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Stroke & Vascular Pharmacology

What Do You Need to Know?

IV thrombolysis (2026 AHA/ASA AIS guideline) — for IVT-eligible adult AIS within 4.5 h: alteplase 0.9 mg/kg (max 90 mg) 10% bolus + 60 min infusion OR tenecteplase 0.25 mg/kg single IV bolus (max 25 mg); BP must be <185/110; tenecteplase 0.4 mg/kg is NOT the AIS dose
Dual antiplatelet therapy (DAPT) — aspirin + clopidogrel × 21 days (default, CHANCE) for minor stroke (NIHSS ≤3) or high-risk TIA; 90 days reserved for severe symptomatic intracranial stenosis (SAMMPRIS-like contexts); then single antiplatelet (aspirin OR clopidogrel depending on context)
DOACs vs warfarin for AF — DOACs superior or non-inferior with less ICH; apixaban has best safety profile (ARISTOTLE); edoxaban contraindicated if CrCl >95
ICH reversal — warfarin → 4-factor PCC + vitamin K; dabigatran → idarucizumab; factor Xa inhibitors → andexanet alfa or 4-factor PCC
Acute BP management — permissive HTN <220/120 (no tPA) or <185/110 (pre-tPA); mild-moderate spontaneous ICH (SBP 150–220): lower smoothly to target ~140 and maintain SBP 130–150; avoid acute SBP <130 (2022 AHA/ASA); secondary prevention <130/80
Statins — high-intensity for all atherosclerotic stroke; SPARCL (atorvastatin 80 mg) reduced recurrent stroke 16%; target LDL <70 (TST 2020 trial)
Nimodipine for SAH — 60 mg PO q4h × 21 days; improves outcomes but does NOT prevent vasospasm; only CCB with proven benefit in SAH

🚩 Don’t Miss — Test-Day Priorities

Alteplase dosing: 0.9 mg/kg (max 90 mg) — 10% as bolus, 90% over 60 min; window ≤4.5 h from LKW; sICH ~6% (NINDS); orolingual angioedema 1–5% — markedly higher in patients on ACE inhibitors.
Tenecteplase (TNK): 0.25 mg/kg single IV bolus (max 25 mg) — 2026 AHA/ASA AIS guideline endorses either alteplase 0.9 mg/kg OR tenecteplase 0.25 mg/kg (max 25 mg) for IVT-eligible adult AIS within 4.5 h; tenecteplase 0.4 mg/kg is NOT recommended for AIS; trials AcT + TRACE-2 showed non-inferiority.
Warfarin-associated ICH reversal: 4F-PCC (Kcentra) 25–50 IU/kg INR-based + IV vitamin K 10 mg — faster INR correction than FFP and preferred; avoid FFP volume load.
DOAC reversal: dabigatran → idarucizumab (Praxbind) 5 g IV; apixaban/rivaroxaban → andexanet alfa (or 4F-PCC if unavailable); edoxaban → 4F-PCC; heparin → protamine 1 mg per 100 IU; post-IVT (alteplase/TNK) sICH → stop infusion, CT/labs including fibrinogen, cryoprecipitate to fibrinogen goal >150–200 mg/dL; consider antifibrinolytic (TXA or aminocaproic acid); platelets ONLY for a specific indication (thrombocytopenia or selected antiplatelet context) — NOT routine.
DAPT for minor stroke / high-risk TIA: CHANCE/POINT → aspirin 81 mg + clopidogrel (300–600 mg load → 75 mg) × 21 days (default) for NIHSS ≤3 or ABCD2 ≥4; 90 days reserved for severe symptomatic intracranial stenosis (SAMMPRIS-like); then single antiplatelet (aspirin OR clopidogrel depending on context); THALES → ticagrelor + aspirin × 30 d alternative; CHANCE-2 → ticagrelor superior to clopidogrel in CYP2C19 LoF carriers; avoid prasugrel in TIA/stroke (excess ICH).
DOAC pitfalls: apixaban dose reduce to 2.5 mg BID if 2 of 3: age ≥80, weight ≤60 kg, Cr ≥1.5; rivaroxaban 20 mg with food; edoxaban contraindicated if CrCl >95; DOACs CONTRAINDICATED in valvular AF (mechanical valves, mod-severe mitral stenosis → warfarin) and triple-positive APS (TRAPS → warfarin).
Warfarin: inhibits vitamin K epoxide reductase; INR 2–3 non-valvular AF, 2.5–3.5 mechanical mitral; bridge with LMWH/UFH periprocedurally; inducers (carbamazepine, phenytoin, phenobarbital) ↓ INR; inhibitors (amiodarone, azoles, Bactrim) ↑ INR.
Secondary prevention statin: high-intensity atorvastatin 80 mg or rosuvastatin 40 mg — SPARCL trial; LDL target <70 (US) / <55 (ESC high-risk); if intolerant → ezetimibe → PCSK9 (alirocumab, evolocumab, inclisiran biannual siRNA) → bempedoic acid.
Nimodipine for aneurysmal SAH: 60 mg PO q4h × 21 days — the only CCB shown to improve outcomes; does not reduce angiographic vasospasm rate; hypotension is dose-limiting (split to 30 mg q2h).
BP targets: acute ischemic stroke permissive <220/120 (no tPA) or <185/110 (pre-tPA); mild-moderate spontaneous ICH (SBP 150–220): target ~140 and maintain SBP 130–150; avoid acute SBP <130 (2022 AHA/ASA — INTERACT2/ATACH-2); secondary prevention SBP <130; ACEi/ARB + thiazide first-line.

🔍 Buzzwords & Pathognomonic FindingsMechanism · Adverse effects / reversal · Use / monitoring

Mechanism

Alteplase / tenecteplase → recombinant tPA → plasminogen → plasmin → fibrinolysis (TNK = higher fibrin specificity, longer half-life)
Warfarin → inhibits vitamin K epoxide reductase → depletes factors II, VII, IX, X + proteins C & S
Apixaban / rivaroxaban / edoxaban → direct factor Xa inhibitors; dabigatran → direct thrombin (IIa) inhibitor
Clopidogrel / prasugrel / ticagrelor / cangrelor → P2Y12 ADP receptor antagonists (clopidogrel + prasugrel irreversible prodrugs; ticagrelor + cangrelor reversible)
Aspirin → irreversible COX-1 acetylation → ↓ thromboxane A2; dipyridamole → phosphodiesterase + adenosine reuptake inhibitor
Statins → HMG-CoA reductase inhibitors; ezetimibe → NPC1L1 cholesterol absorption blocker; PCSK9 mAbs → ↑ LDL-receptor recycling; inclisiran → siRNA against PCSK9; bempedoic acid → ATP-citrate lyase inhibitor
Nimodipine → dihydropyridine L-type CCB with cerebral vascular selectivity
Heparin / LMWH / fondaparinux → antithrombin III potentiation (UFH = IIa + Xa; LMWH = Xa > IIa; fondaparinux = pure Xa)

Adverse effects / reversal

Orolingual angioedema after tPA → ACE inhibitor use (1–5% incidence)
Warfarin-associated ICH → 4F-PCC (Kcentra) 25–50 IU/kg + IV vitamin K 10 mg (faster than FFP)
Dabigatran bleed → idarucizumab (Praxbind) 5 g IV; apixaban / rivaroxaban bleed → andexanet alfa (or 4F-PCC); edoxaban → 4F-PCC
Heparin reversal → protamine 1 mg per 100 IU; post-IVT (alteplase/TNK) sICH → stop infusion, check fibrinogen, cryoprecipitate to fibrinogen goal; consider antifibrinolytic (TXA/aminocaproic acid); platelets ONLY for specific platelet-related indication (not routine)
Heparin-induced thrombocytopenia (HIT) → switch to argatroban or bivalirudin (avoid LMWH and platelets)
Statin myopathy / rhabdomyolysis → CK + LFT check; warfarin skin necrosis → protein C deficiency early in initiation
Aggrenox (ASA + extended-release dipyridamole) → headache (limits tolerance)

Use / monitoring / dosing

Aneurysmal SAH vasospasm prophylaxis → nimodipine 60 mg PO q4h × 21 days (improves outcomes, not vasospasm rate)
Minor stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4) → DAPT (ASA + clopidogrel) × 21 days (default, CHANCE); 90 days reserved for severe symptomatic intracranial stenosis; then single antiplatelet (ASA OR clopidogrel); CYP2C19 LoF carriers → ticagrelor (CHANCE-2)
Mechanical mitral valve → warfarin INR 2.5–3.5 (DOACs contraindicated); triple-positive APS → warfarin (TRAPS)
Apixaban dose reduction → 2.5 mg BID if 2 of: age ≥80, weight ≤60 kg, Cr ≥1.5; rivaroxaban with food; edoxaban contraindicated if CrCl >95
Secondary stroke prevention statin → atorvastatin 80 mg or rosuvastatin 40 mg (SPARCL); LDL target <70 mg/dL
Secondary prevention BP → SBP <130 mm Hg; ACEi/ARB + thiazide preferred
Acute pre-tPA BP → <185/110; post-tPA <180/105; mild-moderate spontaneous ICH (SBP 150–220) → target ~140, maintain SBP 130–150; avoid acute SBP <130 (2022 AHA/ASA)
Cryptogenic stroke + PFO age <60 → PFO closure + antiplatelet (CLOSE, REDUCE, RESPECT); AF with bleeding contraindication → LAA occlusion (Watchman)
Post-stroke depression → SSRI when clinically indicated; do NOT prescribe solely for motor recovery (FOCUS, AFFINITY, EFFECTS — negative for functional outcome; ↑ fractures, falls, seizures, hyponatremia)

Thrombolytics

Alteplase (tPA) & Tenecteplase

Feature	Alteplase (tPA)	Tenecteplase (TNK)
Dose	0.9 mg/kg (max 90 mg); 10% bolus, rest over 60 min	0.25 mg/kg single IV bolus (max 25 mg); weight-based
Time window	≤4.5 hours (NINDS ≤3h; ECASS III 3–4.5h)	Same window; Studied in AcT (Menon et al., Lancet 2022) and TRACE-2 (Wang et al., Lancet 2023) trials demonstrating non-inferiority to alteplase.
Mechanism	Recombinant tissue plasminogen activator → plasminogen → plasmin → fibrinolysis	Modified tPA; higher fibrin specificity, longer half-life
Advantages	Long-standing standard; most evidence	Single bolus (easier administration); non-inferior to alteplase; co-equal with alteplase in 2026 AHA/ASA AIS guideline
sICH rate	~6% (NINDS definition)	Similar or lower in comparative trials

tPA Eligibility Criteria

Inclusion	Exclusion
Clinical diagnosis of ischemic stroke with measurable deficit	Evidence of ICH on CT
Symptom onset (LKW) ≤4.5 hours	BP ≥185/110 despite treatment
Age ≥18 years	Platelet count <100,000
CT without hemorrhage	INR >1.7 or PT >15 seconds
—	Therapeutic LMWH within 24 h OR DOAC dose within 48 h (unless specific coagulation assays are normal: dTT/ecarin clotting time for dabigatran; anti-Xa for apixaban/rivaroxaban)
—	Blood glucose <50 mg/dL
—	Major surgery or serious trauma within 14 days
—	GI/GU hemorrhage within 21 days
—	Prior stroke within 3 months

3–4.5 hour window additional exclusions (ECASS III): ECASS III trial exclusions for 3–4.5 h window were age >80, NIHSS >25, history of stroke + DM, or any OAC use. 2019 AHA/ASA guidelines reclassified age >80 and NIHSS >25 as Class IIb (may be reasonable, not absolute exclusions) and allow tPA if INR ≤1.7.
Hemorrhagic transformation rates: symptomatic ICH (sICH) ~6% with tPA (NINDS); asymptomatic petechial hemorrhage is common (~20–40%) and does not require intervention
Post-tPA management: BP <180/105 for 24 hours; no antiplatelets or anticoagulants for 24 hours; repeat CT before starting aspirin
Orolingual angioedema: occurs in ~2% post-tPA; more common with ACE inhibitor use; usually contralateral to ischemic hemisphere; manage with epinephrine, diphenhydramine, methylprednisolone; intubate if airway compromise
If sICH suspected post-IVT (alteplase or tenecteplase): stop infusion immediately → stat CT head → check fibrinogen, CBC, type & screen → cryoprecipitate first (target fibrinogen >150–200 mg/dL); consider antifibrinolytic (TXA or aminocaproic acid); platelet transfusion ONLY for a specific indication (thrombocytopenia or selected antiplatelet context) — NOT a routine reversal step.

Board Pearl

Only TWO tests needed before tPA: NCCT head and blood glucose. Do not delay for other labs unless clinical suspicion of coagulopathy. BP must be <185/110 before AND <180/105 for 24 hours after tPA. Tenecteplase 0.25 mg/kg single bolus (max 25 mg) is co-equal with alteplase per the 2026 AHA/ASA AIS guideline; tenecteplase 0.4 mg/kg is NOT the AIS dose.

Hemorrhagic Transformation Classification

Type	Description	Clinical Significance
HI-1	Small petechiae along infarct margins	Benign; no intervention needed
HI-2	Confluent petechiae within infarct, no mass effect	Usually benign; monitor clinically
PH-1	Hematoma ≤30% of infarct, mild mass effect	May require reversal of anticoagulation; delay antithrombotics
PH-2	Hematoma >30% of infarct, significant mass effect	Symptomatic ICH — worst prognosis; reverse coagulopathy; neurosurgical evaluation

PH-2 is the clinically significant type that correlates with neurological deterioration — this is what “symptomatic ICH” refers to in tPA trials
Risk factors for sICH post-tPA: large infarct (low ASPECTS), hyperglycemia, age >80, high NIHSS, early ischemic changes on CT, protocol violations

Extended-Window Thrombolysis

EXTEND (2019): 4.5–9 h with perfusion mismatch — alteplase improved functional outcome in patients with salvageable tissue on perfusion imaging.
WAKE-UP (2018): wake-up/unknown-onset stroke with FLAIR-DWI mismatch — alteplase improved functional outcome.
SWIFT-DIRECT: thrombectomy alone vs alteplase + thrombectomy — failed to show non-inferiority of skipping IV thrombolysis before EVT in transferred LVO patients.

Mechanical Thrombectomy

HERMES meta-analysis (5 trials): LVO within 6 h — strong benefit (NNT ~2.6 for reduction in disability).
DAWN (6–24 h): imaging mismatch (clinical-core mismatch) extended thrombectomy window.
DEFUSE-3 (6–16 h): perfusion-core mismatch extended thrombectomy window.
2023 large-core trials: ANGEL-ASPECT, SELECT2, RESCUE-Japan LIMIT — extended eligibility to ASPECTS 3–5.

Antiplatelet Agents

Drug Comparison

Drug	Mechanism	Dose	Key Features
Aspirin	Irreversible COX-1 inhibitor → ↓ thromboxane A₂	81–325 mg daily	First-line for non-cardioembolic stroke; no dose-response for efficacy above 75 mg
Clopidogrel (Plavix)	Irreversible P2Y₁₂ ADP receptor antagonist	75 mg daily (300–600 mg load)	Prodrug requiring CYP2C19 activation; poor metabolizers have reduced effect; CAPRIE trial
Ticagrelor (Brilinta)	Reversible P2Y₁₂ ADP receptor antagonist	90 mg BID	Does NOT require CYP2C19 activation; THALES trial; not first-line for stroke but option if clopidogrel resistance
Aspirin-dipyridamole (Aggrenox)	COX inhibition + PDE inhibitor / adenosine reuptake inhibitor	ASA 25 mg / dipyridamole ER 200 mg BID	ESPS-2, ESPRIT, PRoFESS; headache limits tolerability (~40%); largely replaced by clopidogrel
Cilostazol	PDE3 inhibitor → ↑ cAMP in platelets	100 mg BID	Antiplatelet + vasodilatory; used more in Asia for secondary prevention; avoid in heart failure

Key Antiplatelet Trials

Trial	Comparison	Key Result
CHANCE (2013)	ASA + clopidogrel × 21 days vs. ASA alone (minor stroke/TIA)	DAPT reduced stroke from 11.7% to 8.2% (ARR 3.5%, NNT ~29); no excess major hemorrhage
POINT (2018)	ASA + clopidogrel × 90 days vs. ASA alone	DAPT reduced ischemic events but ↑ major bleeding after day 21 → supports 21-day limit
THALES (2020)	ASA + ticagrelor × 30 days vs. ASA alone	Reduced stroke/death (5.5% vs. 6.6%); increased severe bleeding; option if clopidogrel resistance suspected
CAPRIE (1996)	Clopidogrel vs. ASA 325 mg	8.7% RRR for composite vascular events; stroke subgroup alone not significant

Board Pearl

DAPT for 21 days (default) (aspirin + clopidogrel) after minor ischemic stroke (NIHSS ≤3) or high-risk TIA, started within 24 hours. CHANCE showed ARR 3.5% (NNT ~29). POINT showed bleeding risk rises after day 21 — supports the 21-day default. 90 days is reserved for severe symptomatic intracranial stenosis (SAMMPRIS-like contexts), not routine minor stroke / high-risk TIA. After DAPT, the single antiplatelet can be aspirin OR clopidogrel depending on patient context. Aspirin + ticagrelor × 30 d (THALES) is a reasonable alternative, particularly in CYP2C19 loss-of-function carriers (CHANCE-2 trial). Loading doses: 300 mg clopidogrel load (CHANCE); 600 mg load (POINT).

Anticoagulants

Warfarin

Mechanism: Vitamin K antagonist → inhibits vitamin K-dependent clotting factors II, VII, IX, X and anticoagulant proteins C & S
Onset: Full anticoagulant effect takes 5–7 days (factor II half-life ~60 hours); initial hypercoagulable risk because protein C (shorter half-life) is depleted first
Pharmacogenomics: CYP2C9 (metabolism) and VKORC1 (drug target) polymorphisms affect dosing requirements — FDA recommends genotype-guided dosing when available
INR targets: 2.0–3.0 for non-valvular AF; 2.5–3.5 for mechanical heart valves
Drug interactions: Extensive — CYP2C9 inducers (rifampin, phenytoin, carbamazepine) ↓ effect; inhibitors (fluconazole, amiodarone, metronidazole) ↑ effect; vitamin K-rich foods (leafy greens) oppose warfarin
Still required for: mechanical valves (DOACs contraindicated — RE-ALIGN trial showed harm with dabigatran), antiphospholipid syndrome (TRAPS trial showed harm with rivaroxaban), severe mitral stenosis
Time in therapeutic range (TTR): should be >65–70%; if TTR consistently low, switch to a DOAC

DOACs — Comparison Table

Feature	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)	Edoxaban (Savaysa)
Mechanism	Direct thrombin (IIa) inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Dose (AF)	150 mg BID	20 mg daily with food	5 mg BID	60 mg daily
Reversal	Idarucizumab (Praxbind)	Andexanet alfa (Andexxa)	Andexanet alfa	Andexanet alfa
Key trial	RE-LY: 150 mg superior to warfarin	ROCKET-AF: non-inferior	ARISTOTLE: superior + lowest bleeding + ↓ mortality	ENGAGE AF: non-inferior
Renal caution	Avoid CrCl <15	Avoid CrCl <15	Reduce to 2.5 mg BID if ≥2 of: age ≥80, wt ≤60 kg, Cr ≥1.5 mg/dL	Avoid CrCl <15 AND >95
Unique	GI bleeding ↑; PPIs cause minor reduction in dabigatran absorption (~20–30%) but no clinically meaningful impact; not contraindicated. Only DOAC with specific reversal agent (monoclonal Ab fragment)	Must take with food	Best overall safety; most studied in elderly	Only DOAC contraindicated if CrCl >95

Clinical Pearl

Apixaban is the preferred DOAC for most AF patients — ARISTOTLE showed superiority for stroke prevention, major bleeding, AND all-cause mortality vs. warfarin. Dabigatran 150 mg is also superior for efficacy but with more GI bleeding. All DOACs have less intracranial hemorrhage than warfarin.

When to Anticoagulate After Stroke

CHA₂DS₂-VASc Score

Letter	Risk Factor	Points
C	Congestive heart failure	1
H	Hypertension	1
A₂	Age ≥75	2
D	Diabetes mellitus	1
S₂	Prior Stroke/TIA/thromboembolism	2
V	Vascular disease (MI, PAD, aortic plaque)	1
A	Age 65–74	1
Sc	Sex category (female)	1

Score ≥2 in men or ≥3 in women: anticoagulation recommended
Any patient with prior stroke/TIA already scores ≥2 → anticoagulation indicated for ALL AF patients with prior stroke

Timing of Anticoagulation After Acute Ischemic Stroke

Traditional 1-3-6-12 rule (TIA day 1, small non-disabling day 3, moderate day 6, large day 12–14) is historical; ELAN trial (2023) supports earlier initiation across categories: within 48 h for minor/moderate stroke, 6–7 days for major (no excess hemorrhage).
Contraindicated in acute large hemorrhagic transformation — repeat imaging before starting; use aspirin as bridge
No heparin bridging: DOACs have rapid onset (2–4 hours); BRIDGE trial showed bridging increases bleeding without reducing thromboembolism
While awaiting anticoagulation: aspirin as interim therapy; discontinue aspirin once anticoagulation starts (combining long-term aspirin + DOAC increases bleeding without clear benefit unless concurrent indication such as recent coronary stent)
Mechanical heart valves: always warfarin (INR 2.5–3.5); DOACs are absolutely contraindicated (RE-ALIGN trial: dabigatran increased thrombotic and bleeding events in mechanical valve patients)

Board Pearl

Prior stroke = 2 points on CHA₂DS₂-VASc → ALL AF patients with stroke qualify for anticoagulation. Use the 1-3-6-12 day rule for timing. Always repeat brain imaging before starting anticoagulation to exclude hemorrhagic transformation. ELAN supports earlier initiation in most patients.

Blood Pressure Management

BP Targets by Clinical Scenario

Setting	BP Target	Rationale / Trial Evidence
Acute ischemic stroke (NO tPA)	Permissive HTN; treat only if >220/120	Maintain cerebral perfusion to ischemic penumbra; aggressive lowering can worsen infarct
Acute ischemic stroke (tPA candidate)	<185/110 before tPA; <180/105 for 24h after	Reduces risk of symptomatic hemorrhagic transformation post-thrombolysis
Acute mild-moderate spontaneous ICH (SBP 150–220)	Smooth lowering to ~140; maintain SBP 130–150; AVOID acute SBP <130 (2022 AHA/ASA)	INTERACT2: SBP <140 was safe and improved functional outcomes; ATACH-2: intensive lowering (<140 within 2h) did not add benefit over <180 and ↑ renal AEs — supports the 130–150 maintenance band with avoidance of acute overshoot below 130
Secondary prevention (chronic)	SBP <130/80 mmHg	SPRINT: intensive BP control reduced CV events; SPS3: intensive control (<130) reduced ICH after lacunar stroke by 63%; PROGRESS: ACEi + thiazide reduced recurrent stroke 43%

Agents for acute BP lowering: IV labetalol (first-line, 10–20 mg bolus, repeat q10–20 min), nicardipine drip (5–15 mg/hr, titrate q5–15 min), clevidipine (1–2 mg/hr)
Avoid nitroprusside in acute stroke — raises ICP via cerebral vasodilation, unpredictable effect, cyanide toxicity risk
Avoid sublingual nifedipine — rapid, unpredictable BP drops can cause watershed ischemia
Caution with bilateral carotid/intracranial stenosis: aggressive chronic BP lowering risks watershed infarction; individualize target
Preferred agents for chronic secondary prevention: ACE inhibitors or ARBs ± thiazide diuretic (PROGRESS trial: perindopril + indapamide reduced recurrent stroke 43%, even in normotensive patients)

Clinical Pearl

INTERACT2 vs. ATACH-2 for ICH: INTERACT2 showed SBP <140 was safe and improved outcomes. ATACH-2 showed intensive lowering (<140 within 2 hours with IV nicardipine) did NOT add benefit over <180 and increased renal adverse events. The 2022 AHA/ASA ICH guideline takeaway: for mild-moderate spontaneous ICH with SBP 150–220, lower smoothly to target ~140 and maintain SBP 130–150; AVOID acute SBP <130 (potentially harmful).

Statin Therapy for Stroke Prevention

SPARCL Trial & Current Guidelines

SPARCL (2006): Atorvastatin 80 mg in patients with recent stroke/TIA (no CAD) → 16% RRR for recurrent stroke (HR 0.84, NNT ~46 over 5 years); mean LDL achieved 73 mg/dL
Caveat: Small increase in hemorrhagic stroke (HR 1.66) — predominantly in patients with prior hemorrhagic stroke; overall net benefit still favored statin
TST trial (2020): LDL <70 vs. 90–110 mg/dL → lower target reduced recurrent CV events (HR 0.78); supports "lower is better"

Statin Intensity	Drugs & Doses	Expected LDL Reduction
High-intensity	Atorvastatin 40–80 mg; rosuvastatin 20–40 mg	≥50%
Moderate-intensity	Atorvastatin 10–20 mg; rosuvastatin 5–10 mg; simvastatin 20–40 mg	30–49%

Indication: High-intensity statin for ALL patients with atherosclerotic ischemic stroke/TIA (Class I, Level A)
LDL target: <70 mg/dL (AHA/ASA, supported by TST 2020 trial); consider <55 mg/dL for very high-risk patients
Do NOT stop statins acutely — withdrawal is associated with worse outcomes (rebound effect)
Add-on if not at goal: ezetimibe first; then PCSK9 inhibitor (evolocumab, alirocumab) if still above target
Statin + hemorrhagic stroke risk: SPARCL showed a small increase in hemorrhagic stroke (HR 1.66); risk factors include prior ICH, cerebral microbleeds, older age, poorly controlled HTN — weigh against ischemic benefit
Pleiotropic effects: Statins provide benefit beyond LDL reduction — endothelial function improvement, plaque stabilization, anti-inflammatory effects, reduced oxidative stress
Statin myopathy: CK elevation, myalgias; risk increased with CYP3A4 inhibitors (clarithromycin, itraconazole, grapefruit) — rosuvastatin and pravastatin are NOT CYP3A4 substrates and have less interaction risk
Initiation timing: Start high-intensity statin within 48 hours of ischemic stroke; early initiation is associated with improved 90-day outcomes

Board Pearl

SPARCL is a frequently tested trial: Atorvastatin 80 mg reduced recurrent ischemic stroke by 16% (NNT ~46) in patients without known CAD. Target LDL <70 mg/dL. The slight increase in hemorrhagic stroke is outweighed by net benefit. Never discontinue statins acutely after ischemic stroke.

ICH Reversal Agents

Anticoagulant Reversal — Quick Reference

Anticoagulant	Reversal Agent	Key Details
Warfarin	4-factor PCC (Kcentra) + IV vitamin K 10 mg	PCC reverses in minutes; vitamin K takes 6–24 hours but sustains reversal; FFP is second-line (slower, volume overload); check INR at 30 min and 6h
Dabigatran	Idarucizumab (Praxbind) 5 g IV	Monoclonal antibody fragment; immediate, complete reversal; specific to dabigatran only; RE-VERSE AD trial
Rivaroxaban / Apixaban / Edoxaban	Andexanet alfa (Andexxa) or 4-factor PCC	Andexanet alfa = recombinant modified factor Xa decoy; ANNEXA-4 trial. ANNEXA-I (2024 NEJM) was stopped early — andexanet reduced hematoma expansion vs usual care BUT was associated with increased thrombotic events (10.3% vs 5.6%) with unclear functional benefit. 4F-PCC is a reasonable alternative with better safety profile.
Unfractionated heparin	Protamine sulfate	1 mg protamine per 100 units heparin given in last 2–3 hours; max 50 mg; only partially reverses LMWH (~60%)
Thrombocytopenia / post-IVT sICH	Platelet transfusion (only for specific indication)	Target platelets >100,000 only if thrombocytopenic; 1 unit apheresis raises count ~30–50K; transfusion NOT recommended for antiplatelet-related spontaneous ICH with normal platelet count (PATCH 2016 Lancet — worse functional outcomes, ↑ death/dependence). For post-IVT sICH, cryoprecipitate to fibrinogen goal is first-line; platelets ONLY for a specific indication (thrombocytopenia or selected antiplatelet context) — NOT routine.

4-factor PCC contains factors II, VII, IX, X + proteins C & S — preferred over FFP (faster, no volume overload, does not require thawing)
Vitamin K alone is insufficient for acute reversal — takes hours to work; always give PCC simultaneously for warfarin-related ICH
Activated PCC (FEIBA) may be used for factor Xa inhibitor reversal when andexanet alfa is unavailable
Timing is critical: Reversal should be given as soon as ICH is confirmed in patients on anticoagulation — hematoma expansion occurs rapidly in the first hours and drives worse outcomes
Tranexamic acid (TXA): Antifibrinolytic; TICH-2 trial showed reduced hematoma expansion in ICH but no improvement in functional outcomes; role remains adjunctive. FASTEST (2025 NEJM, Liotta et al.) tested ultra-early TXA (<2 h) in spontaneous ICH — NEGATIVE primary outcome. TICH-2 modest signal; TXA not routinely recommended for spontaneous ICH.
INTERACT-3 (2023): Care bundle (early intensive BP lowering + glucose control + temperature + anticoagulation reversal) improved functional outcomes — first ICH trial showing benefit of early aggressive BP control on functional outcomes.

Board Pearl

Match the anticoagulant to its reversal agent: Warfarin → 4-factor PCC + vitamin K. Dabigatran → idarucizumab (only DOAC with a monoclonal antibody reversal). Factor Xa inhibitors → andexanet alfa (or PCC if unavailable; ANNEXA-I raised thrombotic concerns — 4F-PCC is a reasonable alternative). Heparin → protamine. PATCH (2016) showed platelet transfusion in antiplatelet-related spontaneous ICH was associated with WORSE outcomes — do NOT transfuse platelets for antiplatelet-related ICH with normal platelet count.

Vasospasm Prophylaxis — Nimodipine

Nimodipine in SAH

Dose: 60 mg PO (or via NG tube) every 4 hours × 21 days — start within 96 hours of SAH
Mechanism: Dihydropyridine calcium channel blocker with preferential cerebrovascular selectivity
Key distinction: Nimodipine does NOT prevent angiographic vasospasm — it improves neurological outcomes and reduces delayed cerebral ischemia (DCI), likely via neuroprotective and microcirculatory effects
Only calcium channel blocker with proven benefit in SAH — do not substitute with other CCBs (nifedipine, verapamil, etc.)
Side effects: Hypotension (reduce to 30 mg q2h if symptomatic; do NOT stop), diarrhea
CRITICAL safety warning: Must be given orally or via NG tube only — IV administration of the oral formulation has caused fatal cardiovascular collapse
Evidence: British Aneurysm Nimodipine Trial — 34% reduction in poor outcomes; confirmed in meta-analyses
Vasospasm timeline: Onset day 3–5, peaks day 7–10, resolves by day 14–21; nimodipine should cover this entire window
Triple-H therapy (historical): Hypertension, hypervolemia, hemodilution — largely replaced by maintenance of euvolemia with induced hypertension reserved for symptomatic vasospasm. Prophylactic hypervolemia is NOT recommended (Lennihan 2000; multiple negative trials); maintain euvolemia. HIMALAIA (2018) tested induced hypertension for established DCI — negative for functional outcome and stopped early. Intra-arterial vasodilators (nicardipine, verapamil, milrinone) for refractory vasospasm; balloon angioplasty for refractory focal spasm.

Clinical Pearl

Nimodipine reduces delayed cerebral ischemia and improves outcomes (mortality and functional) in aneurysmal SAH; does NOT reliably prevent angiographic vasospasm; only PO/NG — IV causes fatal hypotension (FDA boxed warning). If hypotension occurs, halve the dose and increase frequency (30 mg q2h) — never discontinue.

Board Pearl

Nimodipine is the ONLY pharmacologic agent proven to improve outcomes in SAH. It must be given orally (or via NG tube), 60 mg q4h for 21 days. IV administration of the oral capsule has caused deaths. No other CCB is a substitute. Triple-H therapy has been replaced by euvolemia + induced hypertension for symptomatic vasospasm.

Special Stroke Etiologies

Cerebral Venous Thrombosis (CVT)

Acute treatment: LMWH (preferred over UFH).
Transition to warfarin (3–6 months) or DOAC — ACTION-CVT supports DOAC non-inferiority to warfarin for secondary prevention.
Anticoagulation is appropriate even in the presence of hemorrhagic venous infarction.

Carotid Stenosis

CEA (carotid endarterectomy): preferred for symptomatic high-grade stenosis; CREST — CEA modestly better for >70 yo; CAS comparable in younger patients.
CAS (carotid artery stenting): preferred in surgical high-risk anatomy/comorbidity (SAPPHIRE).
Medical therapy: statin + antiplatelet; aggressive BP control; smoking cessation.

PFO Closure

RESPECT, CLOSE, REDUCE — percutaneous PFO closure reduces recurrent stroke vs antiplatelet alone for select <60 yo with cryptogenic stroke + high-risk PFO (large shunt or atrial septal aneurysm).
Confirm absence of alternative stroke etiology before closure.

Sickle Cell Stroke

Hydroxyurea: primary disease-modifying therapy reducing stroke risk.
Chronic transfusion: STOP trial — primary prevention for children with abnormal TCD velocity.
Adjuncts: voxelotor, crizanlizumab.

Moyamoya

Surgical revascularization: EDAS (encephaloduroarteriosynangiosis), STA-MCA bypass.
Antiplatelet (aspirin) for medical management.
Avoid hypotension and dehydration — can precipitate ischemic events.

CADASIL

Antiplatelet (no proven disease-modifying therapy).
AVOID anticoagulation in primary prevention — increased ICH risk in this microangiopathy.

Heparin-Induced Thrombocytopenia (HIT)

Avoid heparin and LMWH; do not give platelet transfusions (paradoxical thrombosis).
Acute alternative anticoagulants: argatroban, bivalirudin, fondaparinux.
Bridge to warfarin or DOAC once platelets recover (typically >150,000).

GLP-1 / SGLT2 Inhibitors

GLP-1 receptor agonists (semaglutide, liraglutide) and SGLT2 inhibitors (empagliflozin, dapagliflozin) reduce major adverse cardiovascular events in diabetic stroke patients; consider as add-on for cardiovascular risk reduction.

Quick Reference Table