Antithrombotic therapy: antiplatelets and anticoagulants

• Thrombi differ by location: arterial clots are platelet-rich and form under high shear, so antiplatelets (aspirin, P2Y12 inhibitors) matter most; venous and cardiac clots are fibrin-rich, so anticoagulants (heparins, warfarin, DOACs) matter most. This one distinction explains most prescribing choices.
• Atrial fibrillation stroke prevention: oral anticoagulation is indicated for a CHA2DS2-VASc score of 2 or more in men, or 3 or more in women, by current ACC/AHA and ESC standards, with direct oral anticoagulants (DOACs) preferred to warfarin except with mechanical valves or moderate-severe mitral stenosis. ^[2]
• Venous thromboembolism: treat initially with heparin or a DOAC, continue long enough to cover the risk period, and choose the agent and duration by whether the clot was provoked, recurrent, or cancer-associated.
• Dual antiplatelet therapy after acute coronary syndrome lasts 6 to 12 months; combine an anticoagulant with antiplatelet agents for the shortest possible time and drop aspirin early when an anticoagulant is already in use.
• Reversal is drug-specific: protamine for heparin, vitamin K with four-factor prothrombin complex concentrate for warfarin, idarucizumab for dabigatran, and four-factor prothrombin complex concentrate or andexanet alfa dosing protocols for factor Xa inhibitors, with heparin bridging not recommended for DOACs.

By the end of this page you should be able to:

1. Explain why arterial and venous thrombosis need different drugs, and link this to acute coronary syndrome, atrial fibrillation, venous thromboembolism and peripheral arterial disease.
2. Choose and dose an antiplatelet regimen (aspirin, clopidogrel, ticagrelor, prasugrel) for secondary prevention and after percutaneous intervention.
3. Choose and dose an anticoagulant (unfractionated heparin, enoxaparin, warfarin, and the four DOACs) for the common indications.
4. Combine antiplatelet and anticoagulant therapy rationally, with a realistic view of duration and bleeding.
5. Select reversal therapy for each anticoagulant and manage periprocedural interruption.
6. Apply CHA2DS2-VASc and HAS-BLED, and state when guidelines disagree.

Thrombosis is the same process everywhere, but the dominant ingredients change. Vascular injury exposes subendothelial collagen; platelets adhere, activate, and aggregate (this is the arterial, high-shear story); exposed tissue factor triggers the coagulation cascade, generating thrombin and fibrin (this matters in veins, cardiac chambers, and stasis). Flow is the selector. In fast-moving arteries, platelet aggregates predominate: atherosclerotic plaque rupture produces pale, platelet-rich thrombi. In slow or static settings (atria in atrial fibrillation, deep veins, postoperative venous stasis) fibrin and trapped red cells predominate. That is why antiplatelets are the backbone of coronary and cerebrovascular prevention, while anticoagulants are the backbone of atrial fibrillation stroke prevention and venous thromboembolism treatment. The overlap cases (for example a patient with atrial fibrillation who has coronary stents) are the hard ones and are handled below.

Two components create most drug interactions and most dosing errors. First, aspirin and P2Y12 inhibitors act on platelets and have largely irreversible or long-lasting effects on platelet lifespan. Second, heparins, warfarin and DOACs act on the coagulation cascade and are relatively short-acting (hours to days), so their effect tracks renal and hepatic clearance and can be reversed or allowed to wear off.

Aspirin irreversibly acetylates cyclo-oxygenase-1 (COX-1) in platelets, blocking thromboxane A2 synthesis for the lifespan of the platelet. Low doses achieve the platelet COX-1 effect; higher doses buy little additional antiplatelet effect but add gastrointestinal toxicity ^[1].> For secondary prevention of coronary disease aspirin remains first-line monotherapy beyond 12 months ^[1]. In cerebrovascular disease clopidogrel is the preferred single agent in many guidelines, and in peripheral arterial disease aspirin or clopidogrel monotherapy is standard.

Primary prevention is the trap. In people with risk factors but no established vascular disease, there is little evidence of benefit from aspirin, while gastrointestinal and major extracranial bleeding rise; aspirin in primary prevention should therefore be used selectively and individually, if at all ^[1].

Low-dose rivaroxaban (2.5 mg twice daily) combined with aspirin (100 mg daily) reduces major cardiovascular events and major adverse limb events in stable coronary or peripheral arterial disease, at the cost of a modest increase in major bleeding ^[1][8].

Concomitant proton-pump inhibitor therapy should be used for patients at gastrointestinal risk (older age, prior ulcer or bleed, NSAID or steroid use), since acid suppression reduces upper gastrointestinal bleeding on both antiplatelet and anticoagulant regimens ^[6].

P2Y12 inhibitors block ADP-mediated platelet aggregation. Clopidogrel and prasugrel are thienopyridine prodrugs that irreversibly bind the receptor; ticagrelor is a reversible, directly active drug. Clopidogrel is the backbone for chronic oral antiplatelet monotherapy when aspirin is not tolerated or not preferred, and it is the usual partner drug with an oral anticoagulant after percutaneous intervention ^[1][8].

Dosing used in the major trials and guidelines:

• Clopidogrel 75 mg once daily for long-term secondary prevention ^[1].
• Ticagrelor 90 mg twice daily with low-dose aspirin in acute coronary syndrome, and 60 mg twice daily on top of aspirin for selected patients 1 to 3 years after myocardial infarction ^[1].
• Ticagrelor carries reversible binding, faster offset, and dyspnoea as its commonest cause of discontinuation ^[1].
• Prasugrel is licensed only after percutaneous coronary intervention. Its more intense effect is balanced against a clearly unfavourable risk-benefit profile in people with body weight 60 kg or less, a history of stroke or transient ischaemic attack, and people over 75 years ^[1].

P2Y12 inhibitor choice in acute coronary syndrome: prasugrel and ticagrelor are more potent than clopidogrel with faster onset. Recent European guidance gives a strong recommendation in favour of prasugrel over ticagrelor in non-ST-elevation acute coronary syndrome when there is no reason to prefer one over the other ^[1]. Prasugrel's greater surgical bleeding risk means it must be stopped at least as early as, and usually longer than, clopidogrel before planned surgery.

Current guidelines endorse 6 to 12 months of dual antiplatelet therapy (DAPT) after acute coronary syndrome, followed by aspirin monotherapy ^[1]. Shorten this in patients with high bleeding risk; extend beyond 12 months only in patients at high ischaemic risk (stent thrombosis, recurrent acute coronary syndrome on dual therapy, post-infarction diffuse disease) whose bleeding potential is low ^[1].

When an anticoagulant is also needed, the regimen changes:

• Triple therapy (anticoagulant plus aspirin plus P2Y12 inhibitor) substantially increases bleeding and should be kept as short as possible: up to 7 days, and generally not beyond one month ^[6].
• The default is an anticoagulant plus a single P2Y12 inhibitor (usually clopidogrel), dropping aspirin; trials of rivaroxaban-, dabigatran- and apixaban-based dual therapy all showed far less bleeding than triple therapy without an increase in thrombotic events ^[8].
• In stable anticoagulated patients after coronary stenting, or in high-risk chronic coronary syndrome on an anticoagulant, use the anticoagulant alone: adding aspirin increases bleeding without adding efficacy ^[6].

Unfractionated heparin enhances antithrombin and inhibits thrombin (factor IIa) and factor Xa. It is monitored with activated partial thromboplastin time or anti-Xa activity using an institutional nomogram. A common weight-based regimen for acute venous thromboembolism is an 80 units per kilogram bolus followed by 18 units per kilogram per hour infusion ^[5]. Therapeutic anticoagulation should be established quickly, because inadequate initial heparin therapy predisposes to recurrent clot ^[5].

Protamine sulfate is the specific antidote: 1 mg per 100 units of heparin ^[6], with a repeat half-dose if the aPTT remains elevated.

Enoxaparin, a low-molecular-weight heparin, is given 1 mg per kilogram twice daily for treatment of acute venous thromboembolism ^[5]; prophylactic dosing is much lower and should follow local protocol and weight. Low-molecular-weight heparin is partially reversed with protamine, 1 mg per 1 mg of enoxaparin ^[6], with the best effect when given within a few hours of the dose.

Monitoring of low-molecular-weight heparin is not routine; anti-Xa monitoring is reserved for extremes of weight, renal impairment and pregnancy ^[5]. Guidelines differ on dose capping in severe obesity: the evidence is insufficient to mandate a capped regimen, and many units use weight-based dosing with monitoring ^[5].

Heparin-induced thrombocytopenia is an immune, prothrombotic complication occurring after heparin exposure. Stop all heparin immediately and switch to a non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux or a DOAC) with haematology advice. Do not introduce warfarin acutely because of skin necrosis risk.

Warfarin inhibits vitamin K epoxide reductase, lowering the active forms of the vitamin K dependent clotting proteins (two, seven, nine and ten) and of the natural anticoagulants protein C and protein S. It has a narrow therapeutic window, is affected by diet (vitamin K intake), drugs and genetic variation, and requires INR monitoring.

Therapeutic targets:

• 2.0 to 3.0 for non-valvular atrial fibrillation and venous thromboembolism ^[4][6].
• 2.5 for mechanical bileaflet or modern single-tilting-disk aortic valves without additional risk factors; 3.0 for mechanical mitral valves or aortic valves with additional thrombotic risk ^[4].
• 2.0 to 3.0 for atrial fibrillation with rheumatic mitral stenosis ^[4].
• Warfarin is also used with an INR of 2.0 to 3.0 in end-stage renal disease when an oral anticoagulant is chosen ^[4].

When starting warfarin, overlap with heparin until the INR is in the therapeutic range for at least 24 hours; never bridge when starting a DOAC, whose onset is rapid.

Where warfarin beats DOACs ^[4][8]:

• Mechanical heart valves (all DOACs are contraindicated; the RE-ALIGN trial showed excess thrombosis and bleeding with dabigatran) and moderate or severe mitral stenosis with atrial fibrillation (warfarin, INR 2.0 to 3.0).
• Antiphospholipid syndrome with thrombosis and, in practice, patients with very poor renal function (CrCl under 15 mL/min) or on dialysis, where warfarin 2.0 to 3.0 or an evidence-based apixaban dose is reasonable.
• Post-bariatric surgery where absorption of DOACs is unreliable; parenteral anticoagulation initially, then warfarin with INR monitoring.
• Older, frail patients on clinically stable warfarin with polypharmacy, where switching may raise bleeding ^[4].

DOACs directly inhibit thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, edoxaban). They have fixed dosing, rapid onset and offset, few food interactions, and usually need no routine monitoring. Current guidelines recommend a DOAC over warfarin for eligible atrial fibrillation, with exceptions for mechanical heart valves and moderate to severe mitral stenosis ^[4][6][8]. Dabigatran reduced renal elimination 80%; edoxaban 50%; rivaroxaban 35%; apixaban 27% ^[8].

Dosing table for stroke prevention in atrial fibrillation:

Other indications:

• Venous thromboembolism treatment: apixaban 10 mg twice daily for 7 days then 5 mg twice daily; rivaroxaban 15 mg twice daily for 21 days then 20 mg once daily ^[8]. Dabigatran and edoxaban are taken after short initial parenteral therapy.
• Stable atherosclerotic disease: rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily ^[1][8].
• Post-myocardial infarction (Japanese dosing study, AFIRE): rivaroxaban 15 mg daily (10 mg daily if CrCl 15-49) outperformed combination therapy on bleeding and non-inferiority ^[8].
• Cancer-associated venous thromboembolism: edoxaban 60 mg daily or apixaban standard dosing are options compared with low-molecular-weight heparin, with appropriate bleeding assessment ^[8].

Renal handling: dabigatran should be avoided with CrCl under 30 mL/min; rivaroxaban and edoxaban require dose reduction with renal impairment and careful use in severe renal disease; apixaban undergoes the least renal elimination ^[8]. Edoxaban is avoided with CrCl over 95 mL/min because efficacy fell in patients with preserved renal function in the pivotal trial ^[8].

Periprocedural DOAC management: stop 1 to 2 days before low- or moderate-risk procedures and 3 to 4 days before high-risk procedures, with dabigatran stopped earlier if renal function is impaired; no heparin bridging; restart about 24 hours after low- or moderate-risk surgery, 48 to 72 hours after high-risk surgery ^[6].

The CHA2DS2-VASc score components: congestive heart failure or left ventricular dysfunction (1), hypertension (1), age 75 or over (2), diabetes (1), stroke or transient ischaemic attack or systemic embolism (2), vascular disease (1), age 65 to 74 (1), female sex (1), with the 2020 ESC revision assigning a point for heart failure with preserved as well as reduced ejection fraction, hypertrophic cardiomyopathy and angiographically significant coronary disease ^[2]. Guidelines differ on the treatment threshold:

For men 1 and women 2, either guideline band (2019 ACC/AHA and 2020 ESC) recommend a shared decision: oral anticoagulation or no treatment ^[2]. Female sex is best treated as a risk modifier rather than an isolated indication.

The 2026 Asia Pacific guideline is the newest regional edition available and reiterates that stroke prevention is the cornerstone of atrial fibrillation care, with attention to dosing and renal function in Asia-Pacific populations ^[7].

The HAS-BLED score estimates major bleeding risk: hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile INR, elderly (over 65), drugs or excess alcohol. A score of 3 or more identifies high bleeding risk. A high HAS-BLED score should not by itself stop anticoagulation: it exists to identify modifiable risks (blood pressure, alcohol, interacting drugs, NSAIDs) and arrange closer review ^[2][6]. Bleeding and thrombotic risk both change over time and should be reassessed, with stroke risk re-checked roughly every 3 to 4 months after new comorbidity appears ^[2].

Aspirin, or clopidogrel when aspirin is unsuitable, remains first-line single antiplatelet therapy for symptomatic peripheral arterial disease ^[1]. After lower-limb or carotid revascularisation ^[1]:

• a period of dual antiplatelet therapy is used in some regimens, followed by single antiplatelet therapy;
• low-dose rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) reduced major adverse limb events in the VOYAGER PAD trial ^[1];
• ticagrelor did not outperform clopidogrel in symptomatic peripheral arterial disease (EUCLID) ^[1].

Mechanical and bioprosthetic heart valves, and atrial fibrillation with valvular disease, are handled in sections 5 and 6: valve type dictates the agent and the INR.

Reversal is specific to the drug class and should follow institutional protocols, but the agents are:

Andexanet alfa binds factor Xa inhibitors as a decoy; its 10% thrombotic signal in ANNEXA-I (ischaemic stroke 6.5% versus 1.5% with standard care) is the reason for the recent change ^[6]. Idarucizumab showed 100% median maximum reversal by 4 hours in RE-VERSE AD, with 90-day thrombotic events of 6.3 to 7.4% ^[6]. Rebound anticoagulation can occur 12 to 24 hours after idarucizumab in renal impairment ^[6].

Periprocedural DOAC management and bridging are covered in section 6; the key evidence is that heparin bridging increases bleeding without reducing thrombotic events ^[6].

• Pregnancy: warfarin is teratogenic; anticoagulation in pregnancy is with low-molecular-weight heparin. DOACs are not used. Specialist planning is essential.
• Renal disease: avoid dabigatran with CrCl under 30 mL/min; dose-reduce rivaroxaban and edoxaban; apixaban needs the fewest renal adjustments. In end-stage renal disease, warfarin 2.0 to 3.0 or an evidence-based apixaban dose is reasonable ^[4][8].
• Frail, older, polypharmacy patients: stable warfarin may be preferable to switching ^[4].
• Intracranial haemorrhage on an anticoagulant: specific reversal within minutes, CT, neurosurgical and haematology involvement. Factor Xa inhibitor reversal regimens are regimen-based by drug, dose and time since the last dose ^[6].
• Do not under-dose DOACs out of fear of bleeding: inappropriate under-dosing increases thrombotic complications without reducing haemorrhage ^[6].
• Combination antiplatelet plus anticoagulant: minimise duration, avoid long-term triple therapy, and add a proton-pump inhibitor for gastrointestinal protection ^[6][8].
• Low-resource settings: aspirin 75 to 100 mg and clopidogrel 75 mg are inexpensive and form the basis of secondary prevention; warfarin is cheap but needs INR monitoring and reliable supply of vitamin K or prothrombin complex concentrate for reversal; unfractionated heparin needs monitoring; DOACs and specific reversal agents may be unavailable or costly, so protocols should default to the agents and antidotes that are actually in stock.

Atrial fibrillation and flutter; acute coronary syndromes; venous thromboembolism and pulmonary embolism; peripheral arterial disease; stroke and transient ischaemic attack; heparin-induced thrombocytopenia; left atrial appendage occlusion.