Aspirin Monotherapy

• Dose: 50–325 mg daily; most guidelines recommend 81–325 mg for secondary prevention
• Mechanism: Irreversible COX-1 inhibition → decreased thromboxane A₂ → reduced platelet aggregation
• Evidence: Meta-analysis by the Antithrombotic Trialists’ Collaboration showed ~22% RRR in recurrent vascular events with antiplatelet therapy (mostly aspirin-based)
• No clear dose-response relationship — higher doses (>150 mg) increase GI bleeding risk without additional ischemic benefit
• AHA/ASA 2021 guideline: Aspirin 50–325 mg/day is recommended for non-cardioembolic ischemic stroke/TIA (Class I, Level A)

Clopidogrel

• Dose: 75 mg daily (loading dose 300–600 mg when rapid onset needed)
• Mechanism: Irreversible P2Y₁₂ ADP receptor antagonist on platelets
• CAPRIE trial (1996): Clopidogrel vs. aspirin 325 mg in patients with recent stroke, MI, or PAD
  • Primary outcome: Composite of ischemic stroke, MI, or vascular death
  • Result: 8.7% RRR favoring clopidogrel (p = 0.043) — marginal but statistically significant
  • Benefit most pronounced in PAD subgroup; stroke subgroup alone did NOT reach significance
• Reasonable alternative to aspirin for non-cardioembolic stroke; preferred in patients with aspirin allergy or aspirin failure
• CYP2C19 polymorphisms: Poor metabolizers (~2–14% of population, higher in Asian patients) have reduced clopidogrel activation → consider genotyping or alternative agents (ticagrelor, prasugrel — though prasugrel is not used for stroke prevention)

Dual Antiplatelet Therapy (DAPT) — Short-Term

• Indication: Minor ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD² ≥4) within 24 hours of symptom onset
• Regimen: Aspirin + clopidogrel for 21 days, then transition to single antiplatelet (clopidogrel monotherapy preferred)

CHANCE Trial (2013)

• Population: Chinese patients with minor stroke (NIHSS ≤3) or high-risk TIA within 24 hours
• Intervention: Aspirin + clopidogrel × 21 days then clopidogrel alone vs. aspirin alone × 90 days
• Result: DAPT reduced stroke recurrence from 11.7% to 8.2% (HR 0.68, p < 0.001) — ARR 3.5%, NNT ~29
• No significant increase in moderate or severe hemorrhage
• Limitation: Conducted entirely in China; higher rate of CYP2C19 poor metabolizers in study population

POINT Trial (2018)

• Population: International (multinational); minor stroke (NIHSS ≤3) or high-risk TIA within 12 hours
• Intervention: Aspirin + clopidogrel vs. aspirin alone × 90 days
• Result: DAPT reduced ischemic events at 90 days (5.0% vs. 6.5%, HR 0.75, p = 0.02)
• But: Increased major hemorrhage (0.9% vs. 0.4%, HR 2.32, p = 0.02) — particularly after day 21
• Key takeaway: Benefit concentrated in first 21 days; risk increases after → supports 21-day DAPT window (consistent with CHANCE)

THALES Trial (2020)

• Intervention: Aspirin + ticagrelor vs. aspirin alone × 30 days in minor stroke/high-risk TIA
• Result: Reduced composite of stroke or death (5.5% vs. 6.6%, HR 0.83, p = 0.02)
• Increased severe bleeding and higher discontinuation rates
• Ticagrelor is not first-line for DAPT in stroke but is an option if clopidogrel resistance is suspected

Aspirin-Dipyridamole (Aggrenox)

• Formulation: Aspirin 25 mg + extended-release dipyridamole 200 mg, taken BID
• Mechanism: Dipyridamole inhibits phosphodiesterase → increases cAMP → inhibits platelet aggregation; also inhibits adenosine reuptake
• ESPS-2 (1996): Combination superior to aspirin alone and placebo for secondary stroke prevention (37% RRR vs. placebo)
• ESPRIT trial (2006): Aspirin-dipyridamole superior to aspirin alone (HR 0.80 for composite vascular events)
• PRoFESS trial (2008): Aspirin-dipyridamole vs. clopidogrel — non-inferior; no significant difference in stroke recurrence (9.0% vs. 8.8%)
  • Dipyridamole arm had more headaches and GI side effects, leading to higher discontinuation
• Main side effect: Headache (up to 40%) — often limits tolerability; resolves with continued use in many patients
• Current status: Largely replaced by clopidogrel due to tolerability; still listed as an acceptable option in AHA/ASA guidelines

When NOT to Use Antiplatelets Alone

• Cardioembolic stroke (atrial fibrillation) → anticoagulation is superior; antiplatelets are inferior to OAC for AF
• Mechanical heart valves → warfarin required (DOACs contraindicated — RE-ALIGN trial showed harm with dabigatran)
• LV thrombus → anticoagulation (warfarin or DOAC) for at least 3 months
• High-grade intracranial stenosis → DAPT (not single antiplatelet) + aggressive risk factor management (SAMMPRIS protocol)

CHA₂DS₂-VASc Score

• Any patient with prior stroke/TIA already scores ≥2 → anticoagulation is indicated for ALL AF patients with prior stroke
• Annual stroke risk: Score 2 = ~2.2%/year; Score 6 = ~9.8%/year; Score 9 = ~15.2%/year
• HAS-BLED score assesses bleeding risk but should NOT be used to withhold anticoagulation — rather to identify modifiable bleeding risk factors

DOACs vs. Warfarin — Landmark Trials

RE-LY (Dabigatran, 2009)

• Dabigatran 150 mg BID: Superior to warfarin for stroke prevention (RR 0.66) with similar major bleeding
• Dabigatran 110 mg BID: Non-inferior to warfarin with lower bleeding (not FDA-approved in the US)
• Higher rate of GI bleeding with 150 mg dose; higher rate of MI (debated significance)
• Reversal agent: Idarucizumab (Praxbind) — monoclonal antibody fragment

ROCKET AF (Rivaroxaban, 2011)

• Rivaroxaban 20 mg daily (15 mg if CrCl 15–50 mL/min): Non-inferior to warfarin
• Less intracranial hemorrhage; similar major bleeding overall
• Higher-risk population than RE-LY (mean CHADS₂ = 3.5)
• Must be taken with food (improves absorption by 39%)
• Reversal: Andexanet alfa (Andexxa)

ARISTOTLE (Apixaban, 2011)

• Apixaban 5 mg BID: Superior to warfarin for stroke prevention (HR 0.79) AND for major bleeding (HR 0.69) AND for all-cause mortality (HR 0.89)
• Reduced dose: 2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL
• Best overall safety profile among DOACs in head-to-head comparison with warfarin
• Reversal: Andexanet alfa (Andexxa)

ENGAGE AF-TIMI 48 (Edoxaban, 2013)

• Edoxaban 60 mg daily: Non-inferior to warfarin with significantly less bleeding
• Reduced dose: 30 mg if CrCl 15–50 mL/min, weight ≤60 kg, or concomitant P-gp inhibitors
• Contraindicated if CrCl >95 mL/min — paradoxically, high renal clearance reduces efficacy (unique among DOACs)
• Reversal: Andexanet alfa

DOAC Comparison Table

Timing of Anticoagulation After Acute Ischemic Stroke

• The “1-3-6-12 Day Rule” (European guideline-based practical approach):
  • Day 1: TIA (no infarct on imaging)
  • Day 3: Minor/small stroke (NIHSS <8, small infarct)
  • Day 6: Moderate stroke (NIHSS 8–15, moderate infarct size)
  • Day 12–14: Large/severe stroke (NIHSS >15, large territorial infarct or hemorrhagic transformation)
• Always repeat brain imaging before starting anticoagulation to exclude hemorrhagic transformation
• ELAN trial (2023): Early initiation (≤48h for minor stroke, days 3–4 for moderate, day 6–7 for large) was non-inferior to later initiation with a trend toward fewer recurrent ischemic events — supports earlier anticoagulation in most patients
• Bridge therapy: Avoid heparin bridging in AF patients — DOACs have rapid onset (2–4 hours). BRIDGE trial showed bridging with LMWH increased bleeding without reducing thromboembolism

Left Atrial Appendage (LAA) Occlusion

• Watchman device — percutaneous LAA occlusion for patients with non-valvular AF who have a contraindication to long-term anticoagulation
• PROTECT AF (2009) and PREVAIL (2014): Watchman was non-inferior to warfarin for stroke prevention; superior for hemorrhagic stroke and cardiovascular/unexplained death at long-term follow-up
• Post-procedure: Requires short-term anticoagulation (warfarin + aspirin × 45 days), then DAPT × 6 months, then aspirin alone
• Indication: Primarily for patients with high stroke risk + high bleeding risk who cannot tolerate long-term OAC (e.g., recurrent GI bleeding, prior ICH)
• Does NOT protect against non-LAA sources of cardioembolism

Measurement Methods

• NASCET method: % stenosis = (1 − [narrowest diameter / distal ICA diameter]) × 100 — most widely used in North America
• ECST method: % stenosis = (1 − [narrowest diameter / estimated original bulb diameter]) × 100 — gives higher stenosis values than NASCET for the same lesion
• Conversion approximation: NASCET 70% ≈ ECST 82%; NASCET 50% ≈ ECST 65%
• Imaging modalities: CTA, MRA, carotid duplex ultrasound, and conventional digital subtraction angiography (DSA = gold standard)

Symptomatic Carotid Stenosis

NASCET Trial (1991)

• Severe stenosis (70–99%): CEA dramatically reduced stroke risk — 2-year stroke rate 9% (CEA) vs. 26% (medical) → ARR 17%, NNT ~6
• Moderate stenosis (50–69%): Modest benefit from CEA — 5-year stroke rate 15.7% vs. 22.2% → ARR 6.5%, NNT ~15; benefit most pronounced in men, recent symptoms, hemispheric (not retinal) events
• <50% stenosis: No benefit from CEA

ECST Trial (1998)

• Confirmed benefit of CEA for severe symptomatic stenosis (≥70% by ECST method, equivalent to ≥50% NASCET)
• When re-analyzed using NASCET measurement method, results were concordant

CEA vs. CAS — CREST Trial (2010)

• Compared: Carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) in symptomatic (≥50%) and asymptomatic (≥60%) stenosis
• Primary endpoint (stroke, MI, death): No significant difference between CEA and CAS overall
• Key age interaction:
  • Age <70: CAS may be equivalent or preferred (lower periprocedural MI rate)
  • Age ≥70: CEA preferred (lower periprocedural stroke rate)
• CAS had higher periprocedural stroke rate; CEA had higher periprocedural MI rate
• Both procedures had equivalent long-term (>30-day) stroke prevention

Timing of Intervention

• Intervene within 2 weeks of the index event for maximum benefit (stroke recurrence risk highest in the first 14 days)
• EXPRESS study: Urgent evaluation and treatment within 24 hours reduced 90-day stroke risk by 80%
• If large completed stroke: delay intervention 4–6 weeks to reduce risk of hemorrhagic conversion/reperfusion injury

Asymptomatic Carotid Stenosis

• ACAS (1995) and ACST (2004): CEA showed modest benefit for asymptomatic stenosis ≥60% (annual stroke risk reduced from ~2% to ~1%)
• NNT ~20 over 5 years — much less compelling than symptomatic disease
• Modern medical therapy (aggressive risk factor management, statins, antihypertensives) has dramatically improved — annual stroke risk with medical therapy alone is now ~0.5–1%/year
• CREST-2 (ongoing/recently completed): Re-evaluating CEA/CAS + medical vs. medical alone for asymptomatic stenosis in the era of contemporary medical therapy
• Current guidelines: CEA may be considered for asymptomatic stenosis ≥70% if perioperative risk is <3% and life expectancy >5 years, but shared decision-making is essential

When NOT to Intervene

• Carotid occlusion (100%) — no role for CEA or CAS (consider EC-IC bypass only in select cases, though COSS trial was negative)
• Near-occlusion (“string sign”) — benefit of CEA uncertain; NASCET subgroup showed no clear benefit
• Stenosis <50% (symptomatic) or <60% (asymptomatic) — no benefit
• Severe disability (mRS ≥3) or limited life expectancy — unlikely to benefit from revascularization

WASID Trial (2005)

• Question: Warfarin vs. aspirin for symptomatic intracranial stenosis (50–99%)
• Result: Warfarin was NOT superior to aspirin and had significantly higher bleeding and death rates
• Takeaway: Anticoagulation is NOT recommended for intracranial atherosclerosis — antiplatelet therapy is preferred
• Notable: Annual stroke recurrence rate was ~12% in both groups, highlighting the high-risk nature of this disease

SAMMPRIS Trial (2011)

• Question: Aggressive medical management alone vs. aggressive medical management + Wingspan intracranial stenting for 70–99% symptomatic intracranial stenosis
• Result: Stenting was HARMFUL — 30-day stroke/death rate was 14.7% (stenting) vs. 5.8% (medical) (p = 0.002). Trial stopped early for safety
• Aggressive medical protocol (“SAMMPRIS protocol”):
  • DAPT: Aspirin 325 mg + clopidogrel 75 mg daily × 90 days
  • Then aspirin 325 mg monotherapy
  • SBP target <140 mmHg (or <130 if diabetic)
  • High-intensity statin (target LDL <70 mg/dL)
  • Lifestyle modification program
• Long-term follow-up: Medical superiority persisted at 3 years

Background & Diagnosis

• PFO prevalence: ~25% of the general population; found in up to 40–50% of cryptogenic stroke patients <60 years
• Mechanism: Paradoxical embolism — venous thrombus crosses the PFO into the arterial circulation
• High-risk PFO features: large shunt size, atrial septal aneurysm (ASA), prominent Eustachian valve, Chiari network
• Diagnosis: Transthoracic echocardiography (TTE) with agitated saline (bubble study); transesophageal echocardiography (TEE) is more sensitive for PFO anatomy and ASA
• Transcranial Doppler (TCD) with bubble study: Most sensitive functional test for right-to-left shunt (~100% sensitivity)

RoPE Score

• Risk of Paradoxical Embolism score helps determine whether the PFO is likely pathogenic or incidental
• Range: 0–10; higher score = more likely the PFO caused the stroke

• RoPE ≥7: High probability the PFO is pathogenic (~88% PFO-attributable fraction) → consider closure
• RoPE ≤6: PFO more likely incidental → medical therapy may be sufficient
• Key concept: A young patient with NO vascular risk factors + cortical infarct + PFO has the highest RoPE score — paradoxical embolism is the most likely mechanism

PFO Closure Trials

CLOSE Trial (2017)

• Population: Age 16–60 with cryptogenic stroke + PFO with ASA or large shunt
• Intervention: PFO closure vs. antiplatelet therapy vs. anticoagulation
• Result: No strokes in closure group vs. 6.0% in antiplatelet group (HR 0.03) — NNT ~20 over 5 years
• Post-closure AF occurred in ~4.6% (mostly transient)

RESPECT Trial (2017 — Extended Follow-Up)

• Population: Age 18–60 with cryptogenic stroke + PFO
• Device: Amplatzer PFO Occluder
• Result: At extended follow-up (median 5.9 years), PFO closure reduced recurrent stroke (HR 0.55, p = 0.046)
• Benefit greatest in patients with ASA or large shunt

REDUCE Trial (2017)

• Population: Age 18–59 with cryptogenic stroke + PFO
• Result: PFO closure reduced ischemic stroke from 5.4% to 1.4% (HR 0.23, p = 0.002)
• Also reduced new brain infarcts on MRI

Medical Therapy for PFO-Related Stroke

• If PFO closure is NOT performed (e.g., PFO without high-risk features, RoPE ≤6, or patient declines surgery):
  • Antiplatelet therapy (aspirin or clopidogrel) is first-line
  • Anticoagulation with a DOAC is an alternative, especially if deep vein thrombosis is identified
  • CLOSE trial showed anticoagulation was numerically better than antiplatelets for PFO-related stroke, but was not powered for statistical comparison
• Screen for DVT (lower extremity and pelvic veins) in all PFO-related stroke patients

CADISS Trial (2015)

• Question: Antiplatelet vs. anticoagulation for cervical artery dissection (carotid or vertebral)
• Population: Extracranial carotid or vertebral dissection within 7 days of symptom onset
• Result: No significant difference between antiplatelet and anticoagulation for recurrent stroke (2% vs. 1%, p = 0.63)
• Limitations: Underpowered (very low event rates in both groups); non-randomized allocation in initial phase
• AHA/ASA guideline: Either antiplatelet or anticoagulation is reasonable for extracranial dissection (Class IIa, Level B)

Practical Approach

• Antiplatelet preferred if:
  • Large completed infarct (bleeding risk with anticoagulation)
  • Intracranial extension of dissection (risk of SAH)
  • Pseudoaneurysm formation
• Anticoagulation preferred if:
  • Luminal thrombus or free-floating thrombus
  • Recurrent embolic events despite antiplatelet therapy
  • High-grade stenosis or occlusion with ongoing symptoms
• Duration: Typically 3–6 months, then reassess with repeat vascular imaging
• Most dissections heal spontaneously (60–80% recanalize by 3–6 months)
• If vessel normalizes on follow-up imaging → may discontinue therapy or switch to low-dose aspirin
• If persistent stenosis/occlusion → continue long-term antiplatelet therapy

Key Trials

PROGRESS Trial (2001)

• Intervention: Perindopril (ACE inhibitor) ± indapamide (thiazide diuretic) vs. placebo
• Population: History of stroke or TIA (hypertensive or normotensive)
• Result: 28% RRR for recurrent stroke overall; 43% RRR with combination therapy (perindopril + indapamide)
• Mean BP reduction: 9/4 mmHg (monotherapy) and 12/5 mmHg (combination)
• Takeaway: BP lowering reduces stroke recurrence even in “normotensive” patients

SPS3 Trial (2013)

• Population: Lacunar stroke (small subcortical infarct on MRI)
• BP targets: <130 mmHg (intensive) vs. 130–149 mmHg (standard)
• Result: Non-significant 19% RRR for recurrent stroke with intensive BP control (p = 0.08) — trend toward benefit
• Significantly reduced ICH in the intensive group (63% RRR, p = 0.03)
• Also tested aspirin + clopidogrel vs. aspirin alone → DAPT did NOT reduce recurrent stroke but increased bleeding and death

SPRINT Trial (2015)

• Population: High cardiovascular risk (excluded stroke patients and diabetics)
• Result: Intensive SBP <120 reduced cardiovascular events and mortality vs. SBP <140
• Relevance to stroke: Supports aggressive BP targets but direct applicability to secondary stroke prevention is limited since stroke patients were excluded

BP Targets & Guidelines

• AHA/ASA recommendation: SBP target <130/80 mmHg for secondary stroke prevention (Class I for lacunar stroke; Class IIa for other subtypes)
• Wait ≥24–72 hours after acute stroke before initiating chronic antihypertensive therapy (avoid hypotension during acute phase)
• Exception: Do not aggressively lower BP if there is significant bilateral carotid or intracranial stenosis (risk of watershed ischemia)
• Preferred agents: ACE inhibitors or ARBs ± thiazide diuretic (strongest evidence from PROGRESS)
• Lifestyle: DASH diet, sodium restriction (<2.3 g/day), weight loss, regular exercise

SPARCL Trial (2006)

• Population: Patients with recent stroke or TIA and no known coronary artery disease, LDL 100–190 mg/dL
• Intervention: Atorvastatin 80 mg daily vs. placebo
• Result: 16% RRR for recurrent stroke (HR 0.84, p = 0.03); ARR ~2.2%, NNT ~46 over 5 years
• Also reduced major coronary events by 35%
• Concern: Small increase in hemorrhagic stroke (55 vs. 33 events, HR 1.66, p = 0.02) — predominantly in patients with prior hemorrhagic stroke or small vessel disease; overall net benefit still favored statin
• Mean LDL achieved: 73 mg/dL in statin group vs. 129 mg/dL in placebo

Current Recommendations

• High-intensity statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) recommended for all patients with atherosclerotic ischemic stroke or TIA (Class I, Level A)
• LDL target: <70 mg/dL for atherosclerotic stroke (AHA/ASA); some guidelines recommend <55 mg/dL for very high-risk patients
• TST trial (2020): Target LDL <70 vs. 90–110 mg/dL in atherosclerotic stroke → lower LDL target reduced recurrent cardiovascular events (HR 0.78); supported more aggressive LDL lowering
• Start in acute phase — do NOT discontinue statins if patient was already taking one (acute withdrawal associated with worse outcomes)
• Ezetimibe can be added if LDL not at goal on maximally tolerated statin
• PCSK9 inhibitors (evolocumab, alirocumab) for patients not at goal despite statin + ezetimibe; FOURIER trial showed reduced cardiovascular events; role in stroke-specific secondary prevention still being defined

Statin & Hemorrhagic Stroke Risk

• SPARCL showed slight increase in hemorrhagic stroke with high-dose atorvastatin
• Risk factors for statin-related ICH: Prior hemorrhagic stroke, cerebral microbleeds, older age, poorly controlled hypertension
• Clinical decision: For patients with prior ICH, weigh ischemic benefit against hemorrhagic risk — use shared decision-making. If the stroke was atherosclerotic in mechanism, the ischemic benefit generally outweighs the small hemorrhagic risk

Exercise

• Recommendation: Moderate-intensity aerobic exercise ≥40 minutes, 3–4 days/week (AHA/ASA Class I, Level B)
• Even moderate physical activity reduces stroke recurrence by ~25–30%
• Benefits: BP reduction, improved lipid profile, insulin sensitivity, weight management, endothelial function
• Supervised cardiac rehabilitation programs recommended when available

Diet

• Mediterranean diet has the strongest evidence for cardiovascular event reduction (PREDIMED trial: ~30% RRR for composite CV events)
• DASH diet: Emphasized for BP reduction (rich in fruits, vegetables, whole grains, low-fat dairy; low in saturated fat)
• Sodium restriction: <2.3 g/day (ideally <1.5 g/day for hypertensive patients) — reduces SBP by 5–8 mmHg
• Potassium-rich foods inversely associated with stroke risk

Smoking Cessation

• Smoking doubles stroke risk; cessation is one of the most impactful modifiable risk factors
• Offer at every visit: Behavioral counseling + pharmacotherapy (NRT, bupropion, or varenicline)
• Stroke risk returns to non-smoker baseline within 5 years of cessation
• Secondhand smoke also increases stroke risk (~30% increased risk)

Alcohol

• Heavy alcohol use (>2 drinks/day) increases stroke risk (both ischemic and hemorrhagic)
• Moderate intake (≤1 drink/day for women, ≤2 for men) has been associated with lower ischemic stroke risk in observational studies, but this should NOT be recommended as a prevention strategy
• Binge drinking is a significant risk factor for both ischemic and hemorrhagic stroke

Diabetes Management

• Target HbA1c <7% for most patients; individualize in elderly/frail patients
• SGLT2 inhibitors and GLP-1 receptor agonists have shown cardiovascular benefit beyond glucose control
• Pioglitazone (IRIS trial): Reduced recurrent stroke/MI by 24% in insulin-resistant patients with recent stroke — but weight gain and fracture risk limit use

Dual Pathology: AF + Carotid Stenosis

• If AF is present and symptomatic carotid stenosis ≥50% → both conditions should be treated
• CEA/CAS can be performed while on anticoagulation (perioperative management varies by center)
• Long-term: Anticoagulation alone (for AF) — do NOT add long-term antiplatelet unless another indication (e.g., recent coronary stent)
• Anticoagulation alone does NOT adequately prevent atherothrombotic events at the carotid plaque site → revascularization should still be pursued if indicated

Stroke on Anticoagulation

• First: Confirm compliance and therapeutic levels
  • Warfarin: Check INR (goal 2.0–3.0 for AF; was the patient subtherapeutic?)
  • DOACs: Confirm medication adherence, check renal function (dose adjustment needed?), drug interactions
• If stroke occurred at therapeutic INR/proper DOAC dose:
  • Reconsider stroke mechanism — may be non-cardioembolic (atherosclerotic, small vessel, etc.)
  • Options: Switch to a different anticoagulant, add antiplatelet (with caution — increases bleeding), or consider LAA occlusion
  • Some experts recommend switching from one DOAC class to another (e.g., factor Xa inhibitor to direct thrombin inhibitor or vice versa)
• If on warfarin with labile INR: Switch to a DOAC (more predictable pharmacokinetics, no INR monitoring needed)

Recurrent Stroke Despite Medical Therapy

• Systematic re-evaluation:
  • Reassess stroke mechanism (repeat cardiac monitoring, vascular imaging, hypercoagulable workup)
  • Consider prolonged cardiac monitoring (30-day event monitor or implantable loop recorder) to detect paroxysmal AF
  • CRYSTAL AF trial: Implantable cardiac monitor detected AF in 12.4% of cryptogenic stroke patients at 12 months vs. 2% with conventional monitoring
• Check medication compliance — this is the most common reason for treatment failure
• Intensify risk factor management: Lower LDL further, tighter BP control, diabetes optimization
• Consider referral to a specialized stroke center for advanced evaluation

Antiphospholipid Syndrome

• First-time stroke with positive APL antibodies: Anticoagulation with warfarin (target INR 2.0–3.0) is standard
• DOACs are NOT recommended for APS — TRAPS trial (rivaroxaban vs. warfarin in triple-positive APS) was stopped early for increased thromboembolic events with rivaroxaban
• Triple-positive APS (lupus anticoagulant + anticardiolipin + anti-β₂-glycoprotein I) carries the highest thrombotic risk — lifelong anticoagulation required

Sickle Cell Disease

• Primary prevention: Chronic blood transfusions to maintain HbS <30% in children with abnormal TCD velocities (>200 cm/s) — STOP trial reduced stroke risk by 90%
• Secondary prevention: Chronic exchange transfusions (maintain HbS <30%); hydroxyurea may be used as an adjunct
• SWiTCH trial: Transfusions + chelation were superior to hydroxyurea + phlebotomy for secondary stroke prevention