Stroke & Vascular Pharmacology
Stroke & Vascular Pharmacology
What Do You Need to Know?
- Alteplase (tPA) — 0.9 mg/kg (max 90 mg), 10% bolus + 60 min infusion; window ≤4.5 hours; BP must be <185/110; tenecteplase is emerging as single-bolus alternative
- Dual antiplatelet therapy (DAPT) — aspirin + clopidogrel × 21 days for minor stroke (NIHSS ≤3) or high-risk TIA (CHANCE/POINT); then clopidogrel monotherapy
- 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); ICH target SBP <140 (INTERACT2); secondary prevention <130/80
- Statins — high-intensity for all atherosclerotic stroke; SPARCL: atorvastatin 80 mg reduced recurrent stroke 16%; target LDL <70
- Nimodipine for SAH — 60 mg PO q4h × 21 days; improves outcomes but does NOT prevent vasospasm; only CCB with proven benefit in SAH
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-TRACE trials |
| Mechanism | Recombinant tissue plasminogen activator → plasminogen → plasmin → fibrinolysis | Modified tPA; higher fibrin specificity, longer half-life |
| Advantages | Standard of care; most evidence | Single bolus (easier administration); non-inferior to alteplase; emerging as preferred agent |
| 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 or DOAC within 24–48 hours |
| — | 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): age >80, NIHSS >25, OAC use regardless of INR, history of both diabetes AND prior stroke
- 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-tPA: stop infusion immediately → stat CT head → check fibrinogen, CBC, type & screen → give cryoprecipitate (target fibrinogen >200 mg/dL) + tranexamic acid; consider platelet transfusion
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 is given as a single bolus and is emerging as a simpler, non-inferior alternative.
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
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 exactly 21 days (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. Then switch to clopidogrel monotherapy. Ticagrelor (THALES) is an alternative if clopidogrel resistance is suspected.
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 | Avoid CrCl <15 AND >95 |
| Unique | GI bleeding ↑; avoid PPI (needs acid); 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
- "1-3-6-12 Day Rule" for timing after acute ischemic stroke:
- Day 1: TIA (no infarct on imaging)
- Day 3: Small stroke (minor infarct)
- Day 6: Moderate stroke
- Day 12–14: Large stroke or hemorrhagic transformation present
- ELAN trial (2023): Early anticoagulation (within 48 hours for minor, days 3–4 for moderate, days 6–7 for large) was non-inferior to later initiation → supports earlier anticoagulation
- 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 ICH | SBP <140 mmHg | 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 |
| 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 practical takeaway: target SBP <140 but do not pursue overly rapid or aggressive reduction.
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); 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; PCC is used if andexanet not available |
| 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 | Platelet transfusion | Target platelets >100,000 for ICH; 1 unit apheresis raises count ~30–50K; benefit of transfusion in aspirin/clopidogrel-related ICH is uncertain (PATCH trial negative) |
- 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
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). Heparin → protamine. PATCH trial showed platelet transfusion did NOT improve outcomes in antiplatelet-related ICH.
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 euvolemia + induced hypertension for symptomatic vasospasm; prophylactic hypervolemia is NOT recommended (HIMALAIA trial)
- Intra-arterial rescue: verapamil or nicardipine infusion directly into spastic vessels + balloon angioplasty for refractory vasospasm (interventional, not pharmacologic prophylaxis)
Clinical Pearl
Nimodipine improves outcomes in SAH WITHOUT reducing angiographic vasospasm. This is a frequently tested board distinction. Its benefit likely comes from neuroprotection and microvascular effects rather than large vessel vasodilation. 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.
Quick Reference Table
Stroke & Vascular Pharmacology — At a Glance
| Category | Key Drug / Concept | Board-Yield Detail |
|---|---|---|
| Thrombolysis | Alteplase 0.9 mg/kg, max 90 mg | ≤4.5h window; BP <185/110; 10% bolus, 60 min infusion |
| Tenecteplase | Single bolus, non-inferior | Emerging alternative; simpler administration |
| DAPT (minor stroke) | ASA + clopidogrel × 21 days | CHANCE/POINT; NIHSS ≤3 or high-risk TIA; then clopidogrel mono |
| Clopidogrel | Irreversible P2Y12 | CYP2C19 prodrug; poor metabolizers have reduced effect |
| Ticagrelor | Reversible P2Y12 | THALES trial; no CYP2C19 dependence; not first-line |
| Warfarin | Vitamin K antagonist | INR 2–3 (AF); 2.5–3.5 (mechanical valves); CYP2C9/VKORC1 polymorphisms |
| Dabigatran | Direct thrombin inhibitor | RE-LY (150 mg superior); reversed by idarucizumab |
| Apixaban | Factor Xa inhibitor | ARISTOTLE (best safety profile); reversed by andexanet alfa |
| Edoxaban | Factor Xa inhibitor | Contraindicated if CrCl >95; only DOAC with this restriction |
| Anticoagulation timing | 1-3-6-12 day rule | Small stroke early; large stroke wait; always re-image first |
| Acute ischemic BP | <220/120 (no tPA); <185/110 (tPA) | Permissive HTN to maintain penumbral perfusion |
| Acute ICH BP | SBP <140 | INTERACT2 positive; ATACH-2 showed no benefit of ultra-rapid lowering |
| Chronic BP target | <130/80 | SPRINT, SPS3, PROGRESS; ACEi + thiazide best evidence |
| Statins | Atorvastatin 80 mg (SPARCL) | 16% RRR; LDL <70; do not stop acutely |
| Warfarin reversal | 4-factor PCC + vitamin K | PCC works in minutes; vitamin K sustains reversal |
| Dabigatran reversal | Idarucizumab 5 g IV | Monoclonal Ab fragment; immediate reversal |
| Factor Xa reversal | Andexanet alfa or PCC | ANNEXA-4 trial; PCC if andexanet unavailable |
| Heparin reversal | Protamine sulfate | 1 mg per 100 units; partially reverses LMWH |
| Nimodipine (SAH) | 60 mg PO q4h × 21 days | Improves outcomes; does NOT prevent vasospasm; oral ONLY |
References
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke (NINDS). N Engl J Med. 1995;333(24):1581–1587.
- Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III). N Engl J Med. 2008;359(13):1317–1329.
- Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE). N Engl J Med. 2013;369(1):11–19.
- Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA (POINT). N Engl J Med. 2018;379(3):215–225.
- Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA (THALES). N Engl J Med. 2020;383(3):207–217.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY). N Engl J Med. 2009;361(12):1139–1151.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation (ROCKET AF). N Engl J Med. 2011;365(10):883–891.
- Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation (ARISTOTLE). N Engl J Med. 2011;365(11):981–992.
- Fischer U, Koga M, Strbian D, et al. Early versus later anticoagulation for stroke with atrial fibrillation (ELAN). N Engl J Med. 2023;388(26):2411–2421.
- Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral haemorrhage (INTERACT2). Lancet. 2013;382(9890):397–408.
- Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage (ATACH-2). N Engl J Med. 2016;375(11):1033–1043.
- Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack (SPARCL). N Engl J Med. 2006;355(6):549–559.
- Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal — full cohort analysis (RE-VERSE AD). N Engl J Med. 2017;377(5):431–441.
- Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4). N Engl J Med. 2019;380(14):1326–1335.
- Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British Aneurysm Nimodipine Trial. BMJ. 1989;298(6674):636–642.