Management of DVT

Overview of Treatment

The management of acute deep vein thrombosis (DVT) is a comprehensive approach aimed at preventing clot propagation, minimizing complications, and reducing the risk of embolization. Central to this strategy is anticoagulation therapy, which inhibits further clot formation and decreases the likelihood of embolism. First-line anticoagulants like low molecular weight heparin (LMWH) or fondaparinux are administered initially due to their rapid onset and parenteral route. Subsequently, oral agents such as warfarin or direct oral anticoagulants (DOACs) can be used, offering convenience and predictability.

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Parenteral Anticoagulants

Low-Molecular-Weight Heparin (LMWH) – Enoxaparin

• Mechanism of Action: Enoxaparin primarily inhibits Factor Xa but also has an effect on thrombin (Factor IIa), albeit to a lesser extent. It achieves its anticoagulant effect by binding to antithrombin, thereby accelerating the inhibition of Factor Xa.
• Dosing Strategy:
  • Enoxaparin (Lovenox) – 1 mg/kg SC q12h or 1.5 mg/kg SC q24h
    • In renal impairment, the dose should be reduced if CrCl <30 mL/min to 1 mg/kg q24H 
      • Anti-Xa monitoring can help guide dosing.
      In pregnancy, additional monitoring with anti-Xa levels is recommended, with target peak levels of 0.6-1.0 units/mL. 
• • Dalteparin (Fragmin) – 100 units/kg SC q12h or 200 units/kg SC q24h
• • Tinzaparin (Innohep) – 175 units/kg SC q24h
• • Nadroparin (Not available in US) – 86 units/kg SC q12h or 171 units/kg SC q24h
• Advantages of LMWH:
  • Greater bioavailability with SC administration
  • Longer half-life allowing once or twice daily dosing
  • Lower risk of HIT and osteoporosis
  • Fixed, weight-based dosing without need for monitoring
  • Can be used in outpatient setting

• • Pharmacokinetics: Enoxaparin is absorbed rapidly when administered subcutaneously, boasting nearly complete bioavailability. Its half-life ranges between 4-7 hours, and it is predominantly excreted renally. Its longer half-life allows for more convenient dosing schedules compared to UFH.
  • Adverse Effects: The primary concern is bleeding, which necessitates regular monitoring of hemoglobin levels and platelet counts. Enoxaparin can also induce heparin-induced thrombocytopenia (HIT), a prothrombotic condition that requires immediate cessation of the drug. Long-term use can lead to osteoporosis.
  • Monitoring and Reversal: Anti-factor Xa levels serve as the gold standard for therapeutic monitoring. Protamine sulfate can partially reverse the anticoagulant effects but is generally less effective than its action on UFH.
  • Risk Stratification: Enoxaparin is often preferred in moderate to high-risk PE cases, given its more predictable anticoagulant effect and lesser need for continuous monitoring compared to UFH.
  • Transition of Therapy: When transitioning to oral anticoagulants like warfarin, an overlap of at least 5 days is recommended until the INR is stable and within the therapeutic range for at least 24 hours.
  • Drug Interactions: Enoxaparin can interact with drugs like antiplatelet agents, increasing the risk of bleeding. It can also interact with drugs affecting renal function, as it is primarily renally cleared.
  • Special Populations: In elderly patients and those with renal impairment, dose adjustments and close monitoring are vital to prevent adverse effects. Pregnant women may also require dosing adjustments and more frequent monitoring.
  • Cost and Accessibility: Enoxaparin is more expensive than UFH, which may be a consideration in resource-limited settings.

Unfractionated Heparin (UFH)

• Mechanism of Action: UFH binds to antithrombin via a unique pentasaccharide sequence, leading to conformational changes in antithrombin. This increases its inhibitory activity >1000 fold. UFH primarily inhibits thrombin (factor IIa) and factor Xa, blocking the coagulation cascade.

• Dosing Strategy: For treatment of acute DVT, initial IV bolus dosing is 80 units/kg, followed by a continuous infusion starting at 18 units/kg/hr. Adjustments are made based on aPTT or Anti-Xa.
  • Dose adjustments can also be made based on anti-Xa levels using specific nomograms, although aPTT monitoring is more common. Example nomograms are:
    • Anti-Xa <0.35 IU/mL: Bolus 80 units/kg, increase infusion by 4 units/kg/hr
    • Anti-Xa 0.35-0.7 IU/mL: Therapeutic range, no change
    • Anti-Xa >0.7 IU/mL: Decrease infusion by 2-4 units/kg/hr
  • In pregnancy, higher doses may be required due to increased distribution volume and accelerated clearance. Many experts suggest maintaining anti-Xa levels of 0.35-0.7 units/mL.
  • Obese patients often need higher doses. Dosing based on ideal body weight with anti-Xa monitoring is recommended.
  • In renal impairment, UFH does not require dose adjustments but anti-Xa monitoring can be considered.

• Pharmacokinetics: UFH has a much shorter half-life (1-2 hours) compared to LMWH and is metabolized in the liver. Its anticoagulant effects are immediate but short-acting due to its short half-life of 60-90 minutes.This makes it a safer option for those with renal impairment.

• Adverse Effects: UFH shares similar adverse effects with LMWH, such as bleeding and HIT. However, the risk of osteoporosis is less prominent with UFH due to its shorter half-life and different metabolic pathway.
• Monitoring and Reversal: Continuous aPTT monitoring is essential. Protamine sulfate serves as an effective reversal agent, neutralizing UFH almost completely.
• Risk Stratification: UFH is often reserved for patients with severe renal impairment or those who might require rapid reversal of anticoagulation, such as individuals at high risk for bleeding or those requiring emergent surgery.
• Transition of Therapy: Transition to oral anticoagulants should overlap with UFH therapy until a stable and therapeutic INR is achieved for at least 24 hours.
• Drug Interactions: UFH can interact with other drugs that affect coagulation, like aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), increasing the risk of bleeding.
• Special Populations: UFH is often preferred in patients with severe renal impairment. It’s also the anticoagulant of choice in pregnant women needing therapeutic anticoagulation due to its inability to cross the placenta.
• Cost and Accessibility: UFH is generally cheaper than LMWH but requires more intensive monitoring, which could offset the cost benefits.

 

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Oral Anticoagulants

 Direct Oral Anticoagulants (DOACs)

DOAC Advantages:

• Oral administration and fixed dosing avoid injections and monitoring
  • Rapid onset of action
  • Shorter half-lives than VKAs
  • Lower risk of intracranial hemorrhage than warfarin
  • Cost-effective avoidance of monitoring

DOAC Considerations:

• Renal dosing adjustments are required depending on agent
  • Not recommended in pregnancy or mechanical valves
  • Interact with P-gp inhibitors/inducers requiring dose adjustments
  • Lack of specific coagulation assays and reversal agents (but now available for some DOACs)
  • Higher cost compared to warfarin

Apixaban

• Mechanism of Action: Apixaban selectively inhibits Factor Xa, disrupting the coagulation cascade and thus exerting anticoagulant effects without the need for a cofactor like antithrombin.
  • Dosing: Initiation with 10 mg twice daily for the first 7 days is recommended, followed by 5 mg twice daily thereafter. Theres data showing safety in chronic kidney disease and end-state renal disease
  • Pharmacokinetics: Apixaban has a half-life of approximately 12 hours and is metabolized primarily through the CYP3A4 pathway. It doesn’t require routine monitoring, making it more convenient but less customizable than warfarin.
  • Adverse Effects: Bleeding is the primary concern, requiring vigilance in patient assessment and monitoring. Other less common effects include nausea and mild liver enzyme elevations.
  • Monitoring and Reversal: Routine monitoring is generally not required for DOACs, but in emergency situations, coagulation assays like anti-Factor Xa levels can be used. Andexanet alfa is the recommended reversal agent for life-threatening bleeding.
  • Risk Stratification: Apixaban is suitable for a wide range of PE risk categories but is especially beneficial for patients who require long-term anticoagulation due to its favorable safety profile.
  • Transition of Therapy: Direct transition from parenteral anticoagulants like LMWH or UFH can be safely done, without the need for overlap, once their effects have waned.
  • Drug Interactions: Drugs affecting the CYP3A4 enzyme can influence apixaban levels. For example, co-administration with strong CYP3A4 inhibitors like ketoconazole can increase apixaban exposure, increasing the bleeding risk.
  • Special Populations: Apixaban is generally avoided in pregnancy due to limited data. Renal dose adjustments are necessary in severe renal impairment.
  • Cost and Accessibility: Apixaban is considerably more expensive than warfarin but may be cost-effective when considering the reduced need for monitoring.

Rivaroxaban

• Mechanism of Action: Similar to apixaban, rivaroxaban is a direct Factor Xa inhibitor that disrupts the coagulation cascade.
  • Dosing: The initial dosing regimen is 15 mg twice daily for the first 21 days, followed by 20 mg once daily for maintenance therapy. Manufactor package insert says to avoid use in eCrCl < 30 min/min
  • Pharmacokinetics: Rivaroxaban has a shorter half-life (7-11 hours) compared to apixaban and is also metabolized by the CYP3A4 system. It has a more rapid onset of action but requires strict adherence to the dosing schedule.
  • Adverse Effects: Besides bleeding, rivaroxaban can also cause gastrointestinal issues and liver enzyme elevations.
  • Monitoring and Reversal: Like apixaban, routine monitoring is not required, but anti-Factor Xa levels can be assessed in emergencies. Andexanet alfa serves as the reversal agent.
  • Risk Stratification: Rivaroxaban is generally used for low to moderate-risk PE cases. Its once-daily dosing makes it convenient but also risky if a dose is missed.
  • Transition of Therapy: Rivaroxaban can be directly substituted for parenteral anticoagulants like LMWH or UFH, without overlap, once their anticoagulant effects have dissipated.
  • Drug Interactions: Strong CYP3A4 inhibitors or inducers can significantly affect rivaroxaban levels, requiring dose adjustments or alternative anticoagulation strategies.
  • Special Populations: Similar to apixaban, rivaroxaban is generally avoided in pregnancy and requires renal dosing adjustments.
  • Cost and Accessibility: Rivaroxaban is also more expensive than warfarin but offers the advantage of less frequent monitoring.

Dabigatran

• Mechanism of Action: Dabigatran is a direct thrombin (Factor IIa) inhibitor. It inhibits both free and fibrin-bound thrombin, thus effectively preventing clot extension and new clot formation.
• Dosing: For the treatment of acute PE, an initial parenteral anticoagulant should be given for at least 5-10 days, followed by Dabigatran 150 mg twice daily. There’s a recommendation against its use in patients with eCrCl < 30 ml/min
• Pharmacokinetics: Dabigatran is unique among the DOACs because it requires prodrug conversion and has a lower bioavailability. It has a half-life of 12-17 hours and is primarily excreted by the kidneys.
• Adverse Effects: Besides bleeding risks, dabigatran can cause dyspepsia and stomach pain in some patients. It has a similar risk profile for gastrointestinal bleeding compared to other DOACs.
• Monitoring and Reversal: Routine monitoring is not generally required, but a diluted thrombin time (dTT) can be used in emergencies. Idarucizumab is a specific reversal agent available for dabigatran.
• Risk Stratification: Dabigatran is used across a range of risk profiles for PE but is particularly useful when a reversible agent is preferred.
• Transition of Therapy: Dabigatran requires an initial period of parenteral anticoagulation before initiation. There is no need for overlap once the parenteral anticoagulant is discontinued.
• Drug Interactions: Dabigatran should not be used concurrently with other anticoagulants, and caution should be exercised with antiplatelets or NSAIDs.
• Special Populations: Dabigatran is contraindicated in patients with severe renal impairment. It is not recommended during pregnancy due to insufficient data.
• Cost and Accessibility: Dabigatran is relatively expensive compared to warfarin but offers the advantage of no routine monitoring.

Edoxaban

• Mechanism of Action: Edoxaban is a direct Factor Xa inhibitor, similar to apixaban and rivaroxaban.
• Dosing: After at least 5 days of initial treatment with a parenteral anticoagulant, edoxaban can be initiated at a dose of 60 mg once daily. CrCl 15- 50 ml/min reduce dose to 30 mg daily, and is not recommended for CrCl < 15 min/min
• Pharmacokinetics: It has a half-life of approximately 10-14 hours and is 50% renally excreted. The other half undergoes hepatic metabolism.
• Adverse Effects: Bleeding is the most significant risk, but edoxaban also has a similar side effect profile to other Factor Xa inhibitors, including potential liver enzyme elevations.
• Monitoring and Reversal: Routine monitoring is not required, but anti-Factor Xa levels can be checked in emergencies. There is currently no specific reversal agent for edoxaban.
• Risk Stratification: Edoxaban has been shown to be effective across a broad spectrum of patients with PE and is generally considered for those who have received initial parenteral anticoagulation without complications.
• Transition of Therapy: Edoxaban should be initiated after a minimum of 5 days of parenteral anticoagulation. There’s no need for overlap as edoxaban can be initiated once the parenteral agent is discontinued.
• Drug Interactions: Edoxaban interacts with drugs that are strong inhibitors or inducers of P-glycoprotein and should be avoided in such combinations.
• Special Populations: It is not recommended in patients with severe renal or hepatic impairment and should be avoided in pregnancy.
• Cost and Accessibility: Similar to other DOACs, edoxaban is more expensive upfront compared to warfarin but may be cost-effective when considering the reduced need for monitoring.

Vitamin K Antagonists (VKAs) – Warfarin

• Mechanism of Action: Warfarin inhibits Vitamin K epoxide reductase, an enzyme involved in the regeneration of active Vitamin K. This action depletes functional Vitamin K reserves, thereby inhibiting the synthesis of Vitamin K-dependent clotting factors (II, VII, IX, X).
  • Dosing Strategy: Initial dosing varies between 5-10 mg daily, with subsequent adjustments based on INR levels. The target INR is generally between 2 and 3 for PE treatment.
  • Pharmacokinetics: Warfarin is metabolized by multiple CYP450 enzymes, has a half-life of 36-42 hours, and requires frequent monitoring due to its narrow therapeutic window.
  • Adverse Effects: The primary risk is bleeding, especially when INR exceeds the therapeutic range. Rare but severe adverse effects include skin necrosis and purple toe syndrome.
  • Monitoring and Reversal: Frequent INR monitoring is essential, with dose adjustments made accordingly. Vitamin K serves as the reversal agent for warfarin toxicity, and fresh frozen plasma can be used for immediate reversal in life-threatening bleeds.
  • Risk Stratification: Warfarin is usually reserved for patients who cannot tolerate DOACs or in whom DOACs are contraindicated, such as those with mechanical heart valves.
  • Transition of Therapy: Overlap with parenteral anticoagulation is necessary until a therapeutic INR is maintained for at least 24-48 hours.
  • Drug Interactions: Numerous drug-drug and drug-food interactions exist, including antibiotics that can either potentiate or inhibit its effects.
  • Special Populations: Warfarin is generally avoided in pregnancy, especially during the first trimester and the peripartum period due to its teratogenicity and the risk of fetal bleeding, respectively.
  • Cost and Accessibility: Warfarin is inexpensive but necessitates frequent monitoring, which can be a burden for some patients.

Monitoring Parameters

• UFH: Monitor aPTT every 6 hours initially; target range depends on the hospital protocol.
• LMWH: Anti-Factor Xa levels in special populations (e.g., obesity, pregnancy).
• Warfarin: Regular INR monitoring; target 2.0-3.0 for PE.
• DOACs: Periodic renal and liver function tests; specific coagulation tests are not routinely required.

 

Selection of Anticoagulants: Key Considerations

The choice between parenteral agents like UFH or LMWH and oral agents like DOACs or warfarin depends on multiple factors:

• Patient Stability: Unstable patients may benefit from UFH due to its rapid onset and reversibility.
• Renal Function: Renal impairment may influence the choice of anticoagulant and dosing.
• Outpatient vs. Inpatient Treatment: LMWH is often preferred for outpatient treatment.
• Special Populations: LMWH is preferred in pregnancy and cancer-associated PE.
• Patient Preferences: DOACs may offer convenience without routine monitoring.
• Cost Considerations
  • UFH and Warfarin: Generally low cost.
  • LMWH: Moderate cost; varies by brand.
  • DOACs: Typically higher cost, but may be offset by reduced monitoring expenses.

• Drug Interactions: A careful review of other medications may influence the choice of anticoagulant.

 

Summary

This expanded section offers a comprehensive and detailed overview of the anticoagulation options for PE, focusing on dosing, renal adjustments, adverse effects, clinical guidance, and practical considerations. It serves as an essential reference for pharmacists and physicians in individualizing treatment plans for patients with PE.

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Tables for Anticoagulants

Table 1: Unfractionated Heparin (UFH)

Standard Dosing	Renal Dose Adjustments	Adverse Effects
IV infusion, adjusted by aPTT	No adjustment	Bleeding, HIT, hyperkalemia

 

Table 2: Low Molecular Weight Heparin (LMWH) – Enoxaparin (Lovenox)

Standard Dosing	Renal Dose Adjustments	Adverse Effects
1 mg/kg SC every 12 hours	1 mg/kg once daily if CrCl <30 mL/min	Bleeding, HIT (lower risk), local reactions

 

Table 3: Direct Oral Anticoagulants (DOACs)

Agent	Standard Dose	Initial Higher Dose	Renal Adjustment	Drug Interactions
Dabigatran	150 mg BID	N/A	CrCl ≤30 mL/minute or on dialysis: Dosing recommendation cannot be provided	P-gp inhibitors/inducers
Rivaroxaban	20 mg daily	15 mg BID x21 days	Avoid if CrCl <30 mL/min	Potent CYP3A4 inhibitors
Apixaban	5 mg BID	10 mg BID x7 days	No Renal Adjustments	P-gp and CYP3A4 inhibitors
Edoxaban	60 mg daily	N/A	Yes if CrCl 15-50 mL/min Avoid crcl<15 ml/min	P-gp inhibitors

Table 4: DOAC Pharmacokinetics

Agent	Bioavailability	Time to Peak	Half-Life	Excretion
Dabigatran	3-7%	0.5-2 hours	12-17 hours	80% renal
Rivaroxaban	>80% with food	2-4 hours	5-13 hours	33% renal
Apixaban	50%	3-4 hours	12 hours	27% renal
Edoxaban	62%	1-2 hours	10-14 hours	50% renal

Table 5: Comparison of Parenteral Anticoagulants

Agent	Mechanism of Action	Monitoring	Reversal	Dosing Frequency	Renal Adjustment
UFH	Anti-thrombin mediated inhibition of IIa, Xa	aPTT or Anti-Xa	Protamine sulfate	Continuous infusion	No
LMWH	Anti-thrombin mediated inhibition of Xa > IIa	Anti-Xa (optional)	Protamine (partial)	Once or twice daily	Yes if CrCl <30 mL/min
Fondaparinux	Anti-thrombin mediated inhibition of Xa	Anti-Xa (optional)	None	Once daily	Yes if CrCl <50 mL/min

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