented, there was good representation of patients with lacunar stroke in the background trials and there is no convincing evidence that patient with lacunar stroke subtypes should be treated differently from other ischaemic stroke subtypes with regards to management of lipid profiles.
<figure><img src="image_28.png" /><figcaption>**Figure 14.** PICO 8. Effect of lipid lowering on recurrent stroke or TIA in patients with lacunar ischaemic stroke.</figcaption></figure>

## Additional information

The Heart Protection Study included 3280 patients with cerebrovascular disease (defined as non-disabling stroke, TIA or having had a carotid endarterectomy) in whom treatments with simvastatin 40 mg versus placebo reduced subsequent major vascular events over 5 years follow up *n*=406 (24.7%) versus 488 (29.8%); *p*=0.001.²⁰⁴ Although patients with lacunar stroke are likely to have been recruited to this study there is no mention of the proportion with lacunar stroke.

Similarly, in the Treat Stroke to Target Trial 2860 patients with recent stroke or TIA and ‘atherosclerotic disease’ were randomised in France and South Korea to receive lipid lowering medication (statin, ezetimibe or both) with a lower target (LDL-C<1.8 mmol/L (<70 mg/dL)) or higher target (2.3–2.8 mmol/L (90–110 mg/dL)).²⁰⁵ The composite primary end point (MACE) occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (aHR 0.78, 95% CI 0.61, 0.98; *p*=0.04) suggesting benefit to a lower target. Again, stroke was not subtyped.

International US,²¹ European¹⁶,²⁰⁶ and local guidelines (UK/Ireland https://www.strokeguideline.org/ Sweden https://www.socialstyrelsen.se/globalassets/share-point-dokument/artikelkatalog/nationella-riktlinjer/2020-1-6545-kunskapsunderlag-2020.pdf) recommend

### Evidence-based Recommendation

There is continued uncertainty regarding the effect of lipid lowering specific to lacunar stroke. However we recognise that lipid lowering is effective in reducing clinically adverse outcomes in patients with undifferentiated ischaemic stroke.
Quality of evidence: Low ⊕⊕
Strength of recommendation: -

### Expert Consensus Statement

Twelve of 12 MWG members agreed that patients with lacunar ischaemic stroke should receive lipid lowering therapy given there is some evidence of benefit and no clear evidence of harm.

intensive LDL-C lowering therapy in patients following ischaemic stroke with the AHA and UK guidance specifying atorvastatin 80 mg od and to consider other agents based upon co-morbidities with the AHA recommending a target level of LDL-C<1.8 mmol/L (<70 mg/dL) (Table 1). Where documented, there was good representation of patients with lacunar stroke in the background trials and there is no convincing evidence that patient with lacunar stroke subtypes should be treated differently from other ischaemic stroke subtypes with regards to management of lipid profiles.
<table><caption>**Table 7.** GRADE evidence profile for PICO 8 long-term lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, to reduce stroke or TIA in patients with lacunar ischaemic stroke.</caption><thead><tr><th colspan="3">Certainty assessment</th><th colspan="3">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirect-ness</th><th>Imprecision</th><th>Other considerations</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td colspan="10"><strong>Stroke/TIA</strong></td></tr><tr><td>2</td><td>randomised trials</td><td>serious</td><td>not serious</td><td>not serious</td><td>serious<sup>a</sup></td><td>none</td><td>RR 0.93 (0.77, 1.12)</td><td>11 fewer per 1000 (from 35 fewer to 18 more)</td><td>⊕⊕⊕ Low</td><td>CRITICAL</td></tr></tbody></table>

CI: confidence interval; RR: risk ratio; TIA: Transient Ischaemic Attack.

Explanations

<sup>a</sup>Confidence interval crosses the clinical decision threshold.

## PICO 9:

In patients with lacunar ischaemic stroke, does treatment with lifestyle interventions (e.g. smoking cessation, dietary interventions, weight reduction, physical exercise, cognitive/behavioural or social interventions, sleep disorder/ sleep apnoea interventions, or a mixture of these), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

Lifestyle factors such as smoking, physical inactivity, diet and sodium intake are well-known modifiable risk factors for stroke<sup>21,207-209</sup> and have been associated with the severity of SVD brain changes in observational studies.<sup>210-212</sup> Rigorous management of lifestyle factors has been recommended alongside evidence-based medications.<sup>211</sup> However, trials investigating the impact of lifestyle and behavioural interventions in SVD are still scarce. The ESO Guideline on covert cerebral SVD in 2021 gave no recommendation for any specific lifestyle intervention due to insufficient direct evidence but stated that it is reasonable to promote healthy lifestyle interventions as recommended in primary prevention for vascular disease.<sup>1</sup> None of the previous stroke prevention guidelines have explicitly referred to stroke subtype when discussing lifestyle modifications (Table 1).<sup>1,24,213-215</sup> Here, we evaluate the evidence for different lifestyle interventions on adverse outcomes in patients with clinically evident lacunar stroke.

## Analysis of current evidence

The literature search identified two RCTs addressing the effect of lifestyle interventions in reducing adverse clinical outcomes in patients with lacunar stroke (Supplement PRISMA diagram), one on physical exercise and the other on a dietary intervention (nutritional supplement). As it was not possible to pool the studies for meta-analysis, we describe the results narratively. Summary of the main findings is given in Supplemental Table 16.

**Physical exercise.** The HITPALS study included patients with acute/postacute lacunar stroke or TIA with MRI-confirmed signs of a previous lacunar stroke.<sup>208,216</sup> The patients were randomised within 3 weeks after the symptom onset to 3-month home-based high-intensity interval training (15 min a day, 5 days per week, with weekly telephone calls to ensure compliance) or usual care including encouragement to lifestyle changes (baseline *n*=31+32). The primary outcome was cardiorespiratory fitness (Graded Cycling Test with Talk Test), while the secondary outcomes included measures of post-stroke fatigue, depression, mental well-being, chronic stress, cognition (Montreal Cognitive Assessment), blood pressure, BMI and physical activity. The home-based training protocol
<table><caption>**Table 7.** GRADE evidence profile for PICO 8 long-term lipid lowering agents (considering a particular agent, dose, target), compared to less intense or avoiding this intervention, to reduce stroke or TIA in patients with lacunar ischaemic stroke.</caption><thead><tr><th colspan="3">Certainty assessment</th><th colspan="3">No of patients</th><th colspan="2">Effect</th><th rowspan="2">Certainty</th><th rowspan="2">Importance</th></tr><tr><th>No of studies</th><th>Study design</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirect-ness</th><th>Imprecision</th><th>Other considerations</th><th>Relative (95% CI)</th><th>Absolute (95% CI)</th></tr></thead><tbody><tr><td colspan="10"><strong>Stroke/TIA</strong></td></tr><tr><td>2</td><td>randomised trials</td><td>serious</td><td>not serious</td><td>not serious</td><td>serious<sup>a</sup></td><td>none</td><td>RR 0.93 (0.77, 1.12)</td><td>11 fewer per 1000 (from 35 fewer to 18 more)</td><td>⊕⊕⊕ Low</td><td>CRITICAL</td></tr></tbody></table>

CI: confidence interval; RR: risk ratio; TIA: Transient Ischaemic Attack.

Explanations

<sup>a</sup>Confidence interval crosses the clinical decision threshold.

## PICO 9:

In patients with lacunar ischaemic stroke, does treatment with lifestyle interventions (e.g. smoking cessation, dietary interventions, weight reduction, physical exercise, cognitive/behavioural or social interventions, sleep disorder/ sleep apnoea interventions, or a mixture of these), compared to less intense or avoiding this intervention, reduce recurrent ischaemic stroke, dependency, death, cognitive impairment or dementia, haemorrhagic stroke, MACE, mobility or gait disorder, and mood disorders?

Lifestyle factors such as smoking, physical inactivity, diet and sodium intake are well-known modifiable risk factors for stroke<sup>21,207-209</sup> and have been associated with the severity of SVD brain changes in observational studies.<sup>210-212</sup> Rigorous management of lifestyle factors has been recommended alongside evidence-based medications.<sup>211</sup> However, trials investigating the impact of lifestyle and behavioural interventions in SVD are still scarce. The ESO Guideline on covert cerebral SVD in 2021 gave no recommendation for any specific lifestyle intervention due to insufficient direct evidence but stated that it is reasonable to promote healthy lifestyle interventions as recommended in primary prevention for vascular disease.<sup>1</sup> None of the previous stroke prevention guidelines have explicitly referred to stroke subtype when discussing lifestyle modifications (Table 1).<sup>1,24,213-215</sup> Here, we evaluate the evidence for different lifestyle interventions on adverse outcomes in patients with clinically evident lacunar stroke.

## Analysis of current evidence

The literature search identified two RCTs addressing the effect of lifestyle interventions in reducing adverse clinical outcomes in patients with lacunar stroke (Supplement PRISMA diagram), one on physical exercise and the other on a dietary intervention (nutritional supplement). As it was not possible to pool the studies for meta-analysis, we describe the results narratively. Summary of the main findings is given in Supplemental Table 16.

**Physical exercise.** The HITPALS study included patients with acute/postacute lacunar stroke or TIA with MRI-confirmed signs of a previous lacunar stroke.<sup>208,216</sup> The patients were randomised within 3 weeks after the symptom onset to 3-month home-based high-intensity interval training (15 min a day, 5 days per week, with weekly telephone calls to ensure compliance) or usual care including encouragement to lifestyle changes (baseline *n*=31+32). The primary outcome was cardiorespiratory fitness (Graded Cycling Test with Talk Test), while the secondary outcomes included measures of post-stroke fatigue, depression, mental well-being, chronic stress, cognition (Montreal Cognitive Assessment), blood pressure, BMI and physical activity. The home-based training protocol