Anticoagulants & Antithrombotics — Pharmacology · ICU Topics

Cinematic ICU scene of anticoagulant and antithrombotic pharmacology — a coagulation cascade annotated with heparin, LMWH, warfarin and the DOACs at their targets, protamine, vitamin K and PCC for reversal, an antiplatelet panel, clinical-blue lighting, medical educational, no faces, no text — FigureAnticoagulants and antithrombotics — by mechanism. The heparins potentiate antithrombin (UFH: aPTT, protamine, safe in renal failure; LMWH: anti-Xa, partial protamine). Warfarin blocks the vitamin-K epoxide reductase (INR 2–3, slow, teratogenic, overlap heparin against the protein-C skin necrosis). The DOACs by their target — dabigatran the thrombin, apixaban and rivaruban the Xa — with idarucizumab and andexanet alfa for reversal. The antiplatelets: aspirin the COX, clopidogrel the P2Y12. Know the antidote.

Educational coagulation cascade schematic highlighting heparin-antithrombin, warfarin vitamin K pathway, direct thrombin and factor Xa inhibitor targets, and antiplatelet COX/P2Y12 nodes — FigureKnow the target — ATIII-dependent heparins, VKOR for warfarin, direct IIa/Xa for DOACs, and COX/P2Y12 for antiplatelets — because the antidote follows the mechanism.

Overview & definition

Anticoagulants and antithrombotics — by the mechanism of action. The indirect (heparins via antithrombin), the direct (DTI, FXa), the vitamin K antagonist (warfarin). The antiplatelets (COX, P2Y12, GPIIb/IIIa). The PK/PD and the reversal.[1]

The intensivist must master four therapeutic axes: (1) coagulation factor inhibition (parenteral heparins, oral warfarin/DOACs) for VTE, AF, and mechanical valves; (2) platelet inhibition (aspirin, P2Y12 inhibitors, GPIIb/IIIa) for ACS and stents; (3) the specific reversal agents (protamine, idarucizumab, andexanet alfa, vitamin K, PCC); and (4) the bleeding-risk framework (HAS-BLED) that governs drug choice. The unifying principle: match the drug to the indication, the patient's renal/hepatic function, and the realistic bleeding risk — then know precisely how to reverse each agent when bleeding occurs. [1]

By class

Class	Mechanism	Monitoring	Reversal
UFH	Antithrombin → IIa + Xa	APTT / anti-Xa	Protamine
LMWH	Antithrombin → Xa	Anti-Xa (if needed)	Protamine (partial ~60%)
Fondaparinux	Antithrombin → Xa	Not routine	None (rFVIIa)
Dabigatran	Direct thrombin (IIa)	Thrombin time	Idarucizumab
Apixaban/rivaroxaban	Direct Xa	Anti-Xa (calibrated)	Andexanet alfa / PCC
Warfarin	Vit K epoxide reductase	INR	Vit K + PCC
Argatroban	Direct thrombin (IIa)	APTT	None (short t1/2)
Bivalirudin	Direct thrombin (IIa)	APTT	None (short t1/2)

The anticoagulant landscape at a glance

Parenteral vs oral anticoagulants — the master comparison

Drug	Mechanism	Onset	Half-life	Elimination	Monitoring	Reversal agent
UFH	Binds antithrombin III → inactivates IIa + Xa	Immediate (IV) / 20-30 min (SC)	60-90 min (dose-dependent)	Reticuloendothelial (hepatic) + renal	aPTT (or anti-Xa)	Protamine 1 mg per 100 U heparin
LMWH (enoxaparin)	Antithrombin → preferential Xa inhibition	3-5 h (SC)	4-7 h	Renal (unchanged)	Anti-Xa (renal impairment, obesity, pregnancy)	Protamine PARTIAL (~60%)
Fondaparinux	Synthetic pentasaccharide → antithrombin → Xa only	2-3 h (SC)	17-21 h	Renal (unchanged)	None routine	None (rFVIIa, haemodialysis)
Warfarin	Vitamin K epoxide reductase inhibitor (↓II, VII, IX, X, protein C/S)	3-5 days	36-42 h	Hepatic (CYP2C9)	INR (target 2-3, or 2.5-3.5 mechanical mitral)	Vitamin K + 4F-PCC ± FFP
Dabigatran	Direct thrombin inhibitor (IIa)	1-3 h	12-17 h (prolonged in renal failure)	80% renal	Thrombin time (TT), dTT, ECT	Idarucizumab (5 g IV)
Rivaroxaban	Direct factor Xa inhibitor	2-4 h	5-9 h (11-13 h elderly)	33% renal, 66% hepatic/fecal	Anti-Xa (rivaroxaban-calibrated)	Andexanet alfa (high/low dose) ± PCC
Apixaban	Direct factor Xa inhibitor	3-4 h	12 h	27% renal, 73% hepatic/fecal	Anti-Xa (apixaban-calibrated)	Andexanet alfa ± PCC
Argatroban	Direct thrombin inhibitor	Immediate (IV)	39-51 min	Hepatic (bilirubin caution)	aPTT (target 1.5-3× baseline)	None — short t1/2 + haemodialysis
Bivalirudin	Direct thrombin inhibitor	Immediate (IV)	25 min	Enzymatic (80%) + renal (20%)	aPTT / ACT	None — short t1/2

[1]

Heparin (UFH) — the workhorse parenteral anticoagulant

The one-paragraph exam answer — UFH

Unfractionated heparin (UFH) is a heterogeneous mixture of glycosaminoglycans (MW 3-30 kDa). Its active pentasaccharide sequence binds antithrombin III (AT III), inducing a conformational change that accelerates AT-mediated inactivation of thrombin (IIa) and factor Xa ~1000-fold (it cannot inactivate clot-bound thrombin or factor Xa within the clot). Pharmacokinetics: rapid onset (IV immediate, SC 20-30 min); dose-dependent half-life 60-90 min (longer at higher doses — saturatable reticuloendothelial clearance); hepatic clearance → SAFE in renal failure (the preferred anticoagulant in AKI/CKD, pregnancy bridging, and weight-based titration). Monitoring: aPTT (target 1.5-2.5× control, ~60-100 s) or anti-Xa level (preferred in lupus anticoagulant, consumptive states, high factor VIII). Reversal: protamine sulfate — 1 mg neutralises 100 U of heparin (max 50 mg/dose); dose based on heparin given in the last 2-3 h due to heparin's short half-life. Major adverse effects: bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis (>1 month therapy), and hyperkalaemia (suppresses aldosterone). The key advantage over LMWH: short half-life + full reversibility + safe in renal failure — ideal for ICU patients who may need procedures or rapid reversal.[1]

UFH dosing strategies in ICU practice

Indication	Regimen	Target
DVT/PE treatment	80 U/kg bolus → 18 U/kg/hr infusion	aPTT 1.5-2.5× control (or anti-Xa 0.3-0.7 IU/mL)
ACS	60 U/kg bolus (max 4000 U) → 12 U/kg/hr (max 1000 U/hr)	aPTT 1.5-2.0× (60-85 s); usually with aspirin + P2Y12
Atrial fibrillation (bridging)	No bolus → 18 U/kg/hr infusion	aPTT 1.5-2.5×
Mechanical valve (perioperative bridging)	SC 250 U/kg BD or infusion	aPTT 2-3×
Extracorporeal circuits (CRRT, ECMO)	20-50 U/kg bolus → 5-20 U/kg/hr	Anti-Xa 0.25-0.35 IU/mL (CRRT) or ACT 180-220 s (ECMO)
VTE prophylaxis	5000 U SC TDS	None (fixed dose)

[1]

LMWH (enoxaparin) — predictable, no routine monitoring

The one-paragraph exam answer — LMWH

Low-molecular-weight heparin (LMWH) is produced by depolymerising UFH (MW 4-6 kDa). The shorter chains preferentially inactivate factor Xa over thrombin (anti-Xa:anti-IIa ratio ~3-4:1 for enoxaparin, vs 1:1 for UFH). Pharmacokinetics: predictable SC absorption (bioavailability ~90%); half-life 4-7 h; renal excretion → DANGEROUS in renal failure (avoid if CrCl <30; the dose accumulates → bleeding); the dose-dependent half-life problem of UFH is eliminated → no routine monitoring needed in stable patients. Dosing: enoxaparin 1 mg/kg SC BD for treatment of VTE/ACS, or 1.5 mg/kg OD (VTE), or 40 mg OD (prophylaxis, or 20 mg OD if CrCl <30). Monitoring (when required): anti-Xa level (target 0.5-1.0 IU/mL BD, 4 h post-dose) — in renal impairment, pregnancy, obesity (>150 kg), and extremes of weight. Reversal: protamine provides only PARTIAL (~60%) reversal — give 1 mg per 1 mg enoxaparin in last 8 h (then 0.5 mg per mg if >8 h). Advantages over UFH: lower HIT risk (~10× lower), no routine monitoring, lower osteoporosis risk, outpatient therapy possible. Disadvantages: NOT safe in severe renal impairment, partial reversal only, longer half-life (cannot be rapidly switched off).[1]

UFH vs LMWH — when to choose which

Feature	UFH	LMWH (enoxaparin)
Molecular weight	3-30 kDa (heterogeneous)	4-6 kDa (uniform)
Mechanism	Antithrombin → IIa + Xa equally	Antithrombin → Xa preferentially (3-4:1)
Half-life	60-90 min (dose-dependent)	4-7 h (fixed)
Clearance	Hepatic/reticuloendothelial + renal	Renal only
Bioavailability (SC)	Variable (~30-50%)	High (~90%, predictable)
Routine monitoring	Yes (aPTT)	No
HIT risk	1-5%	~0.2% (10× lower)
Osteoporosis risk	Higher (long-term)	Lower
Reversal	Protamine (complete)	Protamine PARTIAL (~60%)
Renal failure safety	SAFE	AVOID (CrCl <30)
Preferred when	AKI, need for rapid reversal/procedures, haemodynamic instability, CRRT/ECMO	Stable VTE treatment/prophylaxis, oncology (LMWH preferred in cancer — longer-term), outpatient

[1]

Warfarin — the vitamin K antagonist

The one-paragraph exam answer — warfarin

Warfarin is a vitamin K epoxide reductase (VKORC1) inhibitor, depleting the reduced vitamin K needed for γ-carboxylation of clotting factors II, VII, IX, X and the anticoagulant proteins C and S. The net effect is production of functionally inactive (uncarboxylated) factors. Pharmacokinetics: complete oral absorption; slow onset 3-5 days (factors II and X have the longest half-lives — 60 h and 40 h respectively; factor VII depletes first at ~6 h); CYP2C9 metabolism; narrow therapeutic window with extensive food and drug interactions (CYP2C9 polymorphisms — *1/*1 normal, *2/*3 reduced dose). Monitoring: INR — target 2-3 for VTE/AF, 2.5-3.5 for mechanical mitral valves. Major pitfalls: (1) slow onset — must overlap heparin/LMWH for ≥5 days until INR >2 for 24 h; (2) protein C depletion paradox — protein C (half-life 8 h) depletes before the procoagulant factors → transient hypercoagulable state → warfarin-induced skin necrosis (especially in protein C deficiency); (3) teratogenic (crosses placenta → fetal warfarin syndrome — nasal hypoplasia, chondrodysplasia, CNS abnormalities) — CONTRAINDICATED in pregnancy (use LMWH). Reversal: (a) minor — hold dose ± vitamin K 1-2.5 mg PO; (b) major bleeding — vitamin K 5-10 mg IV + 4-factor prothrombin complex concentrate (PCC) 25-50 IU/kg (preferred over FFP — faster, smaller volume, no thawing); (c) supratherapeutic without bleeding — hold + vitamin K 1-5 mg PO/IV. PCC has displaced FFP for warfarin reversal (more rapid INR correction, less volume overload).[1]

Warfarin reversal by clinical scenario — the bedside algorithm

Clinical scenario	INR	Intervention	Speed of INR correction
INR supratherapeutic, NO bleeding	5-9	Hold warfarin; consider vitamin K 1-2.5 mg PO	24-48 h
INR ≥10, NO bleeding	≥10	Hold warfarin; vitamin K 2.5-5 mg PO (IV if high bleeding risk)	24-48 h
Minor bleeding	>3	Hold; vitamin K 1-5 mg PO/IV	12-24 h
Major bleeding	Any elevated	Hold + vitamin K 5-10 mg IV + 4F-PCC 25-50 IU/kg ± FFP	Immediate (within minutes — PCC)
Life-threatening bleed / ICH	Any elevated	Hold + vitamin K 10 mg IV + 4F-PCC 50 IU/kg + FFP 15 mL/kg	Immediate
Need for rapid pre-procedure reversal	Any	4F-PCC + vitamin K 5 mg IV	Within 30-60 min

[1]

Direct oral anticoagulants (DOACs) — the modern era

The one-paragraph exam answer — DOACs

The direct oral anticoagulants (DOACs) are classified by target: direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). Compared with warfarin they offer predictable pharmacokinetics → no routine monitoring, rapid onset (1-4 h) → no bridging, short half-life → rapid offset, fewer food/drug interactions, and equivalent or superior efficacy/safety versus warfarin in VTE and non-valvular AF. Dabigatran (150 mg BD) is the only oral direct thrombin inhibitor — 80% renally cleared (avoid CrCl <30; risk of accumulation in AKI), reversed by idarucizumab 5 g IV (a monoclonal Fab fragment). Rivaroxaban (15-20 mg OD) and apixaban (5 mg BD) are direct Xa inhibitors — ~25-30% renally cleared; reversed by andexanet alfa (a recombinant modified FXa decoy protein) when available, otherwise 4F-PCC/aPCC. CRITICAL contraindications: (1) mechanical heart valves — RE-ALIGN showed dabigatran caused more thrombosis/bleeding than warfarin → warfarin only; (2) antiphospholipid syndrome with triple positivity — DOACs inferior to warfarin (RAPS trial). Monitoring (rarely needed): dabigatran → thrombin time (TT) or diluted TT; rivaroxaban/apixaban → anti-Xa calibrated to the specific drug (NOT a standard anti-Xa). DO NOT use PT/INR for DOAC monitoring — they are unreliable. In the bleeding patient, a normal thrombin time excludes clinically significant dabigatran; a normal anti-Xa excludes significant Xa-inhibitor levels.[1][2][3]

The four DOACs — mechanism, dose, reversal, and clearance

Drug	Target	Standard dose (VTE/AF)	Renal clearance	Half-life	Reversal	Pregnancy
Dabigatran	Thrombin (IIa)	150 mg BD	80%	12-17 h (prolonged in renal failure; up to 28 h)	Idarucizumab 5 g IV	Contraindicated
Rivaroxaban	Xa	20 mg OD (15 mg OD if CrCl 15-50)	33%	5-9 h (11-13 h elderly)	Andexanet alfa ± PCC	Contraindicated
Apixaban	Xa	5 mg BD (2.5 mg BD if ≥2 of: age ≥80, Cr ≥133, weight ≤60 kg)	27%	12 h	Andexanet alfa ± PCC	Contraindicated
Edoxaban	Xa	60 mg OD (30 mg if CrCl 15-50, ≤60 kg, concomitant P-gp inhibitor)	50%	10-14 h	Andexanet alfa ± PCC	Contraindicated

[1]

Specific reversal agents — the modern pharmacology

The one-paragraph exam answer — DOAC reversal

Dabigatran → idarucizumab: a humanised monoclonal Fab fragment that binds dabigatran with 350× higher affinity than thrombin itself, effectively removing it from circulation. Dose: 5 g IV (2 × 2.5 g vials, given as two consecutive infusions/boluses). RE-VERSE AD demonstrated immediate (within minutes) and complete reversal of anticoagulant effect (diluted thrombin time normalised in 88-98% of patients); full-cohort analysis confirmed sustained reversal at 24 h and 72 h. Idarucizumab is itself inert (no procoagulant effect, no hepatic/renal metabolism of consequence) — the only specific reversal that is truly "clean". Rivaroxaban/apixaban → andexanet alfa: a recombinant modified human FXa (active-site Ser195→Ala) that acts as a decoy, binding Xa inhibitors and freeing endogenous FXa to restore haemostasis. Dosing is weight- and dose-dependent: HIGH dose (800 mg bolus → 8 mg/min for 120 min) for high-dose Xa-inhibitor (rivaroxaban >10 mg, apixaban >5 mg, any dose if <8 h); LOW dose (400 mg bolus → 4 mg/min for 120 min) otherwise. ANNEXA-4 demonstrated 82-92% reduction in anti-Xa activity and good/excellent haemostasis in ~82%. Caveats: andexanet has a short half-life (~1 h) → unbound Xa-inhibitor rebounds at 1-3 h after infusion (consider extended infusion); theoretical thrombotic risk (~10% in ANNEXA-4); high cost. If reversal agents unavailable: 4-factor PCC (4F-PCC) 50 IU/kg or activated PCC provides a reasonable alternative for Xa-inhibitor reversal (off-label, based on healthy-volunteer data). For all DOAC bleeding: also give activated charcoal if ingestion within 2-4 h, supportive care, and haemodialysis (effective for dabigatran due to low protein binding; not effective for rivaroxaban/apixaban due to high protein binding).[8][9][10][11]

Anticoagulant reversal agents — dose, mechanism, and limitations

Anticoagulant	Reversal agent	Dose	Mechanism	Time to effect	Limitations
UFH	Protamine sulfate	1 mg per 100 U heparin (max 50 mg)	Cationic protein binds anionic heparin → inactive complex	<5 min (IV)	Anaphylaxis (1%); hypotension if rapid push; dosing uncertain after 2-3 h of heparin
LMWH	Protamine PARTIAL (~60%)	1 mg per 1 mg enoxaparin (last 8 h)	Binds ~60% of LMWH	<5 min	Only PARTIAL reversal — longer LMWH t1/2 means residual anticoagulation
Fondaparinux	None (rFVIIa 90 mcg/kg)	rFVIIa if life-threatening	Off-label; bypasses inhibition	Variable	No reliable reversal; supportive care + waiting (t1/2 17-21 h)
Warfarin	Vitamin K + 4F-PCC	Vit K 5-10 mg IV + 4F-PCC 25-50 IU/kg	Vit K restores hepatic γ-carboxylation; PCC replaces factors	Vit K: 6-12 h; PCC: minutes	PCC has small thrombosis risk; FFP inferior (volume, thawing); INR rebound at 24 h if vit K omitted
Dabigatran	Idarucizumab	5 g IV (2 × 2.5 g)	Monoclonal Fab → binds dabigatran 350× more avidly than thrombin	Minutes	Thrombotic risk if dabigatran re-initiated; expensive; rebound if ongoing absorption
Rivaroxaban/Apixaban	Andexanet alfa (HIGH: 800 mg bolus + 8 mg/min ×120 min; LOW: 400 mg + 4 mg/min ×120 min)	Weight + drug dose-dependent	Modified FXa decoy → sequesters Xa inhibitor	Minutes (bolus)	Short t1/2 → rebound; ~10% thrombotic risk; costly. Alternative: 4F-PCC 50 IU/kg
Edoxaban	Andexanet (off-label) / 4F-PCC	As for rivaroxaban	As above	Minutes	Limited evidence
Argatroban / Bivalirudin	None (short t1/2)	Supportive; wait	Short half-life = spontaneous reversal	1-2 h off drug	Argatroban hepatic-safe but INR artefact; bivalirudin partial renal

[1]

Antiplatelets — the ACS and stroke-prevention armamentarium

The one-paragraph exam answer — antiplatelets

Antiplatelet agents target three distinct steps in platelet activation/aggregation. Aspirin — irreversible COX-1 inhibition (acetylates serine-530) → blocks thromboxane A2 (TXA2) synthesis → inhibits platelet activation; the effect persists for the entire platelet lifespan (7-10 days) since platelets are anucleate (cannot synthesise new COX-1). Loading dose 300 mg → maintenance 75-100 mg OD. P2Y12 (ADP receptor) inhibitors — block the final amplification step of ADP-mediated platelet activation: clopidogrel (600 mg load → 75 mg OD) is a prodrug activated by hepatic CYP2C19 (genetic polymorphism → 30% poor metabolisers → reduced efficacy; irreversibly binds P2Y12); prasugrel (60 mg load → 10 mg OD) more potent + faster onset (no CYP2C19 dependence) but higher bleeding (contraindicated in prior stroke/TIA, caution >75 yr and <60 kg); ticagrelor (180 mg load → 90 mg BD) is a reversible cyclopentyl-triazolo-pyrimidine — fastest/most potent, mortality benefit in PLATO — but causes dyspnoea and bradyarrhythmias. GPIIb/IIIa antagonists block the FINAL common pathway of platelet aggregation (fibrinogen cross-linking): abciximab (ReoPro — monoclonal antibody, long receptor occupancy), tirofiban (small molecule, short t1/2), eptifibatide (cyclic heptapeptide) — used IV during high-risk PCI (large thrombus burden, acute stent thrombosis); significant bleeding/thrombocytopenia risk. Reversal: no specific reversal for aspirin/clopidogrel — platelet transfusion (1 adult dose) is the only reversal (but takes hours; transfused platelets are themselves inhibited if antiplatelet still circulating); desmopressin (DDAVP) 0.3 mcg/kg may help in uraemia. Ticagrelor's reversibility means it wears off in 3-5 days (vs 7-10 for clopidogrel).[18][19][22]

The P2Y12 inhibitors — clopidogrel vs prasugrel vs ticagrelor

Feature	Clopidogrel	Prasugrel	Ticagrelor
Class	Thienopyridine (prodrug)	Thienopyridine (prodrug)	Cyclopentyl-triazolo-pyrimidine (direct)
Activation	Hepatic CYP2C19 (variable — ~30% poor metabolisers)	Rapid hepatic esterases (NOT CYP2C19-dependent)	None (active drug)
Onset	Slow (2-6 h after 600 mg load)	Fast (~30 min after 60 mg load)	Fast (~30 min after 180 mg load)
Potency	Moderate	High	High
Reversibility	Irreversible (lifespan of platelet, 7-10 d)	Irreversible (7-10 d)	Reversible (3-5 d)
Dose	75 mg OD (600 mg load)	10 mg OD (60 mg load)	90 mg BD (180 mg load) — then 60 mg BD in long-term
Key trial	CURE (PCI/ACS)	TRITON-TIMI 38	PLATO (mortality benefit)
Contraindications	CYP2C19 LOF + ACS/PCI	Prior stroke/TIA; caution >75 yr, <60 kg	Active bleeding; caution in bradyarrhythmia
Adverse effects	Rare thrombocytopenia	More major bleeding	Dyspnoea (10-15%), bradycardia/AV block, ↑uric acid/creatinine
Reversal	Platelet transfusion (wait 6-12 h after dose)	Platelet transfusion (no specific antidote)	Platelet transfusion less effective (reversible); bentalurase investigational

[1]

The antiplatelets (continued)

Aspirin — irreversible COX-1 (acetylation); platelet inhibition for lifespan (7-10 days).[1]
Clopidogrel/prasugrel — irreversible P2Y12 (prodrugs; CYP2C19). Ticagrelor — reversible P2Y12.[1]
GPIIb/IIIa (abciximab, tirofiban, eptifibatide) — block the final common pathway of platelet aggregation; the TARGET trial found abciximab superior to tirofiban for high-risk PCI.[1][23]

Key PK/PD

UFH — short half-life (60-90 min); hepatic clearance; safe in renal failure. Dose-dependent half-life.[1]
LMWH — renal excretion; avoid CrCl under 30. More predictable (no routine monitoring).[1]
Warfarin — slow onset (days; the II/VII/IX/X + protein C/S); the narrow therapeutic window; the CYP2C9 metabolism; the drug interactions. The protein C depletion paradox (the early hypercoagulable → the warfarin skin necrosis → overlap with heparin for 5 days).[1]
DOACs — oral; the predictable (no routine monitoring); the peak 1-4 h; the renal (dabigatran 80 per cent; apixaban/rivaroxaban 25-30 per cent).[1]

Indications — matching drug to disease

Anticoagulation indications by clinical scenario

Indication	First-line anticoagulant	Rationale / comment
VTE treatment (DVT/PE) — first 5-10 days	LMWH OR UFH OR fondaparinux OR rivaroxaban/apixaban (oral from day 1) OR dabigatran (after 5-10 d parenteral — RE-COVER)	LMWH preferred initial; DOACs allow outpatient treatment without parenteral lead-in (rivaroxaban/apixaban); dabigatran requires parenteral lead-in[4]
VTE long-term (3-6 months)	DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) preferred over warfarin	DOACs: non-inferior efficacy, less major bleeding, no monitoring; cancer → LMWH or edoxaban/rivaroxaban
VTE extended (cancer-associated)	LMWH (dalteparin) historically; now rivaroxaban/apixaban or edoxaban	Selected-DURATION: oral DOACs non-inferior to LMWH
Stroke prevention in non-valvular AF	DOAC (apixaban, rivaroxaban, dabigatran, edoxaban) preferred over warfarin	ARISTOTLE: apixaban superior (↓stroke + ↓bleeding + ↓mortality); AVERROES: apixaban superior to aspirin in AF unsuitable for warfarin; DOACs avoid dietary/drug interactions[2][29]
Mechanical heart valve	Warfarin ONLY — DOACs CONTRAINDICATED	RE-ALIGN: dabigatran more thrombosis/bleeding than warfarin in mechanical valves. INR target: mitral 2.5-3.5, aortic 2.0-3.0
Atrial fibrillation (valvular — moderate-severe MS or rheumatic)	Warfarin (NOT DOAC)	DOACs not validated in valvular AF; warfarin remains standard
Antiphospholipid syndrome (triple positive)	Warfarin (NOT DOAC)	Triple-positive APS → DOACs inferior (RAPS trial)
Acute coronary syndrome (post-PCI)	Aspirin + P2Y12 (DAPT) — ticagrelor preferred; DOAC added only if AF (then triple → double therapy)	ATLAS-ACS: low-dose rivaroxaban (2.5 mg BD) reduced death; APPRAISE-2 apixaban STOPPED — excess bleeding/death
Chronic stable CAD/PAD	Aspirin ± low-dose rivaroxaban 2.5 mg BD (COMPASS)	COMPASS: reduced CV death/stroke/MI but ↑major bleeding
VTE prophylaxis (medical/surgical ICU)	LMWH 40 mg SC OD (enoxaparin) OR UFH 5000 U SC TDS	UFH if renal impairment; mechanical prophylaxis if contraindicated
Pregnancy (any indication)	LMWH ONLY (warfarin teratogenic; DOACs contraindicated)	Enoxaparin 1 mg/kg BD; switch to UFH near delivery (shorter t1/2); resume LMWH postpartum + warfarin for 6 weeks postpartum if needed
HIT	Argatroban (hepatic-safe) OR bivalirudin OR danaparoid	DO NOT use warfarin alone until platelets recover (warfarin potentiates protein C depletion → skin necrosis + venous limb gangrene)
Bridging around surgery (mechanical valve, AF)	Stop warfarin 5 days pre-op; LMWH bridging dose when INR <2; stop LMWH 24 h pre-op	PERIOP2: postoperative LMWH bridging did not reduce arterial thromboembolism

Stroke and bleeding risk scores — CHA2DS2-VASc and HAS-BLED

Computing CHA2DS2-VASc and HAS-BLED — the AF risk stratification

Compute CHA2DS2-VASc (stroke risk — each letter a point):
- C Congestive heart failure (1) — or LV dysfunction
- H Hypertension (1)
- A2 Age ≥75 (2) — note double points
- D Diabetes (1)
- S2 prior Stroke/TIA/thromboembolism (2) — double points
- V Vascular disease (prior MI, PAD, aortic plaque) (1)
- A Age 65-74 (1)
- Sc Sex category female (1)
Apply the threshold for anticoagulation:
- Score 0 (male) or 1 (female) → no anticoagulation (truly low risk)
- Score ≥2 (male) or ≥3 (female) → oral anticoagulation recommended (DOAC preferred)
- Score 1 (male) / 2 (female) → consider anticoagulation (shared decision)
Compute HAS-BLED (bleeding risk — each letter a point):
- H Hypertension (uncontrolled, SBP >160) (1)
- A Abnormal renal/liver function (1 each, max 2) — dialysis, transplant, cirrhosis, bilirubin >2×
- S Stroke (prior) (1)
- B Bleeding history/predisposition (1)
- L Labile INR (TTR <60%) (1)
- E Elderly (age >65) (1)
- D Drugs/alcohol concomitantly (antiplatelet/NSAID, ≥8 drinks/week) (1 each, max 2)
Interpret HAS-BLED:
- Score ≥3 → "high risk" — review/correct modifiable risk factors (BP, NSAIDs, alcohol, labile INR) — NOT a reason to withhold anticoagulation (the stroke risk usually outweighs)
- A high HAS-BLED should trigger caution and modifiable-risk-factor correction, not denial of stroke prevention
Choose the agent — DOAC preferred over warfarin for non-valvular AF (lower intracranial bleeding, comparable/better efficacy); warfarin for mechanical valves, severe MS, triple-positive APS
Re-evaluate annually — recheck renal function (DOAC dose adjustment), bleeding risk, adherence, and new vascular disease[16][17]

Management pathways

Bedside anticoagulant reversal pathway: protamine for UFH and partial LMWH, vitamin K plus four-factor PCC for warfarin, idarucizumab for dabigatran, andexanet or PCC for factor Xa inhibitors — FigureReversal is class-specific — protamine, vitamin K/PCC, idarucizumab, andexanet or PCC — then local control and a documented restart plan.

Major bleeding on an anticoagulant — the universal algorithm

Recognise and resuscitate — ABC; two large-bore IV cannulae; cross-match; activate massive transfusion protocol if haemodynamically unstable; treat hypotension with crystalloid/blood products (1:1:1 PRBC:FFP:platelets in trauma)
Identify the anticoagulant and time of last dose — drug, dose, time of last ingestion, renal function (CrCl/eGFR), and any co-administered antiplatelets/NSAIDs
Stop the anticoagulant immediately (and all antiplatelets/NSAIDs)
Give activated charcoal if recent ingestion — within 2-4 h for dabigatran/rivaroxaban/apixaban (the absorption window); useless if >4 h
Apply local measures — endoscopic/surgical/radiological haemostasis for the bleed source (e.g., GI endoscopy, interventional radiology for retroperitoneal)
Administer the specific reversal agent:
- Warfarin (INR elevated + major bleed) → vitamin K 5-10 mg IV + 4F-PCC 25-50 IU/kg (preferred over FFP — faster, smaller volume)
- Dabigatran → idarucizumab 5 g IV (2 × 2.5 g)
- Rivaroxaban/apixaban → andexanet alfa (HIGH or LOW dose by drug dose/timing); if unavailable → 4F-PCC 50 IU/kg or aPCC 50 IU/kg
- UFH → protamine 1 mg per 100 U heparin in last 2-3 h
- LMWH → protamine 1 mg per 1 mg enoxaparin (PARTIAL reversal ~60%)
- Fondaparinux, argatroban, bivalirudin → no specific agent; supportive (rFVIIa for fondaparinux; short t1/2 of DTIs = wait)
Supportive blood products — PRBC to Hb >70 (or >80 if active/ongoing); platelets if <50 (or antiplatelet/anti-GPIIb/IIIa); fibrinogen (cryoprecipitate or fibrinogen concentrate) if <1.5; FFP if PT/aPTT >1.5×
Adjuncts — tranexamic acid 1 g IV (CRASH-2: reduces mortality in trauma bleeding; role in non-trauma less clear); consider for refractory GI/surgical bleeding
Do NOT delay reversal for confirmatory levels in life-threatening bleeds — give empirically based on history
Re-assess at 1-2 h — if ongoing bleeding, repeat reversal (idarucizumab 5 g repeat in dabigatran rebound; PCC top-up); check anti-Xa/TT if available
Decide on anticoagulation resumption — balance re-thrombosis vs re-bleeding; typically resume 7-14 days post-major GI bleed, sooner for mechanical valve/intracardiac thrombus

[1]

Perioperative management of anticoagulation — bridging

Assess thromboembolic risk:
- HIGH — mechanical mitral valve, any valve + prior stroke/TIA, CHA2DS2-VASc ≥7, recent VTE (<3 months), severe thrombophilia → bridging usually indicated
- MODERATE — bileaflet aortic valve + ≥1 risk factor, CHA2DS2-VASc 5-6, VTE 3-12 months ago → individualise
- LOW — bileaflet aortic valve alone, simple AF CHA2DS2-VASc <5, VTE >12 months → no bridging
Stop warfarin 5 days before surgery (INR falls to ~1.5 by day 4, normal by day 5)
Start bridging LMWH (or UFH) 3 days before surgery — therapeutic dose enoxaparin 1 mg/kg BD when INR <2.0
Stop LMWH 24 h before surgery (last dose morning of day -1); UFH if very high risk (stop 4-6 h pre-op)
On day of surgery — check INR <1.5; neuraxial anaesthesia requires INR ≤1.4 and LMWH held ≥24 h
Resume warfarin 12-24 h post-op (when haemostasis secured)
Resume LMWH 48-72 h post-op (when surgical bleeding risk acceptable) — beware high bleed risk with early LMWH restart
PERIOP2 finding — postoperative bridging (LMWH + warfarin) did NOT reduce arterial thromboembolism vs warfarin alone, and increased major bleeding → reserve for HIGHEST thrombotic risk patients

[1]

Heparin-induced thrombocytopenia (HIT) — recognise and switch

Suspect HIT when platelets fall >50% OR to <100 ×10^9/L, 5-14 days after heparin exposure (or sooner if prior heparin in 30 days). The platelet fall is the hallmark — usually no bleeding, often THROMBOSIS (paradox: 30-50% develop new clot — DVT, limb ischaemia, stroke, MI)
Apply the 4Ts score to estimate pre-test probability:
- Thrombocytopenia (fall pattern and nadir)
- Timing (day of onset — 5-14 d typical; <1 d if prior exposure)
- Thrombosis or other sequelae (skin necrosis, adrenal haemorrhage, acute systemic reaction)
- oTheR cause of thrombocytopenia excluded
- 4Ts 0-3 → unlikely (≈3%); 4-5 → intermediate (≈20%); 6-8 → high (≈60%). Meta-analysis: 4Ts score has good NPV, modest PPV
Stop ALL heparin immediately — UFH, LMWH, heparin flushes, heparin-coated lines — switch to a non-heparin anticoagulant at therapeutic dose (HIT is pro-thrombotic)
Switch to argatroban (hepatic clearance → preferred in renal failure; start 2 µg/kg/min, titrate aPTT 1.5-3× baseline) OR bivalirudin OR danaparoid OR fondaparinux (off-label)
Send confirmatory testing — anti-PF4 antibody ELISA (sensitive, ±specific); serotonin release assay (SRA — gold standard but slow)
Platelets usually recover in 4-14 days — do NOT start warfarin until platelets ≥150 (warfarin alone → catastrophic protein C depletion → venous limb gangrene)
When platelets recovered and on argatroban, transition to warfarin (overlap ≥5 days, INR >2 for 24 h — note argatroban falsely elevates INR)
Lifelong avoidance of heparin — document in chart; future anticoagulation with DOAC, fondaparinux, or argatroban. HIT antibodies fade in ~3 months — re-exposure rarely tested but generally avoided

[1]

DOAC-related intracranial haemorrhage — the time-critical reversal

Confirm ICH (CT brain) and that the patient is on a DOAC — drug, dose, time of last ingestion
Stop the DOAC and any antiplatelets immediately
Activated charcoal if ingestion within 2-4 h (reduce absorption — especially dabigatran)
For dabigatran — give idarucizumab 5 g IV (two consecutive 2.5 g boluses); if idarucizumab unavailable, consider haemodialysis (dabigatran is 35% unbound → dialysable) + aPCC 50 IU/kg
For rivaroxaban/apixaban — give andexanet alfa (HIGH dose if last dose within 8 h or high dose ingested; LOW dose otherwise); if unavailable → 4F-PCC 50 IU/kg (or aPCC 50 IU/kg)
Supportive care — BP control (SBP 140-160 mmHg), ICP management, reverse other coagulopathy (vit K if warfarin overlap, platelets if dual antiplatelet)
Avoid platelet transfusion unless on antiplatelet + undergoing neurosurgery
Neurosurgical evacuation — defer until anticoagulant effect reversed (anti-Xa or TT normal); then proceed as for non-anticoagulated ICH
Do NOT routinely give PCC + andexanet together — additive thrombotic risk; choose one
Plan anticoagulation resumption — balance haemorrhage expansion vs thrombotic indication; typically resume 7-10 days post-ICH if strong indication (mechanical valve sooner)

[1]

Red flags

Clinical pearls

Clinical pearl

UFH potentiates antithrombin III ~1000-fold — it CANNOT inactivate clot-bound thrombin or clot-bound Xa. The heparin-AT III complex inactivates FREE thrombin (IIa) and FREE Xa — but factors bound within a fibrin clot are protected. This is why UFH prevents clot PROPAGATION but does not lyse existing clot (that requires thrombolytics). It also explains the "thrombus on heparin" paradox — surface-bound thrombin continues to generate fibrin even on therapeutic heparin. The short-chain LMWH pentasaccharides preferentially inhibit Xa (less IIa inactivation) — the rationale for cleaner anti-Xa dosing.[1]
UFH half-life is DOSE-DEPENDENT (60-90 min at prophylactic dose; up to 150 min at therapeutic dose). This is because UFH clearance is a saturatable zero-order process (reticuloendothelial + endothelial binding) plus a first-order renal component. At higher doses, the saturatable pathway is overwhelmed → longer half-life. Practically: a 5000 U bolus clears faster than a 10,000 U bolus. This dose-dependent kinetics is why weight-based nomograms outperform fixed dosing.[1]
Protamine dosing is based on the heparin given in the LAST 2-3 HOURS only — not the cumulative dose. Because UFH half-life is 60-90 min, only the heparin circulating at the time of reversal needs neutralising. Dose: 1 mg protamine per 100 U UFH given in the last 2 h (max 50 mg/dose; rapid IV causes histamine release + hypotension → slow push). Excess protamine itself is anticoagulant (anti-thrombin effect) — never give more than calculated. For LMWH, protamine gives only PARTIAL (~60%) reversal because the shorter LMWH chains have lower affinity for protamine.[1]
Warfarin's slow onset (3-5 days) is governed by factor II (prothrombin, t1/2 60 h) and factor X (t1/2 40 h) — NOT factor VII (t1/2 6 h). The INR rises early (factor VII depletes first at 24 h) but is NOT protective until factors II and X are depleted (days 3-5). The INR therefore OVERESTIMATES anticoagulation in the first 48 h — this is why bridging heparin for ≥5 days (until INR >2 for 24 h) is mandatory. Stopping heparin early because "INR is 2.5" is a classic error — the patient is not yet protected.[1]
Warfarin skin necrosis — protein C (t1/2 8 h) depletes before factor II (t1/2 60 h) → transient hypercoagulable state → dermal vascular thrombosis. Protein C and S are anticoagulants (and vitamin K-dependent, so warfarin depletes them too). Because protein C has the SHORTEST half-life of all vitamin K-dependent factors, it depletes within 24-48 h, BEFORE the procoagulant factors II/IX/X reach their nadir. Result: a 3-6 day window of net procoagulant state → skin necrosis (breasts, thighs, buttocks — subcutaneous fat) — especially in patients with hereditary protein C deficiency (catastrophic). Prevention: ALWAYS overlap with heparin for ≥5 days. Treatment: stop warfarin, give vitamin K, heparin, and (in deficiency) protein C concentrate.[1]
RE-LY (2009): dabigatran 150 mg BD reduced stroke/systemic embolism vs warfarin in AF (1.11% vs 1.69%, RR 0.66) — the first DOAC to beat warfarin. Also reduced intracranial haemorrhage (the headline of every DOAC vs warfarin trial — less ICH). BUT increased GI bleeding and, with 150 mg BD, a dyspepsia rate of ~12% (the leading cause of discontinuation). This trial launched the DOAC era. Dabigatran 110 mg BD (not available in ANZ/US) was non-inferior; 150 mg was superior. The 80% renal clearance is the key safety caveat.[1]
ARISTOTLE (2011): apixaban was the FIRST DOAC to show BOTH superior efficacy AND reduced major bleeding AND reduced mortality vs warfarin. Apixaban 5 mg BD reduced stroke/systemic embolism (1.27% vs 1.60%, HR 0.79), major bleeding (2.13% vs 3.09%, HR 0.69), and all-cause mortality (3.52% vs 3.94%, HR 0.89) — the only DOAC trial to achieve all three. This is why apixaban is now the preferred DOAC for AF in most guidelines. The twice-daily dosing is its only practical drawback.[2]
ROCKET AF (2011): rivaroxaban 20 mg OD non-inferior to warfarin in higher-risk AF (CHADS2 mean 3.5). The once-daily rivaroxaban is convenient but the trial had flaws: higher baseline risk population, and on-treatment (per-protocol) analysis favoured rivaroxaban while intention-to-treat (the primary) showed non-inferiority only. Rivaroxaban had higher GI bleeding than warfarin. Renal dose reduction (15 mg OD if CrCl 15-50) is essential. The once-daily dosing and lower cost make it widely used.[3]
EINSTEIN-DVT and EINSTEIN-PE: rivaroxaban allowed oral-only VTE treatment without parenteral lead-in — a paradigm shift. Standard DOAC VTE treatment required 5 days of LMWH/heparin first. Rivaroxaban 15 mg BD ×21 days → 20 mg OD allowed outpatient treatment from day 1 — non-inferior to standard (LMWH + warfarin), with similar/slightly less major bleeding. EINSTEIN-CHOICE (2017) then showed that for extended therapy, rivaroxaban 10 mg or 20 mg OD was better than aspirin 100 mg for preventing recurrent VTE (similar bleeding).[5][6][7]
Idarucizumab (5 g IV) is the CLEANEST reversal — a monoclonal Fab that binds dabigatran with 350× the affinity of thrombin, with NO procoagulant effect. RE-VERSE AD (2015): in patients with serious bleeding or needing urgent surgery on dabigatran, idarucizumab reversed anticoagulation within minutes (diluted thrombin time normalised in 88-98%); the full-cohort analysis (2017, 503 patients) confirmed sustained reversal at 24 h and 72 h with good/excellent haemostasis in ~93%. The thrombin time is the assay of choice (normal TT = no significant dabigatran). Idarucizumab is itself inert (no thrombosis signal in trials) — by far the safest of the specific reversal agents.[8][9]
Andexanet alfa is a DECOY — a modified factor Xa (Ser195→Ala, catalytically inactive) that sequesters Xa inhibitors, freeing endogenous FXa. ANNEXA-A and ANNEXA-R (healthy volunteers) showed andexanet rapidly reversed apixaban and rivaroxaban anti-Xa activity; ANNEXA-4 (bleeding patients, NEJM 2016 + 2019 full report) demonstrated good/excellent haemostasis in ~82% with ~10% thrombotic events. The HIGH- vs LOW-dose regimens are chosen by drug dose and timing of last ingestion. Critical limitation: andexanet's t1/2 (~1 h) is shorter than the Xa inhibitors' (~12 h) → rebound anticoagulation after infusion (consider repeat dosing in ongoing bleeding).[10][11][12]
HAS-BLED ≥3 is NOT a reason to deny anticoagulation — it is a prompt to CORRECT MODIFIABLE RISK FACTORS. Pisters 2010 (CHEST) validated HAS-BLED in a real-world AF cohort; a high score predicts major bleeding, but most components are modifiable (BP control, stop NSAIDs/alcohol, improve INR control by switching to DOAC). The fatal error is using HAS-BLED as a binary "do not anticoagulate" — this leaves patients unprotected from stroke (which is usually higher-risk than bleeding). The correct approach: compute BOTH CHA2DS2-VASc and HAS-BLED; if stroke risk > bleeding risk, anticoagulate and fix the bleed risks.[16]
PLATO (2009): ticagrelor reduced MORTALITY vs clopidogrel in ACS (4.5% vs 5.9%, p<0.001) — the only P2Y12 to show survival benefit. Ticagrelor (reversible, direct P2Y12, 90 mg BD after 180 mg load) reduced CV death, MI, and stroke without increasing overall major bleeding (though non-CABG bleeding was higher). The mortality benefit is partly attributed to ticagrelor's pleiotropic effects (adenosine reuptake inhibition → vasodilation, dyspnoea). Adverse: dyspnoea (~10-15%, usually mild but causes discontinuation), bradyarrhythmias, ↑creatinine and uric acid. The aspirin dose interaction (benefit with low-dose aspirin ≤100 mg) is why low-dose aspirin is mandated with ticagrelor.[19]
TRITON-TIMI 38 (2007): prasugrel more potent than clopidogrel (more ischaemic events prevented) BUT more major bleeding — and CONTRAINDICATED in prior stroke/TIA. Prasugrel (60 mg load → 10 mg OD) is a prodrug but activated by esterases (not CYP2C19) → no pharmacogenomic variability → faster/more consistent than clopidogrel. Reduced ischaemic events (CV death/MI/stroke 9.9% vs 12.1%) but increased major bleeding (2.4% vs 1.8%) and fatal ICH in patients with prior stroke/TIA (absolute contraindication). Reduce to 5 mg OD if >75 yr or <60 kg. Net clinical benefit favours prasugrel in STEMI/diabetes (high thrombotic risk) without prior stroke.[20]
The DAPT study (2014): 30 months vs 12 months of dual antiplatelet therapy after DES — longer reduced stent thrombosis but increased bleeding. DAPT (NEJM 2014) randomised patients to continue thienopyridine or placebo for an additional 18 months after 12 months of DAPT. Continuing reduced stent thrombosis (0.4% vs 1.4%, HR 0.29) and major adverse CV events but increased moderate-severe bleeding (2.5% vs 1.6%). MACCE benefit ~3× bleed cost. Current guidelines: minimum 6 months (12 months in ACS) of DAPT; longer for high thrombotic risk (left main, bifurcation, diabetes, prior stent thrombosis), shorter for high bleeding risk.[21]
ACUITY and HORIZONS-AMI: bivalirudin reduced bleeding vs heparin + GPIIb/IIIa in ACS/PCI — at the cost of more acute stent thrombosis. ACUITY (NEJM 2006, moderate-high-risk ACS): bivalirudin monotherapy was non-inferior for ischaemia with significantly less major bleeding (3.0% vs 5.7%) → net clinical benefit. HORIZONS-AMI (NEJM 2008, primary PCI for STEMI): bivalirudin reduced major bleeding and 30-day mortality vs heparin + abciximab. The catch: more acute stent thrombosis (<24 h) with bivalirudin (absence of upstream platelet inhibition) — mitigated by adding a P2Y12. Bivalirudin is also the anticoagulant of choice in HIT patients needing PCI.[24][25]
Argatroban is the anticoagulant of choice for HIT in renal failure (hepatic clearance) — but it FALSLEY ELEVATES THE INR, complicating warfarin transition. ARG-911 (Circulation 2001) established argatroban in HIT — reduced new thrombosis, the composite endpoint (death/amputation/new thrombosis), and improved platelet recovery. Start at 2 µg/kg/min (0.5 µg/kg/min in hepatic impairment), titrate aPTT to 1.5-3× baseline. When transitioning to warfarin, argatroban's INR artefact means the apparent INR is higher than the true INR — use a chromogenic factor X level or overlap until INR ≥4, then stop argatroban and recheck in 4-6 h (argatroban t1/2 ~45 min). Bivalirudin is the alternative for PCI or argatroban-unavailable.[26]
CRASH-2 (2010): tranexamic acid 1 g IV within 3 h of trauma reduced all-cause mortality (14.5% vs 16.0%, RR 0.91) — but is HARMFUL if given >3 h (especially >24 h) post-injury. TXA inhibits plasminogen → plasmin conversion → stabilises clot. CRASH-2 enrolled 20,211 trauma patients; the benefit was confined to early administration (within 3 h); late administration (>3 h) trended toward harm. Subsequent: WOMAN trial (postpartum haemorrhage) confirmed benefit. TXA has a role in major surgical/trauma/PPH bleeding — not a universal anticoagulant-reversal drug (no proven benefit in DOAC/warfarin bleed, no benefit in upper GI bleed overall — HALT-IT neutral).[28]
The 4Ts score has good NPV but modest PPV — a low score (<4) reliably excludes HIT; a high score mandates non-heparin anticoagulant immediately. Cuker 2012 (Blood): meta-analysis of 4Ts — score 0-3 predicts ~3% probability of HIT (SRA-positive), 4-5 ~20%, 6-8 ~60%. A low/intermediate score still warrants antibody testing, but a high score mandates immediate cessation of all heparin and therapeutic-dose argatroban/bivalirudin while awaiting SRA confirmation. The 4Ts is the bedside tool; the SRA (serotonin release assay) is the laboratory gold standard (slow turnaround).[27]
A normal thrombin time excludes clinically significant dabigatran; a normal anti-Xa excludes clinically significant Xa-inhibitor levels. In the bleeding patient on a DOAC, drug-specific assays are key: dabigatran → thrombin time (TT) or diluted TT (dTT — better for quantitation); rivaroxaban/apixaban → anti-Xa calibrated to that specific drug (a generic anti-Xa assay is misleading). Standard PT/INR/aPTT are unreliable for DOACs — a normal PT does not exclude rivaroxaban, and a normal aPTT does not exclude dabigatran. In a life-threatening bleed, do NOT delay reversal for these — give empirically based on history.[1]
Fondaparinux is a synthetic pentasaccharide (not from heparin) → causes antithrombin-mediated Xa inhibition ONLY, with virtually NO HIT risk and NO routine monitoring. The single pentasaccharide sequence binds antithrombin, amplifying Xa inhibition ~300-fold (no IIa inactivation because the chain is too short to bridge thrombin). Half-life 17-21 h (SC OD). Major orthopaedic trials (Arch Intern Med 2002) showed superior VTE prophylaxis vs enoxaparin. Limitations: 100% renal excretion → contraindicated CrCl <30; no reliable reversal (rFVIIa 90 mcg/kg is theoretical); not reversible by protamine. Has been used off-label for HIT (rare cross-reactivity).[30]
Aspirin resistance / non-responsiveness is real (5-40%) but its clinical significance is debated — do NOT routinely test, but ensure ADHERENCE. Aspirin irreversibly acetylates COX-1 (serine-530) → blocks TXA2 for platelet lifespan. "Resistance" (continued TXA2 production despite aspirin) arises from poor adherence (the biggest cause), high platelet turnover, NSAID competition (ibuprofen blocks COX-1 access), obesity, and rarely genetic polymorphisms. Laboratory tests (VerifyNow, urinary 11-dehydro-TXB2) have poor correlation with outcomes. Practical approach: ask about adherence, avoid concurrent NSAIDs, and consider switching to a P2Y12 in recurrent events.[1]
CYP2C19 polymorphism makes clopidogrel unreliable in ~30% — genetic testing is recommended in EAST ASIAN patients and high-risk ACS/PCI. Clopidogrel is a prodrug activated by hepatic CYP2C19. Loss-of-function alleles (especially *2, *3 — common in East Asian populations, ~50% carriers) reduce active metabolite → less platelet inhibition → more stent thrombosis. Ticagrelor/prasugrel bypass CYP2C19 and are preferred in known LOF carriers or genetically high-risk groups. The converse: CYP2C19 ultrarapid metabolisers may have more bleeding (rare concern).[18]
Pregnancy requires LMWH throughout (warfarin and DOACs both contraindicated) — switch to UFH close to delivery, then resume LMWH + warfarin postpartum. Warfarin is teratogenic (fetal warfarin syndrome weeks 6-12; CNS haemorrhage 2nd/3rd trimester). DOACs are contraindicated (animal data — embryotoxicity, placental transfer). Enoxaparin 1 mg/kg BD (or 1.5 mg/kg OD) does NOT cross the placenta. UFH is preferred in the last 2-4 weeks (shorter t1/2 → allows regional anaesthesia; stop 4-6 h pre-delivery). Postpartum: warfarin is SAFE in breastfeeding (does not pass into milk in active form) — can be used for 6 weeks postpartum VTE prophylaxis, overlapped with LMWH until INR therapeutic.[1]
COMPASS (2017): low-dose rivaroxaban 2.5 mg BD + aspirin reduced CV death/stroke/MI in stable CAD/PAD — at the cost of more major bleeding. COMPASS enrolled 27,395 patients with stable atherosclerotic disease; rivaroxaban 2.5 mg BD + aspirin reduced the composite (CV death/stroke/MI) by 24% vs aspirin alone (4.1% vs 5.4%) but increased major bleeding (3.4% vs 2.2%; no increase in fatal/critical-organ bleeding). Stopped early for benefit. This defined the "dual pathway inhibition" concept — antiplatelet + low-dose anticoagulant for chronic atherothrombosis.[15]
APPRAISE-2 (apixaban in ACS) was STOPPED for excess bleeding/death — high-dose DOACs added to DAPT in ACS are not safe. Unlike low-dose rivaroxaban (ATLAS-ACS, 2.5 mg BD — beneficial), full-dose apixaban 5 mg BD added to antiplatelet therapy after ACS caused excess major bleeding (1.3% vs 0.5%) and a non-significant excess of death. Lesson: in ACS the bleeding hazard of full-dose anticoagulation on top of DAPT outweighs benefit — only very low DOAC doses (rivaroxaban 2.5 mg BD) are tolerated. For ACS + AF requiring anticoagulation, modern strategy is anticoagulant + single antiplatelet (P2Y12) after 1-4 weeks of triple therapy.[13][14]
Equivalent potency conversions you must memorise for warfarin reversal — 4F-PCC 25-50 IU/kg ≈ FFP 15 mL/kg, but PCC is FASTER and SMALLER VOLUME. Four-factor PCC (Beriplex/Kcentra — factors II, VII, IX, X + proteins C/S) reverses warfarin within minutes (vs FFP's 6-12 h for vitamin K effect, and FFP's slower factor repletion). Volume: PCC is ~20 mL vs FFP's ~1 L (3-4 units) → no volume overload. PCC carries a small thrombosis risk (~2-3%) — give with vitamin K to prevent INR rebound. Activated PCC (FEIBA) and recombinant activated factor VII are alternatives for refractory bleeding (off-label for warfarin).[1]
The anticoagulant choice in chronic kidney disease cascades by CrCl — UFH/fondaparinux/argatroban safe; LMWH/dabigatran/edoxaban dose-adjusted; apixaban/rivaroxaban cautiously; warfarin safe at any GFR. Practical CKD pathway: CrCl >50 → all DOACs/LMWH acceptable; CrCl 30-50 → dose-reduce rivaroxaban (15 mg), dabigatran (110 mg), LMWH (enoxaparin OD); CrCl <30 → avoid dabigatran, dose-reduce apixaban (2.5 mg BD), switch LMWH to UFH; CrCl <15 / dialysis → UFH or warfarin (apixaban dose-reduced is sometimes used). In AKI, default to UFH (short t1/2 + reversibility + safe). Always reconsider dosing daily as renal function changes.[1]

Key trials and evidence

RE-LY — Dabigatran vs warfarin in AF (PMID 19717844)

Study design

Multicentre randomised open-label (PROBE) with blinded adjudication — 18,113 patients

Population

Non-valvular AF + ≥1 stroke risk factor (mean CHADS2 2.1)

Intervention

Dabigatran 110 mg BD OR 150 mg BD vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 150 mg 1.11% vs warfarin 1.69% (RR 0.66, p<0.001 for superiority); 110 mg non-inferior

Key secondary findings

Both doses reduced intracranial haemorrhage (~0.23% vs 0.74%); 150 mg increased GI bleeding; dyspepsia ~12% (main discontinuation cause)

Clinical bottom line

First DOAC to beat warfarin in AF — dabigatran 150 mg superior for stroke prevention with less ICH; launched the DOAC era

[1]

ARISTOTLE — Apixaban vs warfarin in AF (PMID 21870978)

Study design

Multicentre randomised double-blind — 18,201 patients

Population

Non-valvular AF + ≥1 stroke risk factor (mean CHADS2 2.1)

Intervention

Apixaban 5 mg BD vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 1.27% vs 1.60% (HR 0.79, p<0.001 superiority)

Key secondary findings

Major bleeding reduced (2.13% vs 3.09%, HR 0.69); haemorrhagic stroke reduced (0.24% vs 0.47%); all-cause mortality reduced (3.52% vs 3.94%, HR 0.89)

Clinical bottom line

Apixaban is the only DOAC to show simultaneous superiority for stroke prevention, reduced major bleeding, AND reduced mortality — preferred DOAC for AF

[1]

ROCKET AF — Rivaroxaban vs warfarin in AF (PMID 21830957)

Study design

Multicentre randomised double-blind double-dummy — 14,264 patients

Population

Non-valvular AF at HIGHER risk (mean CHADS2 3.5)

Intervention

Rivaroxaban 20 mg OD (15 mg if CrCl 30-49) vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 1.7% vs 2.2% (HR 0.88, non-inferior p<0.001; superiority not significant in ITT)

Key secondary findings

Critical-organ and fatal bleeding reduced; intracranial haemorrhage reduced (0.5% vs 0.7%); GI bleeding increased

Clinical bottom line

Once-daily rivaroxaban non-inferior to warfarin in higher-risk AF; less ICH, more GI bleed — convenient once-daily dosing

[1]

RE-VERSE AD — Idarucizumab for dabigatran reversal (PMIDs 26095746, 28693366)

Study design

Multicentre prospective open-label single-arm — 503 patients (full cohort)

Population

Patients on dabigatran with serious bleeding (Group A) OR requiring urgent procedure/surgery (Group B)

Intervention

Idarucizumab 5 g IV (2 × 2.5 g bolus)

Primary outcome

Maximum percentage reversal of dabigatran anticoagulant effect (by diluted TT): 88-98% at 24 h

Key secondary findings

Haemostasis good/excellent in ~93% in bleeding group; thrombotic events ~5% during follow-up (attributed to underlying disease + resumption)

Clinical bottom line

Idarucizumab provides immediate, complete, and safe reversal of dabigatran — the cleanest of the specific reversal agents (no procoagulant effect)

[1]

ANNEXA-4 — Andexanet alfa for Xa-inhibitor bleeding (PMIDs 27573206, 30730782)

Study design

Multicentre prospective open-label single-arm — 352 patients (full study)

Population

Patients on apixaban/rivaroxaban/edoxaban/enoxaparin with acute major bleeding

Intervention

Andexanet alfa — HIGH dose (800 mg bolus + 8 mg/min ×120 min) or LOW dose (400 mg + 4 mg/min ×120 min) by drug dose/timing

Primary outcome

Anti-Xa activity reduced 92% (apixaban) and 92% (rivaroxaban) at end of bolus; good/excellent haemostasis in 82% at 12 h

Key secondary findings

Rebound in anti-Xa at 4 h after infusion (short andexanet t1/2); thrombotic events ~10% within 30 days

Clinical bottom line

Andexanet reverses Xa-inhibitor anti-Xa activity rapidly with good clinical haemostasis; rebound and thrombosis are the main caveats — 4F-PCC 50 IU/kg is an alternative

[1]

EINSTEIN-PE/CHOICE — Rivaroxaban in VTE (PMIDs 22449293, 28316279)

Study design

EINSTEIN-PE: open-label non-inferiority RCT — 4,832 patients. EINSTEIN-CHOICE: double-blind RCT — 3,365 patients

Population

EINSTEIN-PE: acute symptomatic PE ± DVT. EINSTEIN-CHOICE: extended therapy after 6-12 months VTE treatment

Intervention

EINSTEIN-PE: rivaroxaban 15 mg BD ×21d → 20 mg OD vs enoxaparin/warfarin. EINSTEIN-CHOICE: rivaroxaban 20 mg OD OR 10 mg OD vs aspirin 100 mg OD

Primary outcome

EINSTEIN-PE: non-inferior (2.1% vs 1.8% symptomatic recurrent VTE; less major bleeding). EINSTEIN-CHOICE: rivaroxaban 20 mg (1.5%) and 10 mg (1.2%) both superior to aspirin (4.4%); similar bleeding

Clinical bottom line

Rivaroxaban allows oral-only VTE treatment without parenteral lead-in (15 mg BD loading then 20 mg OD); for extended therapy, rivaroxaban 10 or 20 mg OD is superior to aspirin with similar bleeding

[1]

PLATO — Ticagrelor vs clopidogrel in ACS (PMID 19717846)

Study design

Multicentre randomised double-blind — 18,624 patients

Population

Patients hospitalised for ACS (STEMI, NSTEMI, unstable angina) — intended invasive or non-invasive management

Intervention

Ticagrelor 180 mg load → 90 mg BD vs clopidogrel 300-600 mg load → 75 mg OD (both + aspirin)

Primary outcome

Composite CV death/MI/stroke at 12 months: 9.8% vs 11.7% (HR 0.84, p<0.001)

Key secondary findings

All-cause mortality reduced (4.5% vs 5.9%, p<0.001) — first P2Y12 with mortality benefit. Major bleeding similar overall but non-CABG bleeding higher; dyspnoea ~14%; bradyarrhythmias

Clinical bottom line

Ticagrelor preferred over clopidogrel in ACS — superior ischaemic outcomes AND reduced mortality. Benefit greatest with low-dose aspirin ≤100 mg

[1]

TRITON-TIMI 38 — Prasugrel vs clopidogrel in ACS (PMID 17982182)

Study design

Multicentre randomised double-blind — 13,608 patients

Population

Moderate-high-risk ACS undergoing PCI

Intervention

Prasugrel 60 mg load → 10 mg OD vs clopidogrel 300 mg load → 75 mg OD (both + aspirin)

Primary outcome

Composite CV death/MI/stroke: 9.9% vs 12.1% (HR 0.81, p<0.001)

Key secondary findings

Major bleeding increased (2.4% vs 1.8%); fatal ICH in patients with prior stroke/TIA (absolute contraindication); benefit greatest in STEMI + diabetes

Clinical bottom line

Prasugrel more potent/faster than clopidogrel — preferred in high-thrombotic-risk STEMI/diabetes WITHOUT prior stroke; contraindicated in prior TIA/stroke; reduce to 5 mg if >75 yr or <60 kg

[1]

HORIZONS-AMI — Bivalirudin in primary PCI (PMID 18499566)

Study design

Multicentre randomised open-label — 3,602 patients

Population

STEMI undergoing primary PCI

Intervention

Bivalirudin vs heparin + GPIIb/IIIa (abciximab)

Primary outcome

Major bleeding at 30 days: reduced (4.9% vs 8.3%); NACE composite reduced (10.1% vs 14.1%)

Key secondary findings

30-day mortality reduced (2.1% vs 3.1%); BUT acute stent thrombosis (<24 h) increased (1.3% vs 0.3%)

Clinical bottom line

Bivalirudin reduces bleeding and mortality in primary PCI — at the cost of early stent thrombosis (mitigated by adding P2Y12). Bivalirudin is the agent of choice in HIT patients needing PCI

[1]

CRASH-2 — Tranexamic acid in trauma (PMID 20554319)

Study design

Multicentre randomised placebo-controlled — 20,211 patients

Population

Trauma patients with significant bleeding OR systolic BP <90 OR HR >110 within 8 h of injury

Intervention

Tranexamic acid 1 g IV loading over 10 min → 1 g over 8 h vs placebo

Primary outcome

All-cause 28-day mortality: 14.5% vs 16.0% (RR 0.91, p=0.0035)

Key secondary findings

Bleeding death reduced (4.9% vs 5.7%); NO increase in vascular occlusive events, MI, stroke, PE, DVT. Benefit confined to treatment WITHIN 3 h of injury

Clinical bottom line

Early TXA (within 3 h) reduces mortality in trauma bleeding — a cheap, globally available life-saver. Late TXA (>3 h) trends toward harm

[1]

ATLAS ACS 2-TIMI 51 / APPRAISE-2 — DOACs in ACS (PMIDs 22077192, 21780946)

Study design

Both: multicentre randomised double-blind placebo-controlled. ATLAS: 15,526 patients. APPRAISE-2: 7,392 patients (stopped early)

Population

Recent ACS on DAPT (aspirin + clopidogrel)

Intervention

ATLAS: rivaroxaban 2.5 mg or 5 mg BD vs placebo. APPRAISE-2: apixaban 5 mg BD vs placebo

Primary outcome

ATLAS: reduced CV death/MI/stroke (8.9% vs 10.7%, HR 0.84); reduced all-cause/stent thrombosis. APPRAISE-2: STOPPED for excess major bleeding (1.3% vs 0.5%) and a trend toward more death

Key secondary findings

ATLAS: 2.5 mg reduced CV + all-cause mortality, with increased major/non-CABG bleeding but not fatal. APPRAISE-2: TIMI major bleeding and intracranial haemorrhage increased

Clinical bottom line

Only VERY LOW DOSE DOAC (rivaroxaban 2.5 mg BD) added to DAPT is tolerated in ACS; full-dose DOACs (apixaban 5 mg BD) cause excess bleeding with no benefit — defines the narrow therapeutic window

[1]

COMPASS — Rivaroxaban + aspirin in stable CVD (PMID 28844192)

Study design

Multicentre randomised double-blind — 27,395 patients (stopped early for benefit)

Population

Stable coronary artery disease and/or peripheral artery disease

Intervention

Rivaroxaban 2.5 mg BD + aspirin 100 mg OR rivaroxaban 5 mg BD alone OR aspirin 100 mg

Primary outcome

Composite CV death/stroke/MI: 4.1% vs 5.4% for rivaroxaban+ASA vs ASA (HR 0.76, p<0.001)

Key secondary findings

Major bleeding increased (3.4% vs 2.2%, HR 1.61) but no increase in fatal bleeding or intracranial haemorrhage; mortality reduced

Clinical bottom line

Dual pathway inhibition (low-dose rivaroxaban + aspirin) reduces CV events in stable CAD/PAD — at the cost of more (non-fatal) major bleeding

[1]

Prognosis and comparative outcomes

Anticoagulant outcomes by clinical scenario — what the evidence shows

Scenario	Agent	Outcome vs comparator	Evidence
Non-valvular AF	Apixaban	Superior efficacy + reduced major bleeding + reduced mortality vs warfarin	ARISTOTLE (2011)
Non-valvular AF	Dabigatran 150 mg	Superior efficacy + reduced ICH vs warfarin	RE-LY (2009)
Non-valvular AF	Rivaroxaban	Non-inferior efficacy + reduced ICH vs warfarin	ROCKET AF (2011)
Acute VTE	Rivaroxaban/apixaban	Non-inferior to LMWH+warfarin; less major bleeding	EINSTEIN, AMPLIFY
Extended VTE	Rivaroxaban 10/20 mg, apixaban	Superior to aspirin for preventing recurrence	EINSTEIN-CHOICE (2017)
Dabigatran major bleeding reversal	Idarucizumab 5 g	Immediate complete reversal in 88-98%; ~93% haemostasis	RE-VERSE AD (2015/2017)
Xa-inhibitor major bleeding reversal	Andexanet alfa	82-92% reduction in anti-Xa; ~82% haemostasis; ~10% thrombosis	ANNEXA-4 (2016/2019)
ACS post-PCI (DAPT)	Ticagrelor	Superior efficacy + reduced mortality vs clopidogrel	PLATO (2009)
ACS post-PCI (DAPT)	Prasugrel	Superior efficacy vs clopidogrel; more bleeding; CI in prior stroke	TRITON-TIMI 38 (2007)
Primary PCI STEMI	Bivalirudin	Reduced bleeding + mortality vs heparin+GPIIb/IIIa; more acute stent thrombosis	HORIZONS-AMI (2008)
Trauma bleeding	TXA within 3 h	Reduced all-cause mortality (14.5% vs 16.0%)	CRASH-2 (2010)
Stable CAD/PAD	Rivaroxaban 2.5 mg BD + aspirin	Reduced CV death/stroke/MI; more major bleeding	COMPASS (2017)
HIT	Argatroban	Reduced new thrombosis + composite endpoint (death/amputation/thrombosis)	ARG-911 (2001)
Major orthopaedic VTE prophylaxis	Fondaparinux	Superior VTE prophylaxis vs enoxaparin	Turpie 2002

[1]

Bleeding-risk and monitoring summary — the bedside reference

Anticoagulant	Bleeding-risk factor	Laboratory monitor	Reversal agent	Specific note
UFH	High aPTT, renal impairment, weight extremes	aPTT 1.5-2.5×; anti-Xa 0.3-0.7 IU/mL	Protamine 1 mg/100 U (last 2-3 h)	HIT (5-14 d); osteoporosis; hyperkalaemia
LMWH	Renal impairment (CrCl <30), obesity, age	Anti-Xa 0.5-1.0 IU/mL BD (selective)	Protamine PARTIAL ~60%	Lower HIT risk (~0.2%); 4-7 h t1/2
Fondaparinux	Renal impairment, low body weight	None routine	None (rFVIIa, dialysis)	Negligible HIT risk; 17-21 h t1/2
Warfarin	Labile INR, age, drugs, diet, comorbidity	INR 2-3 (2.5-3.5 mech mitral)	Vit K + 4F-PCC ± FFP	Teratogenic; skin necrosis; CYP2C9 polymorphism
Dabigatran	CrCl <30, age >75, GI bleed history	TT/dTT (not PT/INR)	Idarucizumab 5 g IV ± dialysis	80% renal; CRASH-2 not relevant
Rivaroxaban/apixaban	Renal impairment, age, low body weight	Anti-Xa (drug-calibrated)	Andexanet ± 4F-PCC 50 IU/kg	Not dialysable; rebound after andexanet
Argatroban	Hepatic impairment (dose-reduce)	aPTT 1.5-3× baseline	None (wait t1/2 ~45 min)	Falsely elevates INR; HIT choice
Bivalirudin	Renal impairment (mild t1/2 prolongation)	aPTT/ACT	None (wait t1/2 ~25 min)	PCI choice; HIT choice
Aspirin	History of GI bleed, age, NSAID combination	None (VerifyNow optional)	Platelet transfusion ± DDAVP	Irreversible COX-1 (7-10 d)
Clopidogrel	CYP2C19 LOF paradox (less effect + ?reactive bleeding)	None (genotyping optional)	Platelet transfusion	CYP2C19 polymorphism; wait 6-12 h post-dose
Ticagrelor	Age, prior bleeding	None	Platelet transfusion (limited)	Reversible; dyspnoea; bradyarrhythmia
GPIIb/IIIa	Renal impairment (eptifibatide, tirofiban), low weight	Platelet count (thrombocytopenia 1-5%)	Platelet transfusion	Acute profound thrombocytopenia possible

[1]

The exam answer (consolidated)

The one-paragraph exam answer

Anticoagulants: UFH (antithrombin → IIa/Xa; APTT; protamine; short t1/2 60-90 min; safe renal). LMWH (antithrombin → Xa; anti-Xa; partial protamine; avoid CrCl under 30). Fondaparinux (synthetic; not reversible). Dabigatran (direct IIa; thrombin time; idarucizumab; 80% renal). Apixaban/rivaroxaban (direct Xa; anti-Xa; andexanet/PCC). Warfarin (vit K epoxide reductase; INR; vit K + PCC; slow onset; CYP2C9; protein C depletion → skin necrosis → overlap heparin). Antiplatelets: aspirin (irreversible COX-1; 7-10d), P2Y12 (clopidogrel irreversible; ticagrelor reversible — mortality benefit in PLATO), GPIIb/IIIa (abciximab/tirofiban/eptifibatide — final common pathway). Indications: VTE (DOAC first-line), AF (CHA2DS2-VASc ≥2 → DOAC), mechanical valve (warfarin ONLY — DOACs contraindicated per RE-ALIGN), ACS (DAPT; ticagrelor preferred). Bleeding: HAS-BLED stratifies risk but does NOT deny anticoagulation; major bleed → stop drug, charcoal if <2-4 h, specific reversal agent (protamine/idarucizumab/andexanet/vit K + PCC), supportive blood products, TXA in trauma.[1][1][2][8][10][16][19]

Short-answer questions

SAQ — VTE prophylaxis strategy in a critically ill medical ICU patient

10 minutes · 10 marks

A 67-year-old man (110 kg, BMI 36) is admitted to ICU with septic shock from a urinary source, requiring noradrenaline 0.25 mcg/kg/min. He has stage 3 chronic kidney disease (baseline creatinine 170 µmol/L, current eGFR 32 mL/min), type 2 diabetes and a previous distal DVT three years ago. He is intubated and ventilated, has a right internal jugular central line and a femoral arterial line, and his platelet count on admission is 240 × 10⁹/L. There is no active bleeding. The nurse asks you to write up the VTE prophylaxis. Outline your assessment and management.

[1]

SAQ — DOAC versus LMWH for the treatment of acute VTE: choosing, dosing, reversing

10 minutes · 10 marks

A 59-year-old woman (72 kg) presents to the emergency department with acute dyspnoea and pleuritic chest pain. CT pulmonary angiography confirms a segmental pulmonary embolism with right ventricular strain on echo (RV/LV ratio 1.1) but she is haemodynamically stable (BP 124/78, HR 102). She has normal renal function (eGFR 88), no active bleeding, and no anticoagulant allergy. Her sister is asking whether she can be treated with one of the 'new blood thinners' rather than injections. Compare and contrast LMWH with a DOAC for her treatment.

[1]

References

[1]Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med, 2009.PMID 19717844
[2]Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med, 2011.PMID 21870978
[3]Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med, 2011.PMID 21830957
[4]Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med, 2009.PMID 19966341
[5]Bauersachs R, Berkowitz SD, Brenner B, et al. (EINSTEIN Investigators) Oral rivaroxaban for symptomatic venous thromboembolism N Engl J Med, 2010.PMID 21128814
[6]Büller HR, Prins MH, Lensin AW, et al. (EINSTEIN-PE Investigators) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism N Engl J Med, 2012.PMID 22449293
[7]Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism N Engl J Med, 2017.PMID 28316279
[8]Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal N Engl J Med, 2015.PMID 26095746
[9]Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis N Engl J Med, 2017.PMID 28693366
[10]Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors N Engl J Med, 2016.PMID 27573206
[11]Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity N Engl J Med, 2015.PMID 26559317
[12]Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors N Engl J Med, 2019.PMID 30730782
[13]Mega JL, Braunwald E, Wiviott SD, et al. (ATLAS ACS 2-TIMI 51) Rivaroxaban in patients with a recent acute coronary syndrome N Engl J Med, 2012.PMID 22077192
[14]Alexander JH, Lopes RD, James S, et al. (APPRAISE-2) Apixaban with antiplatelet therapy after acute coronary syndrome N Engl J Med, 2011.PMID 21780946
[15]Eikelboom JW, Connolly SJ, Bosch J, et al. (COMPASS) Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease N Engl J Med, 2017.PMID 28844192
[16]Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey Chest, 2010.PMID 20299623
[17]Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation Chest, 2010.PMID 19762550
[18]Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med, 2001.PMID 11519503
[19]Wallentin L, Becker RC, Budaj A, et al. (PLATO Investigators) Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med, 2009.PMID 19717846
[20]Wiviott SD, Braunwald E, McCabe CH, et al. (TRITON-TIMI 38) Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med, 2007.PMID 17982182
[21]Mauri L, Kereiakes DJ, Yeh RW, et al. (DAPT Study Investigators) Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents N Engl J Med, 2014.PMID 25399658
[22]The EPIC Investigators Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty N Engl J Med, 1994.PMID 8121459
[23]Topol EJ, Mark DB, Lincoff AM, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization N Engl J Med, 2001.PMID 11419425
[24]Stone GW, McLaurin BT, Cox DA, et al. (ACUITY Investigators) Bivalirudin for patients with acute coronary syndromes N Engl J Med, 2006.PMID 17124018
[25]Stone GW, Witzenbichler B, Guagliumi G, et al. (HORIZONS-AMI Trial Investigators) Bivalirudin during primary PCI in acute myocardial infarction N Engl J Med, 2008.PMID 18499566
[26]Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia Circulation, 2001.PMID 11294800
[27]Cuker A, Gimotty PA, Crowther MA, Warkentin TE Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis Blood, 2012.PMID 22990018
[28]CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial Lancet, 2010.PMID 20554319
[29]Connolly SJ, Eikelboom J, Joyner C, et al. (AVERROES Steering Committee and Investigators) Apixaban in patients with atrial fibrillation N Engl J Med, 2011.PMID 21309657
[30]Turpie AGG, Bauer KA, Eriksson BI, Lassen MR Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies Arch Intern Med, 2002.PMID 12196081

Overview & definition

By class

Class	Mechanism	Monitoring	Reversal
UFH	Antithrombin → IIa + Xa	APTT / anti-Xa	Protamine
LMWH	Antithrombin → Xa	Anti-Xa (if needed)	Protamine (partial ~60%)
Fondaparinux	Antithrombin → Xa	Not routine	None (rFVIIa)
Dabigatran	Direct thrombin (IIa)	Thrombin time	Idarucizumab
Apixaban/rivaroxaban	Direct Xa	Anti-Xa (calibrated)	Andexanet alfa / PCC
Warfarin	Vit K epoxide reductase	INR	Vit K + PCC
Argatroban	Direct thrombin (IIa)	APTT	None (short t1/2)
Bivalirudin	Direct thrombin (IIa)	APTT	None (short t1/2)

The anticoagulant landscape at a glance

Parenteral vs oral anticoagulants — the master comparison

Drug	Mechanism	Onset	Half-life	Elimination	Monitoring	Reversal agent
UFH	Binds antithrombin III → inactivates IIa + Xa	Immediate (IV) / 20-30 min (SC)	60-90 min (dose-dependent)	Reticuloendothelial (hepatic) + renal	aPTT (or anti-Xa)	Protamine 1 mg per 100 U heparin
LMWH (enoxaparin)	Antithrombin → preferential Xa inhibition	3-5 h (SC)	4-7 h	Renal (unchanged)	Anti-Xa (renal impairment, obesity, pregnancy)	Protamine PARTIAL (~60%)
Fondaparinux	Synthetic pentasaccharide → antithrombin → Xa only	2-3 h (SC)	17-21 h	Renal (unchanged)	None routine	None (rFVIIa, haemodialysis)
Warfarin	Vitamin K epoxide reductase inhibitor (↓II, VII, IX, X, protein C/S)	3-5 days	36-42 h	Hepatic (CYP2C9)	INR (target 2-3, or 2.5-3.5 mechanical mitral)	Vitamin K + 4F-PCC ± FFP
Dabigatran	Direct thrombin inhibitor (IIa)	1-3 h	12-17 h (prolonged in renal failure)	80% renal	Thrombin time (TT), dTT, ECT	Idarucizumab (5 g IV)
Rivaroxaban	Direct factor Xa inhibitor	2-4 h	5-9 h (11-13 h elderly)	33% renal, 66% hepatic/fecal	Anti-Xa (rivaroxaban-calibrated)	Andexanet alfa (high/low dose) ± PCC
Apixaban	Direct factor Xa inhibitor	3-4 h	12 h	27% renal, 73% hepatic/fecal	Anti-Xa (apixaban-calibrated)	Andexanet alfa ± PCC
Argatroban	Direct thrombin inhibitor	Immediate (IV)	39-51 min	Hepatic (bilirubin caution)	aPTT (target 1.5-3× baseline)	None — short t1/2 + haemodialysis
Bivalirudin	Direct thrombin inhibitor	Immediate (IV)	25 min	Enzymatic (80%) + renal (20%)	aPTT / ACT	None — short t1/2

[1]

Heparin (UFH) — the workhorse parenteral anticoagulant

The one-paragraph exam answer — UFH

UFH dosing strategies in ICU practice

Indication	Regimen	Target
DVT/PE treatment	80 U/kg bolus → 18 U/kg/hr infusion	aPTT 1.5-2.5× control (or anti-Xa 0.3-0.7 IU/mL)
ACS	60 U/kg bolus (max 4000 U) → 12 U/kg/hr (max 1000 U/hr)	aPTT 1.5-2.0× (60-85 s); usually with aspirin + P2Y12
Atrial fibrillation (bridging)	No bolus → 18 U/kg/hr infusion	aPTT 1.5-2.5×
Mechanical valve (perioperative bridging)	SC 250 U/kg BD or infusion	aPTT 2-3×
Extracorporeal circuits (CRRT, ECMO)	20-50 U/kg bolus → 5-20 U/kg/hr	Anti-Xa 0.25-0.35 IU/mL (CRRT) or ACT 180-220 s (ECMO)
VTE prophylaxis	5000 U SC TDS	None (fixed dose)

[1]

LMWH (enoxaparin) — predictable, no routine monitoring

The one-paragraph exam answer — LMWH

UFH vs LMWH — when to choose which

Feature	UFH	LMWH (enoxaparin)
Molecular weight	3-30 kDa (heterogeneous)	4-6 kDa (uniform)
Mechanism	Antithrombin → IIa + Xa equally	Antithrombin → Xa preferentially (3-4:1)
Half-life	60-90 min (dose-dependent)	4-7 h (fixed)
Clearance	Hepatic/reticuloendothelial + renal	Renal only
Bioavailability (SC)	Variable (~30-50%)	High (~90%, predictable)
Routine monitoring	Yes (aPTT)	No
HIT risk	1-5%	~0.2% (10× lower)
Osteoporosis risk	Higher (long-term)	Lower
Reversal	Protamine (complete)	Protamine PARTIAL (~60%)
Renal failure safety	SAFE	AVOID (CrCl <30)
Preferred when	AKI, need for rapid reversal/procedures, haemodynamic instability, CRRT/ECMO	Stable VTE treatment/prophylaxis, oncology (LMWH preferred in cancer — longer-term), outpatient

[1]

Warfarin — the vitamin K antagonist

The one-paragraph exam answer — warfarin

Warfarin reversal by clinical scenario — the bedside algorithm

Clinical scenario	INR	Intervention	Speed of INR correction
INR supratherapeutic, NO bleeding	5-9	Hold warfarin; consider vitamin K 1-2.5 mg PO	24-48 h
INR ≥10, NO bleeding	≥10	Hold warfarin; vitamin K 2.5-5 mg PO (IV if high bleeding risk)	24-48 h
Minor bleeding	>3	Hold; vitamin K 1-5 mg PO/IV	12-24 h
Major bleeding	Any elevated	Hold + vitamin K 5-10 mg IV + 4F-PCC 25-50 IU/kg ± FFP	Immediate (within minutes — PCC)
Life-threatening bleed / ICH	Any elevated	Hold + vitamin K 10 mg IV + 4F-PCC 50 IU/kg + FFP 15 mL/kg	Immediate
Need for rapid pre-procedure reversal	Any	4F-PCC + vitamin K 5 mg IV	Within 30-60 min

[1]

Direct oral anticoagulants (DOACs) — the modern era

The one-paragraph exam answer — DOACs

The four DOACs — mechanism, dose, reversal, and clearance

Drug	Target	Standard dose (VTE/AF)	Renal clearance	Half-life	Reversal	Pregnancy
Dabigatran	Thrombin (IIa)	150 mg BD	80%	12-17 h (prolonged in renal failure; up to 28 h)	Idarucizumab 5 g IV	Contraindicated
Rivaroxaban	Xa	20 mg OD (15 mg OD if CrCl 15-50)	33%	5-9 h (11-13 h elderly)	Andexanet alfa ± PCC	Contraindicated
Apixaban	Xa	5 mg BD (2.5 mg BD if ≥2 of: age ≥80, Cr ≥133, weight ≤60 kg)	27%	12 h	Andexanet alfa ± PCC	Contraindicated
Edoxaban	Xa	60 mg OD (30 mg if CrCl 15-50, ≤60 kg, concomitant P-gp inhibitor)	50%	10-14 h	Andexanet alfa ± PCC	Contraindicated

[1]

Specific reversal agents — the modern pharmacology

The one-paragraph exam answer — DOAC reversal

Anticoagulant reversal agents — dose, mechanism, and limitations

Anticoagulant	Reversal agent	Dose	Mechanism	Time to effect	Limitations
UFH	Protamine sulfate	1 mg per 100 U heparin (max 50 mg)	Cationic protein binds anionic heparin → inactive complex	<5 min (IV)	Anaphylaxis (1%); hypotension if rapid push; dosing uncertain after 2-3 h of heparin
LMWH	Protamine PARTIAL (~60%)	1 mg per 1 mg enoxaparin (last 8 h)	Binds ~60% of LMWH	<5 min	Only PARTIAL reversal — longer LMWH t1/2 means residual anticoagulation
Fondaparinux	None (rFVIIa 90 mcg/kg)	rFVIIa if life-threatening	Off-label; bypasses inhibition	Variable	No reliable reversal; supportive care + waiting (t1/2 17-21 h)
Warfarin	Vitamin K + 4F-PCC	Vit K 5-10 mg IV + 4F-PCC 25-50 IU/kg	Vit K restores hepatic γ-carboxylation; PCC replaces factors	Vit K: 6-12 h; PCC: minutes	PCC has small thrombosis risk; FFP inferior (volume, thawing); INR rebound at 24 h if vit K omitted
Dabigatran	Idarucizumab	5 g IV (2 × 2.5 g)	Monoclonal Fab → binds dabigatran 350× more avidly than thrombin	Minutes	Thrombotic risk if dabigatran re-initiated; expensive; rebound if ongoing absorption
Rivaroxaban/Apixaban	Andexanet alfa (HIGH: 800 mg bolus + 8 mg/min ×120 min; LOW: 400 mg + 4 mg/min ×120 min)	Weight + drug dose-dependent	Modified FXa decoy → sequesters Xa inhibitor	Minutes (bolus)	Short t1/2 → rebound; ~10% thrombotic risk; costly. Alternative: 4F-PCC 50 IU/kg
Edoxaban	Andexanet (off-label) / 4F-PCC	As for rivaroxaban	As above	Minutes	Limited evidence
Argatroban / Bivalirudin	None (short t1/2)	Supportive; wait	Short half-life = spontaneous reversal	1-2 h off drug	Argatroban hepatic-safe but INR artefact; bivalirudin partial renal

[1]

Antiplatelets — the ACS and stroke-prevention armamentarium

The one-paragraph exam answer — antiplatelets

The P2Y12 inhibitors — clopidogrel vs prasugrel vs ticagrelor

Feature	Clopidogrel	Prasugrel	Ticagrelor
Class	Thienopyridine (prodrug)	Thienopyridine (prodrug)	Cyclopentyl-triazolo-pyrimidine (direct)
Activation	Hepatic CYP2C19 (variable — ~30% poor metabolisers)	Rapid hepatic esterases (NOT CYP2C19-dependent)	None (active drug)
Onset	Slow (2-6 h after 600 mg load)	Fast (~30 min after 60 mg load)	Fast (~30 min after 180 mg load)
Potency	Moderate	High	High
Reversibility	Irreversible (lifespan of platelet, 7-10 d)	Irreversible (7-10 d)	Reversible (3-5 d)
Dose	75 mg OD (600 mg load)	10 mg OD (60 mg load)	90 mg BD (180 mg load) — then 60 mg BD in long-term
Key trial	CURE (PCI/ACS)	TRITON-TIMI 38	PLATO (mortality benefit)
Contraindications	CYP2C19 LOF + ACS/PCI	Prior stroke/TIA; caution >75 yr, <60 kg	Active bleeding; caution in bradyarrhythmia
Adverse effects	Rare thrombocytopenia	More major bleeding	Dyspnoea (10-15%), bradycardia/AV block, ↑uric acid/creatinine
Reversal	Platelet transfusion (wait 6-12 h after dose)	Platelet transfusion (no specific antidote)	Platelet transfusion less effective (reversible); bentalurase investigational

[1]

The antiplatelets (continued)

Aspirin — irreversible COX-1 (acetylation); platelet inhibition for lifespan (7-10 days).[1]
Clopidogrel/prasugrel — irreversible P2Y12 (prodrugs; CYP2C19). Ticagrelor — reversible P2Y12.[1]
GPIIb/IIIa (abciximab, tirofiban, eptifibatide) — block the final common pathway of platelet aggregation; the TARGET trial found abciximab superior to tirofiban for high-risk PCI.[1][23]

Key PK/PD

UFH — short half-life (60-90 min); hepatic clearance; safe in renal failure. Dose-dependent half-life.[1]
LMWH — renal excretion; avoid CrCl under 30. More predictable (no routine monitoring).[1]
Warfarin — slow onset (days; the II/VII/IX/X + protein C/S); the narrow therapeutic window; the CYP2C9 metabolism; the drug interactions. The protein C depletion paradox (the early hypercoagulable → the warfarin skin necrosis → overlap with heparin for 5 days).[1]
DOACs — oral; the predictable (no routine monitoring); the peak 1-4 h; the renal (dabigatran 80 per cent; apixaban/rivaroxaban 25-30 per cent).[1]

Indications — matching drug to disease

Anticoagulation indications by clinical scenario

Indication	First-line anticoagulant	Rationale / comment
VTE treatment (DVT/PE) — first 5-10 days	LMWH OR UFH OR fondaparinux OR rivaroxaban/apixaban (oral from day 1) OR dabigatran (after 5-10 d parenteral — RE-COVER)	LMWH preferred initial; DOACs allow outpatient treatment without parenteral lead-in (rivaroxaban/apixaban); dabigatran requires parenteral lead-in[4]
VTE long-term (3-6 months)	DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) preferred over warfarin	DOACs: non-inferior efficacy, less major bleeding, no monitoring; cancer → LMWH or edoxaban/rivaroxaban
VTE extended (cancer-associated)	LMWH (dalteparin) historically; now rivaroxaban/apixaban or edoxaban	Selected-DURATION: oral DOACs non-inferior to LMWH
Stroke prevention in non-valvular AF	DOAC (apixaban, rivaroxaban, dabigatran, edoxaban) preferred over warfarin	ARISTOTLE: apixaban superior (↓stroke + ↓bleeding + ↓mortality); AVERROES: apixaban superior to aspirin in AF unsuitable for warfarin; DOACs avoid dietary/drug interactions[2][29]
Mechanical heart valve	Warfarin ONLY — DOACs CONTRAINDICATED	RE-ALIGN: dabigatran more thrombosis/bleeding than warfarin in mechanical valves. INR target: mitral 2.5-3.5, aortic 2.0-3.0
Atrial fibrillation (valvular — moderate-severe MS or rheumatic)	Warfarin (NOT DOAC)	DOACs not validated in valvular AF; warfarin remains standard
Antiphospholipid syndrome (triple positive)	Warfarin (NOT DOAC)	Triple-positive APS → DOACs inferior (RAPS trial)
Acute coronary syndrome (post-PCI)	Aspirin + P2Y12 (DAPT) — ticagrelor preferred; DOAC added only if AF (then triple → double therapy)	ATLAS-ACS: low-dose rivaroxaban (2.5 mg BD) reduced death; APPRAISE-2 apixaban STOPPED — excess bleeding/death
Chronic stable CAD/PAD	Aspirin ± low-dose rivaroxaban 2.5 mg BD (COMPASS)	COMPASS: reduced CV death/stroke/MI but ↑major bleeding
VTE prophylaxis (medical/surgical ICU)	LMWH 40 mg SC OD (enoxaparin) OR UFH 5000 U SC TDS	UFH if renal impairment; mechanical prophylaxis if contraindicated
Pregnancy (any indication)	LMWH ONLY (warfarin teratogenic; DOACs contraindicated)	Enoxaparin 1 mg/kg BD; switch to UFH near delivery (shorter t1/2); resume LMWH postpartum + warfarin for 6 weeks postpartum if needed
HIT	Argatroban (hepatic-safe) OR bivalirudin OR danaparoid	DO NOT use warfarin alone until platelets recover (warfarin potentiates protein C depletion → skin necrosis + venous limb gangrene)
Bridging around surgery (mechanical valve, AF)	Stop warfarin 5 days pre-op; LMWH bridging dose when INR <2; stop LMWH 24 h pre-op	PERIOP2: postoperative LMWH bridging did not reduce arterial thromboembolism

Stroke and bleeding risk scores — CHA2DS2-VASc and HAS-BLED

Computing CHA2DS2-VASc and HAS-BLED — the AF risk stratification

Compute CHA2DS2-VASc (stroke risk — each letter a point):
- C Congestive heart failure (1) — or LV dysfunction
- H Hypertension (1)
- A2 Age ≥75 (2) — note double points
- D Diabetes (1)
- S2 prior Stroke/TIA/thromboembolism (2) — double points
- V Vascular disease (prior MI, PAD, aortic plaque) (1)
- A Age 65-74 (1)
- Sc Sex category female (1)
Apply the threshold for anticoagulation:
- Score 0 (male) or 1 (female) → no anticoagulation (truly low risk)
- Score ≥2 (male) or ≥3 (female) → oral anticoagulation recommended (DOAC preferred)
- Score 1 (male) / 2 (female) → consider anticoagulation (shared decision)
Compute HAS-BLED (bleeding risk — each letter a point):
- H Hypertension (uncontrolled, SBP >160) (1)
- A Abnormal renal/liver function (1 each, max 2) — dialysis, transplant, cirrhosis, bilirubin >2×
- S Stroke (prior) (1)
- B Bleeding history/predisposition (1)
- L Labile INR (TTR <60%) (1)
- E Elderly (age >65) (1)
- D Drugs/alcohol concomitantly (antiplatelet/NSAID, ≥8 drinks/week) (1 each, max 2)
Interpret HAS-BLED:
- Score ≥3 → "high risk" — review/correct modifiable risk factors (BP, NSAIDs, alcohol, labile INR) — NOT a reason to withhold anticoagulation (the stroke risk usually outweighs)
- A high HAS-BLED should trigger caution and modifiable-risk-factor correction, not denial of stroke prevention
Choose the agent — DOAC preferred over warfarin for non-valvular AF (lower intracranial bleeding, comparable/better efficacy); warfarin for mechanical valves, severe MS, triple-positive APS
Re-evaluate annually — recheck renal function (DOAC dose adjustment), bleeding risk, adherence, and new vascular disease[16][17]

Management pathways

Major bleeding on an anticoagulant — the universal algorithm

Recognise and resuscitate — ABC; two large-bore IV cannulae; cross-match; activate massive transfusion protocol if haemodynamically unstable; treat hypotension with crystalloid/blood products (1:1:1 PRBC:FFP:platelets in trauma)
Identify the anticoagulant and time of last dose — drug, dose, time of last ingestion, renal function (CrCl/eGFR), and any co-administered antiplatelets/NSAIDs
Stop the anticoagulant immediately (and all antiplatelets/NSAIDs)
Give activated charcoal if recent ingestion — within 2-4 h for dabigatran/rivaroxaban/apixaban (the absorption window); useless if >4 h
Apply local measures — endoscopic/surgical/radiological haemostasis for the bleed source (e.g., GI endoscopy, interventional radiology for retroperitoneal)
Administer the specific reversal agent:
- Warfarin (INR elevated + major bleed) → vitamin K 5-10 mg IV + 4F-PCC 25-50 IU/kg (preferred over FFP — faster, smaller volume)
- Dabigatran → idarucizumab 5 g IV (2 × 2.5 g)
- Rivaroxaban/apixaban → andexanet alfa (HIGH or LOW dose by drug dose/timing); if unavailable → 4F-PCC 50 IU/kg or aPCC 50 IU/kg
- UFH → protamine 1 mg per 100 U heparin in last 2-3 h
- LMWH → protamine 1 mg per 1 mg enoxaparin (PARTIAL reversal ~60%)
- Fondaparinux, argatroban, bivalirudin → no specific agent; supportive (rFVIIa for fondaparinux; short t1/2 of DTIs = wait)
Supportive blood products — PRBC to Hb >70 (or >80 if active/ongoing); platelets if <50 (or antiplatelet/anti-GPIIb/IIIa); fibrinogen (cryoprecipitate or fibrinogen concentrate) if <1.5; FFP if PT/aPTT >1.5×
Adjuncts — tranexamic acid 1 g IV (CRASH-2: reduces mortality in trauma bleeding; role in non-trauma less clear); consider for refractory GI/surgical bleeding
Do NOT delay reversal for confirmatory levels in life-threatening bleeds — give empirically based on history
Re-assess at 1-2 h — if ongoing bleeding, repeat reversal (idarucizumab 5 g repeat in dabigatran rebound; PCC top-up); check anti-Xa/TT if available
Decide on anticoagulation resumption — balance re-thrombosis vs re-bleeding; typically resume 7-14 days post-major GI bleed, sooner for mechanical valve/intracardiac thrombus

[1]

Perioperative management of anticoagulation — bridging

Assess thromboembolic risk:
- HIGH — mechanical mitral valve, any valve + prior stroke/TIA, CHA2DS2-VASc ≥7, recent VTE (<3 months), severe thrombophilia → bridging usually indicated
- MODERATE — bileaflet aortic valve + ≥1 risk factor, CHA2DS2-VASc 5-6, VTE 3-12 months ago → individualise
- LOW — bileaflet aortic valve alone, simple AF CHA2DS2-VASc <5, VTE >12 months → no bridging
Stop warfarin 5 days before surgery (INR falls to ~1.5 by day 4, normal by day 5)
Start bridging LMWH (or UFH) 3 days before surgery — therapeutic dose enoxaparin 1 mg/kg BD when INR <2.0
Stop LMWH 24 h before surgery (last dose morning of day -1); UFH if very high risk (stop 4-6 h pre-op)
On day of surgery — check INR <1.5; neuraxial anaesthesia requires INR ≤1.4 and LMWH held ≥24 h
Resume warfarin 12-24 h post-op (when haemostasis secured)
Resume LMWH 48-72 h post-op (when surgical bleeding risk acceptable) — beware high bleed risk with early LMWH restart
PERIOP2 finding — postoperative bridging (LMWH + warfarin) did NOT reduce arterial thromboembolism vs warfarin alone, and increased major bleeding → reserve for HIGHEST thrombotic risk patients

[1]

Heparin-induced thrombocytopenia (HIT) — recognise and switch

Suspect HIT when platelets fall >50% OR to <100 ×10^9/L, 5-14 days after heparin exposure (or sooner if prior heparin in 30 days). The platelet fall is the hallmark — usually no bleeding, often THROMBOSIS (paradox: 30-50% develop new clot — DVT, limb ischaemia, stroke, MI)
Apply the 4Ts score to estimate pre-test probability:
- Thrombocytopenia (fall pattern and nadir)
- Timing (day of onset — 5-14 d typical; <1 d if prior exposure)
- Thrombosis or other sequelae (skin necrosis, adrenal haemorrhage, acute systemic reaction)
- oTheR cause of thrombocytopenia excluded
- 4Ts 0-3 → unlikely (≈3%); 4-5 → intermediate (≈20%); 6-8 → high (≈60%). Meta-analysis: 4Ts score has good NPV, modest PPV
Stop ALL heparin immediately — UFH, LMWH, heparin flushes, heparin-coated lines — switch to a non-heparin anticoagulant at therapeutic dose (HIT is pro-thrombotic)
Switch to argatroban (hepatic clearance → preferred in renal failure; start 2 µg/kg/min, titrate aPTT 1.5-3× baseline) OR bivalirudin OR danaparoid OR fondaparinux (off-label)
Send confirmatory testing — anti-PF4 antibody ELISA (sensitive, ±specific); serotonin release assay (SRA — gold standard but slow)
Platelets usually recover in 4-14 days — do NOT start warfarin until platelets ≥150 (warfarin alone → catastrophic protein C depletion → venous limb gangrene)
When platelets recovered and on argatroban, transition to warfarin (overlap ≥5 days, INR >2 for 24 h — note argatroban falsely elevates INR)
Lifelong avoidance of heparin — document in chart; future anticoagulation with DOAC, fondaparinux, or argatroban. HIT antibodies fade in ~3 months — re-exposure rarely tested but generally avoided

[1]

DOAC-related intracranial haemorrhage — the time-critical reversal

Confirm ICH (CT brain) and that the patient is on a DOAC — drug, dose, time of last ingestion
Stop the DOAC and any antiplatelets immediately
Activated charcoal if ingestion within 2-4 h (reduce absorption — especially dabigatran)
For dabigatran — give idarucizumab 5 g IV (two consecutive 2.5 g boluses); if idarucizumab unavailable, consider haemodialysis (dabigatran is 35% unbound → dialysable) + aPCC 50 IU/kg
For rivaroxaban/apixaban — give andexanet alfa (HIGH dose if last dose within 8 h or high dose ingested; LOW dose otherwise); if unavailable → 4F-PCC 50 IU/kg (or aPCC 50 IU/kg)
Supportive care — BP control (SBP 140-160 mmHg), ICP management, reverse other coagulopathy (vit K if warfarin overlap, platelets if dual antiplatelet)
Avoid platelet transfusion unless on antiplatelet + undergoing neurosurgery
Neurosurgical evacuation — defer until anticoagulant effect reversed (anti-Xa or TT normal); then proceed as for non-anticoagulated ICH
Do NOT routinely give PCC + andexanet together — additive thrombotic risk; choose one
Plan anticoagulation resumption — balance haemorrhage expansion vs thrombotic indication; typically resume 7-10 days post-ICH if strong indication (mechanical valve sooner)

[1]

Red flags

Clinical pearls

Clinical pearl

UFH potentiates antithrombin III ~1000-fold — it CANNOT inactivate clot-bound thrombin or clot-bound Xa. The heparin-AT III complex inactivates FREE thrombin (IIa) and FREE Xa — but factors bound within a fibrin clot are protected. This is why UFH prevents clot PROPAGATION but does not lyse existing clot (that requires thrombolytics). It also explains the "thrombus on heparin" paradox — surface-bound thrombin continues to generate fibrin even on therapeutic heparin. The short-chain LMWH pentasaccharides preferentially inhibit Xa (less IIa inactivation) — the rationale for cleaner anti-Xa dosing.[1]
UFH half-life is DOSE-DEPENDENT (60-90 min at prophylactic dose; up to 150 min at therapeutic dose). This is because UFH clearance is a saturatable zero-order process (reticuloendothelial + endothelial binding) plus a first-order renal component. At higher doses, the saturatable pathway is overwhelmed → longer half-life. Practically: a 5000 U bolus clears faster than a 10,000 U bolus. This dose-dependent kinetics is why weight-based nomograms outperform fixed dosing.[1]
Protamine dosing is based on the heparin given in the LAST 2-3 HOURS only — not the cumulative dose. Because UFH half-life is 60-90 min, only the heparin circulating at the time of reversal needs neutralising. Dose: 1 mg protamine per 100 U UFH given in the last 2 h (max 50 mg/dose; rapid IV causes histamine release + hypotension → slow push). Excess protamine itself is anticoagulant (anti-thrombin effect) — never give more than calculated. For LMWH, protamine gives only PARTIAL (~60%) reversal because the shorter LMWH chains have lower affinity for protamine.[1]
Warfarin's slow onset (3-5 days) is governed by factor II (prothrombin, t1/2 60 h) and factor X (t1/2 40 h) — NOT factor VII (t1/2 6 h). The INR rises early (factor VII depletes first at 24 h) but is NOT protective until factors II and X are depleted (days 3-5). The INR therefore OVERESTIMATES anticoagulation in the first 48 h — this is why bridging heparin for ≥5 days (until INR >2 for 24 h) is mandatory. Stopping heparin early because "INR is 2.5" is a classic error — the patient is not yet protected.[1]
Warfarin skin necrosis — protein C (t1/2 8 h) depletes before factor II (t1/2 60 h) → transient hypercoagulable state → dermal vascular thrombosis. Protein C and S are anticoagulants (and vitamin K-dependent, so warfarin depletes them too). Because protein C has the SHORTEST half-life of all vitamin K-dependent factors, it depletes within 24-48 h, BEFORE the procoagulant factors II/IX/X reach their nadir. Result: a 3-6 day window of net procoagulant state → skin necrosis (breasts, thighs, buttocks — subcutaneous fat) — especially in patients with hereditary protein C deficiency (catastrophic). Prevention: ALWAYS overlap with heparin for ≥5 days. Treatment: stop warfarin, give vitamin K, heparin, and (in deficiency) protein C concentrate.[1]
RE-LY (2009): dabigatran 150 mg BD reduced stroke/systemic embolism vs warfarin in AF (1.11% vs 1.69%, RR 0.66) — the first DOAC to beat warfarin. Also reduced intracranial haemorrhage (the headline of every DOAC vs warfarin trial — less ICH). BUT increased GI bleeding and, with 150 mg BD, a dyspepsia rate of ~12% (the leading cause of discontinuation). This trial launched the DOAC era. Dabigatran 110 mg BD (not available in ANZ/US) was non-inferior; 150 mg was superior. The 80% renal clearance is the key safety caveat.[1]
ARISTOTLE (2011): apixaban was the FIRST DOAC to show BOTH superior efficacy AND reduced major bleeding AND reduced mortality vs warfarin. Apixaban 5 mg BD reduced stroke/systemic embolism (1.27% vs 1.60%, HR 0.79), major bleeding (2.13% vs 3.09%, HR 0.69), and all-cause mortality (3.52% vs 3.94%, HR 0.89) — the only DOAC trial to achieve all three. This is why apixaban is now the preferred DOAC for AF in most guidelines. The twice-daily dosing is its only practical drawback.[2]
ROCKET AF (2011): rivaroxaban 20 mg OD non-inferior to warfarin in higher-risk AF (CHADS2 mean 3.5). The once-daily rivaroxaban is convenient but the trial had flaws: higher baseline risk population, and on-treatment (per-protocol) analysis favoured rivaroxaban while intention-to-treat (the primary) showed non-inferiority only. Rivaroxaban had higher GI bleeding than warfarin. Renal dose reduction (15 mg OD if CrCl 15-50) is essential. The once-daily dosing and lower cost make it widely used.[3]
EINSTEIN-DVT and EINSTEIN-PE: rivaroxaban allowed oral-only VTE treatment without parenteral lead-in — a paradigm shift. Standard DOAC VTE treatment required 5 days of LMWH/heparin first. Rivaroxaban 15 mg BD ×21 days → 20 mg OD allowed outpatient treatment from day 1 — non-inferior to standard (LMWH + warfarin), with similar/slightly less major bleeding. EINSTEIN-CHOICE (2017) then showed that for extended therapy, rivaroxaban 10 mg or 20 mg OD was better than aspirin 100 mg for preventing recurrent VTE (similar bleeding).[5][6][7]
Idarucizumab (5 g IV) is the CLEANEST reversal — a monoclonal Fab that binds dabigatran with 350× the affinity of thrombin, with NO procoagulant effect. RE-VERSE AD (2015): in patients with serious bleeding or needing urgent surgery on dabigatran, idarucizumab reversed anticoagulation within minutes (diluted thrombin time normalised in 88-98%); the full-cohort analysis (2017, 503 patients) confirmed sustained reversal at 24 h and 72 h with good/excellent haemostasis in ~93%. The thrombin time is the assay of choice (normal TT = no significant dabigatran). Idarucizumab is itself inert (no thrombosis signal in trials) — by far the safest of the specific reversal agents.[8][9]
Andexanet alfa is a DECOY — a modified factor Xa (Ser195→Ala, catalytically inactive) that sequesters Xa inhibitors, freeing endogenous FXa. ANNEXA-A and ANNEXA-R (healthy volunteers) showed andexanet rapidly reversed apixaban and rivaroxaban anti-Xa activity; ANNEXA-4 (bleeding patients, NEJM 2016 + 2019 full report) demonstrated good/excellent haemostasis in ~82% with ~10% thrombotic events. The HIGH- vs LOW-dose regimens are chosen by drug dose and timing of last ingestion. Critical limitation: andexanet's t1/2 (~1 h) is shorter than the Xa inhibitors' (~12 h) → rebound anticoagulation after infusion (consider repeat dosing in ongoing bleeding).[10][11][12]
HAS-BLED ≥3 is NOT a reason to deny anticoagulation — it is a prompt to CORRECT MODIFIABLE RISK FACTORS. Pisters 2010 (CHEST) validated HAS-BLED in a real-world AF cohort; a high score predicts major bleeding, but most components are modifiable (BP control, stop NSAIDs/alcohol, improve INR control by switching to DOAC). The fatal error is using HAS-BLED as a binary "do not anticoagulate" — this leaves patients unprotected from stroke (which is usually higher-risk than bleeding). The correct approach: compute BOTH CHA2DS2-VASc and HAS-BLED; if stroke risk > bleeding risk, anticoagulate and fix the bleed risks.[16]
PLATO (2009): ticagrelor reduced MORTALITY vs clopidogrel in ACS (4.5% vs 5.9%, p<0.001) — the only P2Y12 to show survival benefit. Ticagrelor (reversible, direct P2Y12, 90 mg BD after 180 mg load) reduced CV death, MI, and stroke without increasing overall major bleeding (though non-CABG bleeding was higher). The mortality benefit is partly attributed to ticagrelor's pleiotropic effects (adenosine reuptake inhibition → vasodilation, dyspnoea). Adverse: dyspnoea (~10-15%, usually mild but causes discontinuation), bradyarrhythmias, ↑creatinine and uric acid. The aspirin dose interaction (benefit with low-dose aspirin ≤100 mg) is why low-dose aspirin is mandated with ticagrelor.[19]
TRITON-TIMI 38 (2007): prasugrel more potent than clopidogrel (more ischaemic events prevented) BUT more major bleeding — and CONTRAINDICATED in prior stroke/TIA. Prasugrel (60 mg load → 10 mg OD) is a prodrug but activated by esterases (not CYP2C19) → no pharmacogenomic variability → faster/more consistent than clopidogrel. Reduced ischaemic events (CV death/MI/stroke 9.9% vs 12.1%) but increased major bleeding (2.4% vs 1.8%) and fatal ICH in patients with prior stroke/TIA (absolute contraindication). Reduce to 5 mg OD if >75 yr or <60 kg. Net clinical benefit favours prasugrel in STEMI/diabetes (high thrombotic risk) without prior stroke.[20]
The DAPT study (2014): 30 months vs 12 months of dual antiplatelet therapy after DES — longer reduced stent thrombosis but increased bleeding. DAPT (NEJM 2014) randomised patients to continue thienopyridine or placebo for an additional 18 months after 12 months of DAPT. Continuing reduced stent thrombosis (0.4% vs 1.4%, HR 0.29) and major adverse CV events but increased moderate-severe bleeding (2.5% vs 1.6%). MACCE benefit ~3× bleed cost. Current guidelines: minimum 6 months (12 months in ACS) of DAPT; longer for high thrombotic risk (left main, bifurcation, diabetes, prior stent thrombosis), shorter for high bleeding risk.[21]
ACUITY and HORIZONS-AMI: bivalirudin reduced bleeding vs heparin + GPIIb/IIIa in ACS/PCI — at the cost of more acute stent thrombosis. ACUITY (NEJM 2006, moderate-high-risk ACS): bivalirudin monotherapy was non-inferior for ischaemia with significantly less major bleeding (3.0% vs 5.7%) → net clinical benefit. HORIZONS-AMI (NEJM 2008, primary PCI for STEMI): bivalirudin reduced major bleeding and 30-day mortality vs heparin + abciximab. The catch: more acute stent thrombosis (<24 h) with bivalirudin (absence of upstream platelet inhibition) — mitigated by adding a P2Y12. Bivalirudin is also the anticoagulant of choice in HIT patients needing PCI.[24][25]
Argatroban is the anticoagulant of choice for HIT in renal failure (hepatic clearance) — but it FALSLEY ELEVATES THE INR, complicating warfarin transition. ARG-911 (Circulation 2001) established argatroban in HIT — reduced new thrombosis, the composite endpoint (death/amputation/new thrombosis), and improved platelet recovery. Start at 2 µg/kg/min (0.5 µg/kg/min in hepatic impairment), titrate aPTT to 1.5-3× baseline. When transitioning to warfarin, argatroban's INR artefact means the apparent INR is higher than the true INR — use a chromogenic factor X level or overlap until INR ≥4, then stop argatroban and recheck in 4-6 h (argatroban t1/2 ~45 min). Bivalirudin is the alternative for PCI or argatroban-unavailable.[26]
CRASH-2 (2010): tranexamic acid 1 g IV within 3 h of trauma reduced all-cause mortality (14.5% vs 16.0%, RR 0.91) — but is HARMFUL if given >3 h (especially >24 h) post-injury. TXA inhibits plasminogen → plasmin conversion → stabilises clot. CRASH-2 enrolled 20,211 trauma patients; the benefit was confined to early administration (within 3 h); late administration (>3 h) trended toward harm. Subsequent: WOMAN trial (postpartum haemorrhage) confirmed benefit. TXA has a role in major surgical/trauma/PPH bleeding — not a universal anticoagulant-reversal drug (no proven benefit in DOAC/warfarin bleed, no benefit in upper GI bleed overall — HALT-IT neutral).[28]
The 4Ts score has good NPV but modest PPV — a low score (<4) reliably excludes HIT; a high score mandates non-heparin anticoagulant immediately. Cuker 2012 (Blood): meta-analysis of 4Ts — score 0-3 predicts ~3% probability of HIT (SRA-positive), 4-5 ~20%, 6-8 ~60%. A low/intermediate score still warrants antibody testing, but a high score mandates immediate cessation of all heparin and therapeutic-dose argatroban/bivalirudin while awaiting SRA confirmation. The 4Ts is the bedside tool; the SRA (serotonin release assay) is the laboratory gold standard (slow turnaround).[27]
A normal thrombin time excludes clinically significant dabigatran; a normal anti-Xa excludes clinically significant Xa-inhibitor levels. In the bleeding patient on a DOAC, drug-specific assays are key: dabigatran → thrombin time (TT) or diluted TT (dTT — better for quantitation); rivaroxaban/apixaban → anti-Xa calibrated to that specific drug (a generic anti-Xa assay is misleading). Standard PT/INR/aPTT are unreliable for DOACs — a normal PT does not exclude rivaroxaban, and a normal aPTT does not exclude dabigatran. In a life-threatening bleed, do NOT delay reversal for these — give empirically based on history.[1]
Fondaparinux is a synthetic pentasaccharide (not from heparin) → causes antithrombin-mediated Xa inhibition ONLY, with virtually NO HIT risk and NO routine monitoring. The single pentasaccharide sequence binds antithrombin, amplifying Xa inhibition ~300-fold (no IIa inactivation because the chain is too short to bridge thrombin). Half-life 17-21 h (SC OD). Major orthopaedic trials (Arch Intern Med 2002) showed superior VTE prophylaxis vs enoxaparin. Limitations: 100% renal excretion → contraindicated CrCl <30; no reliable reversal (rFVIIa 90 mcg/kg is theoretical); not reversible by protamine. Has been used off-label for HIT (rare cross-reactivity).[30]
Aspirin resistance / non-responsiveness is real (5-40%) but its clinical significance is debated — do NOT routinely test, but ensure ADHERENCE. Aspirin irreversibly acetylates COX-1 (serine-530) → blocks TXA2 for platelet lifespan. "Resistance" (continued TXA2 production despite aspirin) arises from poor adherence (the biggest cause), high platelet turnover, NSAID competition (ibuprofen blocks COX-1 access), obesity, and rarely genetic polymorphisms. Laboratory tests (VerifyNow, urinary 11-dehydro-TXB2) have poor correlation with outcomes. Practical approach: ask about adherence, avoid concurrent NSAIDs, and consider switching to a P2Y12 in recurrent events.[1]
CYP2C19 polymorphism makes clopidogrel unreliable in ~30% — genetic testing is recommended in EAST ASIAN patients and high-risk ACS/PCI. Clopidogrel is a prodrug activated by hepatic CYP2C19. Loss-of-function alleles (especially *2, *3 — common in East Asian populations, ~50% carriers) reduce active metabolite → less platelet inhibition → more stent thrombosis. Ticagrelor/prasugrel bypass CYP2C19 and are preferred in known LOF carriers or genetically high-risk groups. The converse: CYP2C19 ultrarapid metabolisers may have more bleeding (rare concern).[18]
Pregnancy requires LMWH throughout (warfarin and DOACs both contraindicated) — switch to UFH close to delivery, then resume LMWH + warfarin postpartum. Warfarin is teratogenic (fetal warfarin syndrome weeks 6-12; CNS haemorrhage 2nd/3rd trimester). DOACs are contraindicated (animal data — embryotoxicity, placental transfer). Enoxaparin 1 mg/kg BD (or 1.5 mg/kg OD) does NOT cross the placenta. UFH is preferred in the last 2-4 weeks (shorter t1/2 → allows regional anaesthesia; stop 4-6 h pre-delivery). Postpartum: warfarin is SAFE in breastfeeding (does not pass into milk in active form) — can be used for 6 weeks postpartum VTE prophylaxis, overlapped with LMWH until INR therapeutic.[1]
COMPASS (2017): low-dose rivaroxaban 2.5 mg BD + aspirin reduced CV death/stroke/MI in stable CAD/PAD — at the cost of more major bleeding. COMPASS enrolled 27,395 patients with stable atherosclerotic disease; rivaroxaban 2.5 mg BD + aspirin reduced the composite (CV death/stroke/MI) by 24% vs aspirin alone (4.1% vs 5.4%) but increased major bleeding (3.4% vs 2.2%; no increase in fatal/critical-organ bleeding). Stopped early for benefit. This defined the "dual pathway inhibition" concept — antiplatelet + low-dose anticoagulant for chronic atherothrombosis.[15]
APPRAISE-2 (apixaban in ACS) was STOPPED for excess bleeding/death — high-dose DOACs added to DAPT in ACS are not safe. Unlike low-dose rivaroxaban (ATLAS-ACS, 2.5 mg BD — beneficial), full-dose apixaban 5 mg BD added to antiplatelet therapy after ACS caused excess major bleeding (1.3% vs 0.5%) and a non-significant excess of death. Lesson: in ACS the bleeding hazard of full-dose anticoagulation on top of DAPT outweighs benefit — only very low DOAC doses (rivaroxaban 2.5 mg BD) are tolerated. For ACS + AF requiring anticoagulation, modern strategy is anticoagulant + single antiplatelet (P2Y12) after 1-4 weeks of triple therapy.[13][14]
Equivalent potency conversions you must memorise for warfarin reversal — 4F-PCC 25-50 IU/kg ≈ FFP 15 mL/kg, but PCC is FASTER and SMALLER VOLUME. Four-factor PCC (Beriplex/Kcentra — factors II, VII, IX, X + proteins C/S) reverses warfarin within minutes (vs FFP's 6-12 h for vitamin K effect, and FFP's slower factor repletion). Volume: PCC is ~20 mL vs FFP's ~1 L (3-4 units) → no volume overload. PCC carries a small thrombosis risk (~2-3%) — give with vitamin K to prevent INR rebound. Activated PCC (FEIBA) and recombinant activated factor VII are alternatives for refractory bleeding (off-label for warfarin).[1]
The anticoagulant choice in chronic kidney disease cascades by CrCl — UFH/fondaparinux/argatroban safe; LMWH/dabigatran/edoxaban dose-adjusted; apixaban/rivaroxaban cautiously; warfarin safe at any GFR. Practical CKD pathway: CrCl >50 → all DOACs/LMWH acceptable; CrCl 30-50 → dose-reduce rivaroxaban (15 mg), dabigatran (110 mg), LMWH (enoxaparin OD); CrCl <30 → avoid dabigatran, dose-reduce apixaban (2.5 mg BD), switch LMWH to UFH; CrCl <15 / dialysis → UFH or warfarin (apixaban dose-reduced is sometimes used). In AKI, default to UFH (short t1/2 + reversibility + safe). Always reconsider dosing daily as renal function changes.[1]

Key trials and evidence

RE-LY — Dabigatran vs warfarin in AF (PMID 19717844)

Study design

Multicentre randomised open-label (PROBE) with blinded adjudication — 18,113 patients

Population

Non-valvular AF + ≥1 stroke risk factor (mean CHADS2 2.1)

Intervention

Dabigatran 110 mg BD OR 150 mg BD vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 150 mg 1.11% vs warfarin 1.69% (RR 0.66, p<0.001 for superiority); 110 mg non-inferior

Key secondary findings

Both doses reduced intracranial haemorrhage (~0.23% vs 0.74%); 150 mg increased GI bleeding; dyspepsia ~12% (main discontinuation cause)

Clinical bottom line

First DOAC to beat warfarin in AF — dabigatran 150 mg superior for stroke prevention with less ICH; launched the DOAC era

[1]

ARISTOTLE — Apixaban vs warfarin in AF (PMID 21870978)

Study design

Multicentre randomised double-blind — 18,201 patients

Population

Non-valvular AF + ≥1 stroke risk factor (mean CHADS2 2.1)

Intervention

Apixaban 5 mg BD vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 1.27% vs 1.60% (HR 0.79, p<0.001 superiority)

Key secondary findings

Major bleeding reduced (2.13% vs 3.09%, HR 0.69); haemorrhagic stroke reduced (0.24% vs 0.47%); all-cause mortality reduced (3.52% vs 3.94%, HR 0.89)

Clinical bottom line

Apixaban is the only DOAC to show simultaneous superiority for stroke prevention, reduced major bleeding, AND reduced mortality — preferred DOAC for AF

[1]

ROCKET AF — Rivaroxaban vs warfarin in AF (PMID 21830957)

Study design

Multicentre randomised double-blind double-dummy — 14,264 patients

Population

Non-valvular AF at HIGHER risk (mean CHADS2 3.5)

Intervention

Rivaroxaban 20 mg OD (15 mg if CrCl 30-49) vs warfarin (INR 2-3)

Primary outcome

Stroke/systemic embolism: 1.7% vs 2.2% (HR 0.88, non-inferior p<0.001; superiority not significant in ITT)

Key secondary findings

Critical-organ and fatal bleeding reduced; intracranial haemorrhage reduced (0.5% vs 0.7%); GI bleeding increased

Clinical bottom line

Once-daily rivaroxaban non-inferior to warfarin in higher-risk AF; less ICH, more GI bleed — convenient once-daily dosing

[1]

RE-VERSE AD — Idarucizumab for dabigatran reversal (PMIDs 26095746, 28693366)

Study design

Multicentre prospective open-label single-arm — 503 patients (full cohort)

Population

Patients on dabigatran with serious bleeding (Group A) OR requiring urgent procedure/surgery (Group B)

Intervention

Idarucizumab 5 g IV (2 × 2.5 g bolus)

Primary outcome

Maximum percentage reversal of dabigatran anticoagulant effect (by diluted TT): 88-98% at 24 h

Key secondary findings

Haemostasis good/excellent in ~93% in bleeding group; thrombotic events ~5% during follow-up (attributed to underlying disease + resumption)

Clinical bottom line

Idarucizumab provides immediate, complete, and safe reversal of dabigatran — the cleanest of the specific reversal agents (no procoagulant effect)

[1]

ANNEXA-4 — Andexanet alfa for Xa-inhibitor bleeding (PMIDs 27573206, 30730782)

Study design

Multicentre prospective open-label single-arm — 352 patients (full study)

Population

Patients on apixaban/rivaroxaban/edoxaban/enoxaparin with acute major bleeding

Intervention

Andexanet alfa — HIGH dose (800 mg bolus + 8 mg/min ×120 min) or LOW dose (400 mg + 4 mg/min ×120 min) by drug dose/timing

Primary outcome

Anti-Xa activity reduced 92% (apixaban) and 92% (rivaroxaban) at end of bolus; good/excellent haemostasis in 82% at 12 h

Key secondary findings

Rebound in anti-Xa at 4 h after infusion (short andexanet t1/2); thrombotic events ~10% within 30 days

Clinical bottom line

Andexanet reverses Xa-inhibitor anti-Xa activity rapidly with good clinical haemostasis; rebound and thrombosis are the main caveats — 4F-PCC 50 IU/kg is an alternative

[1]

EINSTEIN-PE/CHOICE — Rivaroxaban in VTE (PMIDs 22449293, 28316279)

Study design

EINSTEIN-PE: open-label non-inferiority RCT — 4,832 patients. EINSTEIN-CHOICE: double-blind RCT — 3,365 patients

Population

EINSTEIN-PE: acute symptomatic PE ± DVT. EINSTEIN-CHOICE: extended therapy after 6-12 months VTE treatment

Intervention

EINSTEIN-PE: rivaroxaban 15 mg BD ×21d → 20 mg OD vs enoxaparin/warfarin. EINSTEIN-CHOICE: rivaroxaban 20 mg OD OR 10 mg OD vs aspirin 100 mg OD

Primary outcome

EINSTEIN-PE: non-inferior (2.1% vs 1.8% symptomatic recurrent VTE; less major bleeding). EINSTEIN-CHOICE: rivaroxaban 20 mg (1.5%) and 10 mg (1.2%) both superior to aspirin (4.4%); similar bleeding

Clinical bottom line

Rivaroxaban allows oral-only VTE treatment without parenteral lead-in (15 mg BD loading then 20 mg OD); for extended therapy, rivaroxaban 10 or 20 mg OD is superior to aspirin with similar bleeding

[1]

PLATO — Ticagrelor vs clopidogrel in ACS (PMID 19717846)

Study design

Multicentre randomised double-blind — 18,624 patients

Population

Patients hospitalised for ACS (STEMI, NSTEMI, unstable angina) — intended invasive or non-invasive management

Intervention

Ticagrelor 180 mg load → 90 mg BD vs clopidogrel 300-600 mg load → 75 mg OD (both + aspirin)

Primary outcome

Composite CV death/MI/stroke at 12 months: 9.8% vs 11.7% (HR 0.84, p<0.001)

Key secondary findings

All-cause mortality reduced (4.5% vs 5.9%, p<0.001) — first P2Y12 with mortality benefit. Major bleeding similar overall but non-CABG bleeding higher; dyspnoea ~14%; bradyarrhythmias

Clinical bottom line

Ticagrelor preferred over clopidogrel in ACS — superior ischaemic outcomes AND reduced mortality. Benefit greatest with low-dose aspirin ≤100 mg

[1]

TRITON-TIMI 38 — Prasugrel vs clopidogrel in ACS (PMID 17982182)

Study design

Multicentre randomised double-blind — 13,608 patients

Population

Moderate-high-risk ACS undergoing PCI

Intervention

Prasugrel 60 mg load → 10 mg OD vs clopidogrel 300 mg load → 75 mg OD (both + aspirin)

Primary outcome

Composite CV death/MI/stroke: 9.9% vs 12.1% (HR 0.81, p<0.001)

Key secondary findings

Major bleeding increased (2.4% vs 1.8%); fatal ICH in patients with prior stroke/TIA (absolute contraindication); benefit greatest in STEMI + diabetes

Clinical bottom line

Prasugrel more potent/faster than clopidogrel — preferred in high-thrombotic-risk STEMI/diabetes WITHOUT prior stroke; contraindicated in prior TIA/stroke; reduce to 5 mg if >75 yr or <60 kg

[1]

HORIZONS-AMI — Bivalirudin in primary PCI (PMID 18499566)

Study design

Multicentre randomised open-label — 3,602 patients

Population

STEMI undergoing primary PCI

Intervention

Bivalirudin vs heparin + GPIIb/IIIa (abciximab)

Primary outcome

Major bleeding at 30 days: reduced (4.9% vs 8.3%); NACE composite reduced (10.1% vs 14.1%)

Key secondary findings

30-day mortality reduced (2.1% vs 3.1%); BUT acute stent thrombosis (<24 h) increased (1.3% vs 0.3%)

Clinical bottom line

Bivalirudin reduces bleeding and mortality in primary PCI — at the cost of early stent thrombosis (mitigated by adding P2Y12). Bivalirudin is the agent of choice in HIT patients needing PCI

[1]

CRASH-2 — Tranexamic acid in trauma (PMID 20554319)

Study design

Multicentre randomised placebo-controlled — 20,211 patients

Population

Trauma patients with significant bleeding OR systolic BP <90 OR HR >110 within 8 h of injury

Intervention

Tranexamic acid 1 g IV loading over 10 min → 1 g over 8 h vs placebo

Primary outcome

All-cause 28-day mortality: 14.5% vs 16.0% (RR 0.91, p=0.0035)

Key secondary findings

Bleeding death reduced (4.9% vs 5.7%); NO increase in vascular occlusive events, MI, stroke, PE, DVT. Benefit confined to treatment WITHIN 3 h of injury

Clinical bottom line

Early TXA (within 3 h) reduces mortality in trauma bleeding — a cheap, globally available life-saver. Late TXA (>3 h) trends toward harm

[1]

ATLAS ACS 2-TIMI 51 / APPRAISE-2 — DOACs in ACS (PMIDs 22077192, 21780946)

Study design

Both: multicentre randomised double-blind placebo-controlled. ATLAS: 15,526 patients. APPRAISE-2: 7,392 patients (stopped early)

Population

Recent ACS on DAPT (aspirin + clopidogrel)

Intervention

ATLAS: rivaroxaban 2.5 mg or 5 mg BD vs placebo. APPRAISE-2: apixaban 5 mg BD vs placebo

Primary outcome

ATLAS: reduced CV death/MI/stroke (8.9% vs 10.7%, HR 0.84); reduced all-cause/stent thrombosis. APPRAISE-2: STOPPED for excess major bleeding (1.3% vs 0.5%) and a trend toward more death

Key secondary findings

ATLAS: 2.5 mg reduced CV + all-cause mortality, with increased major/non-CABG bleeding but not fatal. APPRAISE-2: TIMI major bleeding and intracranial haemorrhage increased

Clinical bottom line

Only VERY LOW DOSE DOAC (rivaroxaban 2.5 mg BD) added to DAPT is tolerated in ACS; full-dose DOACs (apixaban 5 mg BD) cause excess bleeding with no benefit — defines the narrow therapeutic window

[1]

COMPASS — Rivaroxaban + aspirin in stable CVD (PMID 28844192)

Study design

Multicentre randomised double-blind — 27,395 patients (stopped early for benefit)

Population

Stable coronary artery disease and/or peripheral artery disease

Intervention

Rivaroxaban 2.5 mg BD + aspirin 100 mg OR rivaroxaban 5 mg BD alone OR aspirin 100 mg

Primary outcome

Composite CV death/stroke/MI: 4.1% vs 5.4% for rivaroxaban+ASA vs ASA (HR 0.76, p<0.001)

Key secondary findings

Major bleeding increased (3.4% vs 2.2%, HR 1.61) but no increase in fatal bleeding or intracranial haemorrhage; mortality reduced

Clinical bottom line

Dual pathway inhibition (low-dose rivaroxaban + aspirin) reduces CV events in stable CAD/PAD — at the cost of more (non-fatal) major bleeding

[1]

Prognosis and comparative outcomes

Anticoagulant outcomes by clinical scenario — what the evidence shows

Scenario	Agent	Outcome vs comparator	Evidence
Non-valvular AF	Apixaban	Superior efficacy + reduced major bleeding + reduced mortality vs warfarin	ARISTOTLE (2011)
Non-valvular AF	Dabigatran 150 mg	Superior efficacy + reduced ICH vs warfarin	RE-LY (2009)
Non-valvular AF	Rivaroxaban	Non-inferior efficacy + reduced ICH vs warfarin	ROCKET AF (2011)
Acute VTE	Rivaroxaban/apixaban	Non-inferior to LMWH+warfarin; less major bleeding	EINSTEIN, AMPLIFY
Extended VTE	Rivaroxaban 10/20 mg, apixaban	Superior to aspirin for preventing recurrence	EINSTEIN-CHOICE (2017)
Dabigatran major bleeding reversal	Idarucizumab 5 g	Immediate complete reversal in 88-98%; ~93% haemostasis	RE-VERSE AD (2015/2017)
Xa-inhibitor major bleeding reversal	Andexanet alfa	82-92% reduction in anti-Xa; ~82% haemostasis; ~10% thrombosis	ANNEXA-4 (2016/2019)
ACS post-PCI (DAPT)	Ticagrelor	Superior efficacy + reduced mortality vs clopidogrel	PLATO (2009)
ACS post-PCI (DAPT)	Prasugrel	Superior efficacy vs clopidogrel; more bleeding; CI in prior stroke	TRITON-TIMI 38 (2007)
Primary PCI STEMI	Bivalirudin	Reduced bleeding + mortality vs heparin+GPIIb/IIIa; more acute stent thrombosis	HORIZONS-AMI (2008)
Trauma bleeding	TXA within 3 h	Reduced all-cause mortality (14.5% vs 16.0%)	CRASH-2 (2010)
Stable CAD/PAD	Rivaroxaban 2.5 mg BD + aspirin	Reduced CV death/stroke/MI; more major bleeding	COMPASS (2017)
HIT	Argatroban	Reduced new thrombosis + composite endpoint (death/amputation/thrombosis)	ARG-911 (2001)
Major orthopaedic VTE prophylaxis	Fondaparinux	Superior VTE prophylaxis vs enoxaparin	Turpie 2002

[1]

Bleeding-risk and monitoring summary — the bedside reference

Anticoagulant	Bleeding-risk factor	Laboratory monitor	Reversal agent	Specific note
UFH	High aPTT, renal impairment, weight extremes	aPTT 1.5-2.5×; anti-Xa 0.3-0.7 IU/mL	Protamine 1 mg/100 U (last 2-3 h)	HIT (5-14 d); osteoporosis; hyperkalaemia
LMWH	Renal impairment (CrCl <30), obesity, age	Anti-Xa 0.5-1.0 IU/mL BD (selective)	Protamine PARTIAL ~60%	Lower HIT risk (~0.2%); 4-7 h t1/2
Fondaparinux	Renal impairment, low body weight	None routine	None (rFVIIa, dialysis)	Negligible HIT risk; 17-21 h t1/2
Warfarin	Labile INR, age, drugs, diet, comorbidity	INR 2-3 (2.5-3.5 mech mitral)	Vit K + 4F-PCC ± FFP	Teratogenic; skin necrosis; CYP2C9 polymorphism
Dabigatran	CrCl <30, age >75, GI bleed history	TT/dTT (not PT/INR)	Idarucizumab 5 g IV ± dialysis	80% renal; CRASH-2 not relevant
Rivaroxaban/apixaban	Renal impairment, age, low body weight	Anti-Xa (drug-calibrated)	Andexanet ± 4F-PCC 50 IU/kg	Not dialysable; rebound after andexanet
Argatroban	Hepatic impairment (dose-reduce)	aPTT 1.5-3× baseline	None (wait t1/2 ~45 min)	Falsely elevates INR; HIT choice
Bivalirudin	Renal impairment (mild t1/2 prolongation)	aPTT/ACT	None (wait t1/2 ~25 min)	PCI choice; HIT choice
Aspirin	History of GI bleed, age, NSAID combination	None (VerifyNow optional)	Platelet transfusion ± DDAVP	Irreversible COX-1 (7-10 d)
Clopidogrel	CYP2C19 LOF paradox (less effect + ?reactive bleeding)	None (genotyping optional)	Platelet transfusion	CYP2C19 polymorphism; wait 6-12 h post-dose
Ticagrelor	Age, prior bleeding	None	Platelet transfusion (limited)	Reversible; dyspnoea; bradyarrhythmia
GPIIb/IIIa	Renal impairment (eptifibatide, tirofiban), low weight	Platelet count (thrombocytopenia 1-5%)	Platelet transfusion	Acute profound thrombocytopenia possible

[1]

The exam answer (consolidated)

The one-paragraph exam answer

Short-answer questions

SAQ — VTE prophylaxis strategy in a critically ill medical ICU patient

10 minutes · 10 marks

[1]

SAQ — DOAC versus LMWH for the treatment of acute VTE: choosing, dosing, reversing

10 minutes · 10 marks

[1]

References

[1]Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med, 2009.PMID 19717844
[2]Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med, 2011.PMID 21870978
[3]Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med, 2011.PMID 21830957
[4]Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med, 2009.PMID 19966341
[5]Bauersachs R, Berkowitz SD, Brenner B, et al. (EINSTEIN Investigators) Oral rivaroxaban for symptomatic venous thromboembolism N Engl J Med, 2010.PMID 21128814
[6]Büller HR, Prins MH, Lensin AW, et al. (EINSTEIN-PE Investigators) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism N Engl J Med, 2012.PMID 22449293
[7]Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism N Engl J Med, 2017.PMID 28316279
[8]Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal N Engl J Med, 2015.PMID 26095746
[9]Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis N Engl J Med, 2017.PMID 28693366
[10]Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors N Engl J Med, 2016.PMID 27573206
[11]Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity N Engl J Med, 2015.PMID 26559317
[12]Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors N Engl J Med, 2019.PMID 30730782
[13]Mega JL, Braunwald E, Wiviott SD, et al. (ATLAS ACS 2-TIMI 51) Rivaroxaban in patients with a recent acute coronary syndrome N Engl J Med, 2012.PMID 22077192
[14]Alexander JH, Lopes RD, James S, et al. (APPRAISE-2) Apixaban with antiplatelet therapy after acute coronary syndrome N Engl J Med, 2011.PMID 21780946
[15]Eikelboom JW, Connolly SJ, Bosch J, et al. (COMPASS) Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease N Engl J Med, 2017.PMID 28844192
[16]Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey Chest, 2010.PMID 20299623
[17]Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation Chest, 2010.PMID 19762550
[18]Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med, 2001.PMID 11519503
[19]Wallentin L, Becker RC, Budaj A, et al. (PLATO Investigators) Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med, 2009.PMID 19717846
[20]Wiviott SD, Braunwald E, McCabe CH, et al. (TRITON-TIMI 38) Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med, 2007.PMID 17982182
[21]Mauri L, Kereiakes DJ, Yeh RW, et al. (DAPT Study Investigators) Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents N Engl J Med, 2014.PMID 25399658
[22]The EPIC Investigators Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty N Engl J Med, 1994.PMID 8121459
[23]Topol EJ, Mark DB, Lincoff AM, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization N Engl J Med, 2001.PMID 11419425
[24]Stone GW, McLaurin BT, Cox DA, et al. (ACUITY Investigators) Bivalirudin for patients with acute coronary syndromes N Engl J Med, 2006.PMID 17124018
[25]Stone GW, Witzenbichler B, Guagliumi G, et al. (HORIZONS-AMI Trial Investigators) Bivalirudin during primary PCI in acute myocardial infarction N Engl J Med, 2008.PMID 18499566
[26]Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia Circulation, 2001.PMID 11294800
[27]Cuker A, Gimotty PA, Crowther MA, Warkentin TE Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis Blood, 2012.PMID 22990018
[28]CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial Lancet, 2010.PMID 20554319
[29]Connolly SJ, Eikelboom J, Joyner C, et al. (AVERROES Steering Committee and Investigators) Apixaban in patients with atrial fibrillation N Engl J Med, 2011.PMID 21309657
[30]Turpie AGG, Bauer KA, Eriksson BI, Lassen MR Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies Arch Intern Med, 2002.PMID 12196081

Your progress

Overview & definition

By class

The anticoagulant landscape at a glance

Heparin (UFH) — the workhorse parenteral anticoagulant

LMWH (enoxaparin) — predictable, no routine monitoring

Warfarin — the vitamin K antagonist

Direct oral anticoagulants (DOACs) — the modern era

Specific reversal agents — the modern pharmacology

Antiplatelets — the ACS and stroke-prevention armamentarium

The antiplatelets (continued)

Key PK/PD

Indications — matching drug to disease

Stroke and bleeding risk scores — CHA2DS2-VASc and HAS-BLED

Management pathways

Red flags

Clinical pearls

Key trials and evidence

RE-LY — Dabigatran vs warfarin in AF (PMID 19717844)

ARISTOTLE — Apixaban vs warfarin in AF (PMID 21870978)

ROCKET AF — Rivaroxaban vs warfarin in AF (PMID 21830957)

RE-VERSE AD — Idarucizumab for dabigatran reversal (PMIDs 26095746, 28693366)

ANNEXA-4 — Andexanet alfa for Xa-inhibitor bleeding (PMIDs 27573206, 30730782)

EINSTEIN-PE/CHOICE — Rivaroxaban in VTE (PMIDs 22449293, 28316279)

PLATO — Ticagrelor vs clopidogrel in ACS (PMID 19717846)

TRITON-TIMI 38 — Prasugrel vs clopidogrel in ACS (PMID 17982182)

HORIZONS-AMI — Bivalirudin in primary PCI (PMID 18499566)

CRASH-2 — Tranexamic acid in trauma (PMID 20554319)

ATLAS ACS 2-TIMI 51 / APPRAISE-2 — DOACs in ACS (PMIDs 22077192, 21780946)

COMPASS — Rivaroxaban + aspirin in stable CVD (PMID 28844192)

Prognosis and comparative outcomes

The exam answer (consolidated)

Short-answer questions

SAQ — VTE prophylaxis strategy in a critically ill medical ICU patient

SAQ — DOAC versus LMWH for the treatment of acute VTE: choosing, dosing, reversing

References

Your progress

Overview & definition

By class

The anticoagulant landscape at a glance

Heparin (UFH) — the workhorse parenteral anticoagulant

LMWH (enoxaparin) — predictable, no routine monitoring

Warfarin — the vitamin K antagonist

Direct oral anticoagulants (DOACs) — the modern era

Specific reversal agents — the modern pharmacology

Antiplatelets — the ACS and stroke-prevention armamentarium

The antiplatelets (continued)

Key PK/PD

Indications — matching drug to disease

Stroke and bleeding risk scores — CHA2DS2-VASc and HAS-BLED

Management pathways

Red flags

Clinical pearls

Key trials and evidence

RE-LY — Dabigatran vs warfarin in AF (PMID 19717844)

ARISTOTLE — Apixaban vs warfarin in AF (PMID 21870978)

ROCKET AF — Rivaroxaban vs warfarin in AF (PMID 21830957)

RE-VERSE AD — Idarucizumab for dabigatran reversal (PMIDs 26095746, 28693366)

ANNEXA-4 — Andexanet alfa for Xa-inhibitor bleeding (PMIDs 27573206, 30730782)

EINSTEIN-PE/CHOICE — Rivaroxaban in VTE (PMIDs 22449293, 28316279)

PLATO — Ticagrelor vs clopidogrel in ACS (PMID 19717846)

TRITON-TIMI 38 — Prasugrel vs clopidogrel in ACS (PMID 17982182)

HORIZONS-AMI — Bivalirudin in primary PCI (PMID 18499566)

CRASH-2 — Tranexamic acid in trauma (PMID 20554319)

ATLAS ACS 2-TIMI 51 / APPRAISE-2 — DOACs in ACS (PMIDs 22077192, 21780946)

COMPASS — Rivaroxaban + aspirin in stable CVD (PMID 28844192)

Prognosis and comparative outcomes

The exam answer (consolidated)

Short-answer questions

SAQ — VTE prophylaxis strategy in a critically ill medical ICU patient

SAQ — DOAC versus LMWH for the treatment of acute VTE: choosing, dosing, reversing

References