Stroke & Vascular Pharmacology

What You'll Learn

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

HighYield Pearls

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.

🔍 Quick ReferenceMechanism · 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.

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