Secondary Stroke Prevention After Lacunar Stroke - Antiplatelet Choice

and Risk Factor Control

Bernard PL Chan National University Hospital

Ho Chi Minh City, Vietnam

November 2014

Neurology 1965,15:774-84

Of 1042 brains, 114 (11%) had lacunes (av 3.3).

Small trabeculated cavities - old infarcts.

Usually pale, 30 brown or amber.

Size mostly 1-4 mm, largest 17 mm.

Occlusion of penetrating artery in 6/7 examined.

113 had atherosclerosis of cerebral arteries.

30 had superficial cerebral/cerebellar infarcts.

Hypertension in 113, DM in 13 (11%).

88 had no history of stroke / neurologic deficits.

41 (35%) also had ICH, 17 fatal, same locations.

Ischemic Stroke Classification Oxfordshire Community Stroke Project (OCSP)

Total Anterior Circulation Syndrome (TACS) •  Hemiplegia/severe hemiparesis + Hemianopia + Cortical dysfunction. •  +/- Sensory deficit. Partial Anterior Circulation Syndromes (PACS) •  2/3 of TACS. •  Pure motor/sensory deficit less extensive than LACI. •  Pure cortical dysfunction. Lacunar Syndromes (LACI) •  1. Pure motor stroke; 2, Pure sensory stroke; 3. Ataxic hemiparesis;

4. Sensorimotor stroke. •  No visual field defect, cortical dysfunction or brainstem disturbance. Posterior Circulation Syndrome (POCS) •  Ipsilateral cranial nerve palsy with contralateral motor/sensory deficit. •  Bilateral motor/sensory deficit. •  Conjugate eye movement disorder. •  Cerebellar dysfunction. •  Isolated hemianopia or cortical blindness.

Advantages: requires only clinical signs, provides some information on etiology and prognosis. Disadvantages: different etiologies in same syndrome, not adequate for modern stroke management.

Etiologies of Ischemic Stroke (TOAST Criteria)

•  Large artery atherosclerosis •  Cardioembolism •  Small artery disease •  Other determined causes

–  Large artery dissection, hypercoagulable states, cerebral venous thrombosis, vasculitis.

•  Undetermined cause or multiple etiologies Apart from neuroimaging by CT/MRI, requires vascular studies (duplex US+TCD, CTA or MRA), echocardiogram and Holter for proper classification.

Small vessel disease is an important cause of ischemic stroke in Asia …

Mehndiratta, JNNP 2014

Korean Stroke Registry

Kim, Eur Heart J 2013,34:2760 Kim, J Stroke 2014,16:8 Suwenwela, J Stroke 2014,16:1

Systematic review on stroke subtypes in Chinese vs White Tsai, Neurology 2013,81:264

Age standardized incidence rates

For ICH –

China > Taiwan.

Community > Hospital in China.

Chinese > White.

For Lacunar Stroke –

Chinese > White (different methodologies).

During 1991-2000, ICH decreasing, and IS increasing in China. (Jiang, Stroke 2006;37:63)

Hisayama Study: 13-years cohorts from 1961, 1974, 1988 with 13 years FU.

Decreased incidence rates of IS and lacunar infarcts with better management of hypertension.

Kubo, Circulation 2008; 118:2672

Problems with Lacunar Infarct Definitions

Clinical definition – typical lacunar syndrome with no cortical signs:

•  137 patients with mild cortical or lacunar syndrome: After DWI, 21/93 (23%) with cortical syndrome had LI, 7/44 (16%) with lacunar syndrome had cortical infarct.1

•  LI close to cortex can cause cortical symptoms.1

MRI definition – Size: Acute < 20 mm, Chronic > 3 mm but < 15 mm:

•  Striatocapsular infarcts can shrink markedly to small lacunes with time.2,3

1. Potter, Cerebrovasc Dis 2010; 29:395. 2,3. Wardlaw, Lancet Neurol 2013; 12:483-97 and 822-38.

Lacunar Infarct ≠ Small Vessel Disease

•  Up to 1/3 (usually 10-15%) patients with lacunar stroke also had significant potential embolic source from carotid artery or heart (Horowitz DR, Stroke 1992,23:325-7).

•  Some lacunar strokes are caused by atherosclerosis of the branch artery (branch artery disease) or parent artery (parent artery disease). They should be treated as LAD.

Caplan, Neurology 1989,39:1246 Nah, Stroke 2010,41:2822

Small Artery Disease •  Small infarcts less than 1.5 cm in territories of

penetrating arteries (basal ganglia, thalami, cerebellar hemispheres, pons.

•  Lipohyalinosis leading to vessel occlusion secondary to hypertension and diabetes is the most common mechanism.

•  Lacunar syndromes include pure motor

hemiparesis, pure sensory stroke, sensory-motor syndrome, ataxic hemiparesis, and dysarthria-clumsy hand syndrome.

•  Sites of both lacunar infarcts and hypertensive ICH are the same – territories of small penetrating arteries. Presentation likely related to control of hypertension.

•  Lacunar infarcts and ICH are also more common in Asians.

Warlow. Stroke, Practical Management

MRI Findings in Small Vessel Disease (Wardlaw. Lancet Neurol 2013,12:822-38)

Small Vessel Disease

Neuroimaging findings:

•  Acute lacunar infarction

•  Chronic lacunar cavity

•  Silent brain infarcts

•  White matter hyperintensities

•  Prominent perivascular spaces

•  Cerebral microbleeds

•  Intracerebral hemorrhage

•  Brain atrophy

Clinical Presentations:

•  Acute ischemic stroke

•  Acute hemorrhagic stroke

•  Executive dysfunction

•  Vascular cognitive impairment

•  Dementia

•  Gait impairment

•  Vascular Parkinsonism

Lacunar Infarct vs Deep ICH – Who Gets Which ? North Manhattan Study. Labovitz, Neurology 2007; 68:606

LI patients were older with higher rates of DM and high cholesterol.

Pantoni, Lancet Neurol 2010; 9:689

Lipohyalinosis Microaneurysm

Microatheroma Fibrinoid necrosis

Established Antiplatelet Therapies for Secondary Stroke Prevention

•  Aspirin •  (Ticlopidine) •  Clopidogrel •  Aspirin + Dipyridamole combination

Antiplatelet Drugs / Targets

Cyclo-oxygenase Aspirin, Triflusal

cAMP PDE Dipyridamole, Cilostazol

P2Y12 ADP receptor Ticlodipine, Clopidogrel, Prasugrel, Ticagrelor

5HT (Serotonin) receptor Sapogrelate

TP Thromboxane receptor Terutroban

PAR-1 Thrombin receptor Vorapaxar

Angiolillo. Clinical Guide to the Use of Antithrombotic Durgs in Coronary Artery Disease 2008

Aspirin is not good enough ? 2nd Antiplatelet Trialists Collaboration (BMJ 1994) In high risk patients (history of stroke/TIA, MI/angina or PVD): •  Decrease in odds of vascular events by 27%. •  O.R. attributable to aspirin is 25%. •  O.R. in patients with prior stroke/TIA 22%. •  All subgroups (age, sex, HT, DM) benefit.

Algre and van Gijn (JNNP 1996) •  In patients with prior stroke/TIA, aspirin (30-1300mg per

day) reduced odds of stroke by 13%, vascular events by 16%.

Small increase in bleeding (including ICH) and GI adverse events.

Ticlopidine vs Aspirin Ticlopidine Aspirin Stroke Study (NEJM 1989) •  21% greater risk reduction for stroke at 3 years. •  9% greater risk reduction for stroke, MI and vascular death •  Diarrhoea (2%), skin rash (2%), severe neutropenia (0.9%),

TTP. Monitor FBC q2weeks for 3 months.

African American Antiplatelet Stroke Prevention Study (Gorelick. JAMA 2003)

•  Ticlopidine 250 mg BD performed non-significantly worse than aspirin 325 mg in secondary prevention of vascular events and stroke.

Risk of TTP in combination treatment with aspirin in patients who underwent coronary stenting (1/2000-5000).

Clopidogrel is slightly better than aspirin in patients with vascular disease for combined vascular outcomes,

CAPRIE. Lancet 1996,348:1329-39

But it also causes less bleeding adverse effects compared to aspirin.

Although risk reduction among stroke patients is not significant.

Among Stroke/TIA patients, Aspirin+Dipyridamole Combination is better than Aspirin alone in secondary stroke prevention ESPS (Stroke 1990,21:1122-30) •  Aspirin 975mg and Dipyridamole 225mg (RRR 38%).

ESPS-2 (J Neurol Sci 1996,143:1-13) •  Aspirin (25mg bid): reduced risk of stroke recurrence 18% •  Dipyridamole SR (200mg bid): -16% •  Combination: -37% •  Combination vs Aspirin: -23% (ARR 1.5% per year). •  Concerns on use of placebo group, falsification of data by

one investigator, and no reduction in MI/vascular death.

Adverse effects: •  Headache, diarrhoea, GI upset.

ESPRIT Lancet 2006, 367:1665-73

•  Aspirin + Dipyridamole (n=1363) vs. Aspirin alone (n=1376) for TIA or minor ischaemic stroke of presumed arterial origin within 6 months.

•  Mean FU 3.5 yrs. Mean aspirin dose 75mg (30-325mg), 83% patients of combined Rx on ER-dipyridamole 200mg bd.

•  Primary outcome (stroke, MI, vascular death, major bleeding) reduction from 16% to 13% for combined therapy, ARR 1%/yr. Benefit seen after 2 yrs.

•  More patients on combined Rx (470 vs. 184) discontinued therapy, mainly due to headache.

ESPRIT. Lancet 2006 – Meta-Analysis

Clopidogrel +

Placebo

(5000 pts)

ER-DP + ASA +

Placebo

(5000 pts)

Placebo

Clopidogrel +

Telmisartan

(5000 pts)

ER-DP + ASA +

Telmisartan

(5000 pts)

Telmisartan (80 mg)

Clopidogrel (75 mg)

ER-DP + ASA (400 mg/50 mg)

2x2 factorial design involving 20,000 stroke patients

Trial completed Jan 2008 and results were published in NEJM 2008.

Conclusions from PRoFESS Sacco et al. NEJM 2008

•  ASA+ER-DP and CP had similar rates of recurrent stroke and major vascular events.

•  The pre-specified non-inferiority criteria for ASA+ER-DP vs CP were not met.

•  Major hemorrhagic events, including intracranial bleeds, were more frequent among those treated with ASA+ER-DP.

•  Net benefit/risks were similar with the 2 agents, choice mainly influenced by cost, side effects and compliance.

Comment: Clopidogrel likely preferred with less bleeding complications and headaches, and once daily dosing.

Aspirin – Clopidogrel Combination

Clopidogrel / Aspirin Combination (1) Long Term Rx, Lacunar Stroke

SPS3 (NEJM 2012) : ASA+CLO vs ASA •  3020 patients with recent MRI-confirmed lacunar infarcts

within 6 months. •  Clopidogrel 75 mg or placebo plus Aspirin 325 mg. •  Mean FU 28 months. Trial terminated 10 months early. •  No significant decrease in recurrent stroke (2.5 vs 2.7%

per year), ischemic stroke (2.0 vs 2.4%) or major vascular events (3.1 vs 3.4%).

•  Significant increase in major hemorrhage (2.1 vs 1.1%), extracranial bleed (1.7 vs 0.79%) and GI bleed (1.1 vs 0.52%), with non-significant increase in intracranial bleed and ICH.

Clopidogrel / Aspirin Combination (2) Short Term Rx (1-3M), TIA, Minor Stroke

Urgent treatment for TIA and effect on 90-Day Stroke Rate

•  EXPRESS (CLO-ASA 34%): 12.4% (Pre) vs 4.4% (Post).

•  SOS-TIA : 5.96% (Predicted) vs 1.24%.

•  FASTER (CLO-ASA vs ASA) in TIA or minor stroke: 10.1% vs 7.8% (NS) with 0 vs 2 ICH.

90-Day Major Bleeding in EXPRESS-FASTER cohort (Geraghty. CVD 2010)

•  Aspirin-naïve - 3.7% •  Prior Aspirin – 0.5% New Studies •  POINT, TARDIS

Stroke risk in TIA patients in EXPRESS

Pre

Post

90-day risk of major and life-threatening bleeding

CHANCE Wang Y. NEJM 2013,369:11-19

•  5170 patients from 114 centres in China.

•  Randomised within 24 hours of TIA or minor stroke.

•  CLO+ASA for 21 days then CLO vs ASA only, FU for 90 days.

•  Stroke (IS+HS) in 8.2% vs 11.7% (HR 0.68, 0.57-0.81, p<0.001).

•  HS same in each group at 0.3%.

•  Moderate to severe bleeding 0.3% vs 0.4%.

Comment: Benefit likely less in centers with lower recurrent stroke rates.

Aspirin – Clopidogrel Combination …

•  Should not be used for long-term secondary stroke prevention in general, and is contraindicated in patients with lacunar stroke, due to increased bleeding risks.

•  Can be considered for short-term use in high-risk stroke / TIA secondary to SVD (e.g. TIA with high ABCD2 score, crescendo TIA, capsular warning syndrome), preferably not more than 1 month.

Current trials investigating short-term combination antiplatelet therapy in TIA / minor stroke (12-48 H):

•  POINT (NIH): CLO-ASA vs ASA for 3 months. •  TARDIS (BHF): CLO-ASA-DIP vs CLO or ASA-DIP for

1 month.

Cilostazol Stroke Prevention Study Gotoh, J Stroke Cerebrovasc Dis 2000; 9:147 Shinohara, Cerebrovasc Dis 2008; 26:63

•  Cilostazol 100mg bd vs Placebo.

•  Post-hoc subgroup analysis showed possibly more benefits in lacunar stroke patients and those with DM and HT.

Cilostazol CASISP. Huang. Lancet Neurol 2008

•  Cilostazol 100mg bd vs Aspirin 100mg. •  Among 720 IS patients, recurrent

stroke in 12 vs 20 patients (HR 0.62 NS), with less sym ICH (1 vs 4), asym ICH (1 vs 5) and all ICH (1 vs 7).

Cilostazol CSPS-2. Shinohara. Lancet Neurol 2010

•  Cilostazol 100mg bd vs Aspirin 81mg.

•  2672 IS patients with mean FU of 29 months.

•  Significant reduction in all strokes (2.76 vs 3.71% per year, and major hemorrhages (0.77 vs 1.78%).

•  Increase in headaches (23 vs 16%), diarrhea, palpitation and dizziness.

Meta-analysis of Cilostazol vs Aspirin Kamal AK. Cochrane Sys Rev 2011

↓ Vasc events ↓ All strokes ↓ ICH ↓ Bleeds

≈  IS ≈ MI ≈ Vasc death ≈ All death

↑ Headache ↑ GI intol ↑ Dizziness

Clopidogrel vs Cilostazol in Asia

Cilostazol is preferred in some Asian countries for secondary stroke prevention, especially in Japan and Korea:

•  Cilostazol has been developed by a Japanese company.

•  Cilostazol, as a vasodilator, may have favorable properties for stroke patients with intracranial atherosclerosis, which is prevalent among Asian stroke patients. (TOSS – Kwon, Stroke 2005; 36:782)

•  Cilostazol is associated with lower bleeding complications.

JS Kim, J Stroke 2014; 16:105

Stroke Risk Factors Non-modifiable •  Age, Sex, Genetic makeup.

Modifiable IS Risk •  Hypertension 4X •  Diabetes mellitus 2X •  Hyperlipidaemia 2X •  Smoking 2X •  Obesity 2X •  Atrial fibrillation >4X •  Symptomatic severe carotid stenosis >4X

Hypertension

Evidence from Primary Prevention

•  Hypertension is the most important risk factor for stroke.

•  Hypertension increases the risk of stroke more than the risk of myocardial infarction.

•  With hypertension, the risk of hemorrhagic stroke is likely higher than that of ischemic stroke, especially in young Asian patients with uncontrolled hypertension.

Stroke and IHD Mortality versus Age Prospective Studies Collaboration. Lancet 2002

↓  Mortality with ↓ BP down to 115/75 mm Hg

Stroke (steeper curves) IHD

Larger effect of BP in hemorrhagic compared to ischemic strokes (Song, BMJ 2004)

SBP Effect in Asia-Pacific. APCSC. J Hypertension 2003

Stroke

IHD

Treatment for hypertension also beneficial in secondary stroke prevention

•  UK-TIA Trial data.

•  PROGRESS Study.

UK-TIA Trial : Each 5 mmHg decrease in DBP or 10 mmHg decrease in SBP was associated with 34% and 28% reduction in stroke respectively Rodgers, BMJ 1996; 313:147

PROGRESS Trial : Effect of blood pressure control with Perindopril +/- Indapamide after Stroke or TIA. Lancet 2001,358:1033

PROFESS Lancet 2001 358:1011

•  6105 patients with stroke or TIA within 5 years.

•  Perindopril +/- Indapamide vs Placebo for 3.9 years.

•  Asian patients well represented (China 1520, Japan 815).

•  BP reduction (9/4 mm Hg) with 28% RRR: Combined tx (12/5mm Hg, 43% RRR), Single tx (5/3mm Hg, ns).

•  Benefit more likely related to intensity of BP reduction.

•  Suggestion of more benefit for HS than IS.

PROGRESS

Subgroup analysis according to qualifying and outcome events Chapman, Stroke 2004; 35:316

•  Reduction in lacunar stroke in line with other IS subtypes.

•  Suggestion of more benefits for hemorrhagic stroke patients and for HS outcome.

PROGRESS Substudies:

Active treatment –

Delayed progression of white matter disease after 36 months. Dufuoil, Circulation 2005; 112:1644

Reduced risks of dementia and cognitive decline after 3.9 years. Arch Int Med 2003; 163:1069

PRoFESS – Telmisartan study Yusuf, NEJM 2008; 359:1225

Telmisartan 80mg vs Placebo.

Baseline BP 144/84, BP reduction 3.8/2.0 mm Hg, followed up 2.5 years.

No benefit in any outcomes but all with favorable trend.

(PROGRESS - baseline 147/86, reduction 9/4, FU 3.9 years).

Should lacunar stroke patients be subjected to more intensive BP control? SPS3 Lancet 2013; 382:507

•  3020 patients (mean age 63 years, BP 142-144 / 78-79) with MRI confirmed lacunar stroke within 6 months, randomized to SBP target of 130-149 vs < 130 mm Hg.

•  After 1 year, mean SBP were 138 vs 127 mm Hg. All stroke (HR 0.81), disabling / fatal stroke (HR 0.81) and MI/vascular death (HR 0.84) were non-significantly reduced.

•  ICH was significantly less (HR 0.37, p=0.03).

BP Control in Stroke Prevention ≤ 140/90 mm Hg •  Ischemic stroke (IS) ≤ 130/80 mm Hg •  IS + DM, CRF, IHD, CCF; Hemorrhagic stroke (HS) •  Consider in patients with recent lacunar stroke. Individualised •  Acute stroke (IS vs HS), Major artery stenosis / occlusion

BP lowering agents •  ACEIs, ARBs have less effects on cerebral perfusion •  May start with ACEI soon after acute stroke, add diuretic

later. •  CCBs have more BP lowering effect and possibly larger

reduction in stroke risk. •  Beta blockers is now less favored for stroke prevention,

but may be indicated for concomitant IHD and CCF.

Diabetes Mellitus / Blood Glucose

Positive relationship of fasting glucose and risk of CVD down to 4.9 mmol/L. Each 1 mmol/L lower fasting glucose associated with 21% lower stroke risk and 23% lower IHD risk. APCSC. Diabetes Care 2004

Does DM control does decrease stroke risk ?

•  In young Type I DM patients (mean age 27), intensive control reduced microvascular but not macrovascular complications (DCCT. NEJM 2003).

•  Same results in Type II DM patients (median age 54) despite HbA1C reduced from 7.9% to 7.0% over 10 years of follow up (UKPDS 33. Lancet 1998).

•  Tight BP control in Type II DM patients associated with 44% reduction in stroke and 37% reduction in microvascular endpoints (UKPDS 38. BMJ 1998).

Good DM control does decrease stroke risk, but you need to wait …

•  In UKPDS cohort, each 1% reduction in HbA1C associated with 12% decrease in stroke, 14% decrease in MI and 37% decrease in microvascular endpoints (UKPDS 35. BMJ 2000).

•  Metformin use in overweight DM patients associated with stroke reduction (UKPDS 34. Lancet 1998).

Legacy Effect •  Follow up of DCCT cohort showed that intensive DM control (1983-93)

resulted in > 50% reduction in stroke and other macrovascular outcomes during 1993-2005 despite similar control of DM and other vascular risk factors (NEJM 2005).

•  In UKPDS cohort, 10 more years of follow up revealed significant decrease in MI with intensive DM control. However, beneficial effect of intensive BP control was lost after end of trial (NEJM 2008).

Hyperglycemia associated with worse outcome in acute stroke and after receiving thrombolytic therapy.

Diabetic Drugs for Stroke Prevention

•  Metformin is the first choice agent in Type 2 DM. •  Although sulphonylureas and insulin are commonly

used agents, they decrease insulin sensitivity and lead to obesity.

•  Beware of risk of MI and CCF with use of thiazolidinediones (glitazones) especially rosiglitazone.

•  In difficult to control DM patients, referral to specialist diabetic clinic under a team of endocrinologist, nurse educator and dietician is recommended. This will enable comprehensive management of life style, diet, medications, related vascular risk factors, and diabetic complications.

High Cholesterol

Complex relationship, with positive relationship for ischaemic stroke and weaker negative relationship with haemorrhagic stroke.

Each 1 mmol/L higher total cholesterol associated with 35% increased risk of IHD death, 25% increased fatal or non-fatal IS, and 20% decreased risk of fatal HS. APCSC. Int J Epedmiol 2003

In SPARCL Study, patients with stroke or TIA within 6 months randomised to receive atorvastatatin 80 mg per day or placebo. Mean LDL cholesterol 1.9 vs 3.3 mmol/L. Treatment associated with reduction in cardiovascular events and all strokes, but increased hemorrhagic strokes Atorvastatin – 218 IS, 55 HS; Placebo – 274 IS, 33 HS. NEJM 2006

In SPARCL, HS risk increased in those treated with atorvastatin, in those with HS as entry event, in men, and associated with increased age and uncontrolled BP. But not associated with LDL cholesterol level. Goldstein. Neurology 2008

All ischemic stroke subtypes benefit from atorvastatin in SPARCL Amarenco, Stroke 2009; 40:1405

Lipid Lowering for Stroke Prevention

Main target is to lower LDL-cholesterol level Target LDL-C : •  Primary prevention > Secondary prevention •  HS > IS > High-risk IS •  Ensure good BP control in those with low LDL-C.

High Triglycerides and Low HDL-C are also risk factors •  Add Fibrate agent when TG high. •  Beware of AEs (↑ liver enzymes, ↑ CK) in

combination therapy (statin + fibrate).

Recommended Targets for Stroke Prevention Blood pressure

Ischaemic stroke, TIA < 140/90 mm Hg DM, renal failure, haemorrhagic stroke, lacunar stroke < 130/80 mm Hg

Glycaemic control

HbA1C < 7.0% Preprandial plasma glucose 5.0-7.2 mmol/L (90-130 mg/dL) Peak postprandial plasma glucose < 10.0 mmol/L (180 mg/dL)

Lipids

LDL-Cholesterol Primary prevention < 3.4 mmol/L (100 mg/dL) Secondary prevention

- Ischemic stroke, TIA < 2.6 mmol/L (100 mg/dL) - Recurrent ischemic strokes, < 1.8-2.0 mmol/L (70-80 mg/dL) significant vascular stenosis/occlusion, concurrent IHD and/or PVD - Hemorrhagic stroke < 3.4 mmol/L (130 mg/dL) with DM or vascular stenosis/occlusion < 2.6 mmol/L (100 mg/dL)

STENO-2 Study. Multifactorial Intervention on Type II DM and micoalbuminuria (160 patients). Gaede. NEJM 2008

STENO-2. Gaede. NEJM 2008