Dabigatran
Dabigatran
Generic Name
Dabigatran
Brand Names
*Pradaxa*) is an orally‑active, direct thrombin (Factor IIa) inhibitor used primarily for stroke prevention in non‑valvular atrial fibrillation and for the treatment and secondary prevention of venous thromboembolism.
Mechanism
- Direct, reversible inhibition of factor IIa (thrombin) by reversible binding to the catalytic site of the enzyme.
- Prevents conversion of fibrinogen to fibrin, platelet activation, and thrombin‑mediated clot propagation.
- Does not interfere with coagulation factors I, II, VII, VIII, IX, X, or the intrinsic/extrinsic pathways.
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Pharmacokinetics
| Parameter | Value | Notes |
| Absorption | Oral prodrug (dabigatran etexilate) | Limited GI absorption; peaks within 2–3 hr; bioavailability ≈ 0.5 % (after prodrug conversion) |
| Distribution | Volume‑of‑distribution ~ 18 L | ~ 80 % protein‑bound (albumin & α‑1‑acid glycoprotein) |
| Metabolism | Minimal → converted from prodrug by esterases | No major CYP involvement |
| Elimination | Renal excretion (≈ 80 %) via glomerular filtration & tubular secretion | Half‑life 12–14 hrs (normal renal function) |
| Drug Interactions | P‑gp inhibitors (e.g., ketoconazole) ↑ concentration; inducers (e.g., rifampicin) ↓ concentration | Avoid concomitant drugs that further reduce renal clearance |
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Indications
- Primary prevention of embolic events (stroke/TIA) in non‑valvular atrial fibrillation.
- Treatment & secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5–10 days of parenteral anticoagulation.
- Not approved for valvular atrial fibrillation (e.g., mitral stenosis) or mechanical prosthetic heart valves.
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Contraindications
- Renal impairment: CrCl < 15 ml/min → contraindicated.
- Active bleeding or high bleeding risk (e.g., recent intracranial hemorrhage).
- Pregnancy (Category D) and lactation – avoid unless benefits outweigh risks.
- Concurrent use with P‑gp inhibitors (e.g., ketoconazole, clarithromycin) that dramatically ↑ dabigatran levels.
- Major surgery: hold 24 hr before elective surgery; rescue strategy requires dialysis or protamine sulfate (limited efficacy).
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Dosing
| Indication | Dose | Frequency | Renal Dosing |
| Paroxysmal/ persistent AF | 150 mg po BID (after initial 5–10 days of 110 mg BID) | BID | CrCl 30–49 ml/min → 110 mg BID; CrCl <30 ml/min → contraindicated |
| VTE (DVT/PE) | 150 mg po BID (after 5–10 days LMWH/UFH) | BID | Same renal adjustment as AF |
• Take with water no milk or high‑fat meal (reduces absorption).
• Administer exactly, as adherence influences efficacy.
• Re‑initiation after bleeding event requires restarting 5–10 days before first repeat dose, if clinically appropriate.
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Adverse Effects
- Common (≤ 10 %)
- Dyspepsia
- Nausea
- Epigastric pain (often mild)
- Hematuria (micro‑)
- Abnormal liver function tests (rare)
- Serious (≤ 1 %)
- Major bleeding (intracranial, GI, genitourinary).
- Acute kidney injury (especially in dehydrated or septic patients).
- Severe hypersensitivity (rash, urticaria).
Bleeding risk mitigation: avoid NSAIDs, antiplatelets unless necessary; use PPI for ulcer prophylaxis when indicated.
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Monitoring
| Parameter | Frequency | Rationale |
| Renal function (CrCl) | Baseline, then every 4–6 weeks, or more frequently if CrCl < 60 ml/min | Doses adjusted, risk of accumulation |
| Hemoglobin/hematocrit | Baseline, then every 8–12 weeks | Detect occult bleeding |
| Liver enzymes | Baseline, then annually | Rare hepatotoxicity |
| Coagulation tests (PT/INR, aPTT) | Not routine | Dabigatran does not affect standard coag tests reliably |
| PTT/activated clotting time | If bleeding or peri‑operative assessment | For off‑label monitoring |
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Clinical Pearls
- “On‑Demand” Rescues: For emergency reversal, dabigatran can be cleared by hemodialysis in 60–90 min; consider if bleeding is uncontrolled or urgent surgery required.
- Drug‑Drug Interaction Hot‑Spot: Any P‑gp inhibitor (ketoconazole, clarithromycin) can raise dabigatran up to 2‑fold – counsel patients to avoid these when possible.
- Dose Adjustment in Elderly: Age alone isn’t a contraindication but renal clearance declines with age; perform regular CrCl assessments in patients > 65 y.
- Non‑intravenous Alternatives: For acute VTE post‑parenteral anticoagulation, a short 5‑day course of LMWH followed by dabigatran yields similar efficacy with lower bleeding risk versus prolonged heparin therapy.
- Kidney Failure Escapology: In patients with CrCl 15–30 ml/min, consider alternatives (e.g., apixaban or edoxaban) or implement a renally‑adjusted dosing strategy, as dabigatran’s renal dependence can precipitate accumulation and bleeding.
- Patient Education: Emphasize the need to take the medication twice daily at consistent times; missed doses can rapidly increase stroke risk in AF.
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• Bottom Line: Dabigatran’s direct thrombin inhibition provides a convenient, once or twice daily oral anticoagulant for AF and VTE that does not require INR monitoring. When prescribing, always weigh renal function, drug interactions, and bleeding risk to individualize therapy and optimize patient outcomes.