New Horizons in Anticoagulation: Direct Oral Anticoagulant Use in Special Populations

Thromboembolic disorders such as atrial fibrillation (AF), deep vein thrombosis (DVT), and pulmonary embolism (PE) remain significant contributors to global morbidity, mortality, and healthcare utilization. The prevalence of atrial fibrillation alone is estimated to exceed 33 million worldwide and continues to grow with population aging and increasing cardiovascular risk factors. Anticoagulation plays a central role in preventing ischemic stroke and recurrent thromboembolism in these patient groups. Historically, vitamin K antagonists (VKAs), such as warfarin, have served as the primary oral anticoagulants. Despite their clinical effectiveness, VKAs carry multiple limitations, including a narrow therapeutic range, variable dose-response relationships, numerous food and drug interactions, and the need for frequent international normalized ratio (INR) monitoring to maintain therapeutic anticoagulation. These challenges contribute to suboptimal adherence, reduced effectiveness, and increased bleeding complications in real-world settings. The introduction of direct oral anticoagulants, including dabigatran, rivaroxaban, apixaban, and edoxaban, has altered the therapeutic landscape by offering targeted inhibition of specific coagulation factors, predictable pharmacokinetics, fewer interactions, and fixed dosing without the need for routine monitoring.^[1][2][3][4] DOACs have demonstrated non-inferiority or superiority to warfarin in prevention of stroke and systemic embolism in AF and in the treatment and secondary prevention of VTE. As a result, DOACs are now widely recommended as first-line oral anticoagulants in multiple international guidelines. Despite these advantages, substantial uncertainty persists regarding DOAC use in patient groups who were excluded or underrepresented in pivotal clinical trials. Large registration trials often limited enrollment based on renal function, liver disease, pregnancy, active malignancy, advanced age, body weight extremes, and concurrent therapies. Consequently, clinicians face challenges in interpreting whether trial outcomes can be extrapolated to high-risk patients commonly encountered in everyday practice. For instance, renal impairment markedly affects the pharmacokinetics of dabigatran and edoxaban due to their high rates of renal elimination, thereby increasing exposure and bleeding risk with standard dosing. ^[5][6] Similarly, hepatic dysfunction alters the metabolism and clearance of factor Xa inhibitors, while cancer patients present dynamic thrombotic and bleeding risks based on tumor biology, chemotherapy regimens, surgical requirements, and thrombocytopenia. Older adults, particularly those over 75 years, may have increased frailty, fall risk, sarcopenia, polypharmacy, and impaired renal function all of which contribute to dosing uncertainty. Additionally, pregnant women and children were excluded from landmark DOAC trials due to safety concerns, leading to continued reliance on LMWH in these groups. Pharmacists, as medication optimization specialists, have become increasingly visible in guiding DOAC therapy selection, dose adjustments, monitoring, counseling, and perioperative planning. Their knowledge of drug properties and patient-specific factors allows them to navigate complexities such as drug–drug interactions, renal function fluctuations, and dose modifications based on evolving clinical status. This review provides a detailed evaluation of current evidence on DOAC pharmacology, clinical outcomes, trial data, real-world registry analyses, and guideline recommendations across special populations. Particular attention is paid to:

• Renal impairment
• Hepatic dysfunction
• Frail elderly
• Cancer-associated thrombosis
• Extremes of body weight
• Pregnancy and lactation
• Pediatric patients
• Perioperative and periprocedural management
• Drug–drug interaction surveillance

Emerging innovations including factor XI inhibitors, pharmacogenomic applications, improved monitoring tools, artificial intelligence-driven risk prediction, and decentralized clinical trials are examined to illustrate future directions for personalized anticoagulation management.

Pharmacology Of DOACS

Direct oral anticoagulants differ from traditional anticoagulants in their molecular targets, pharmacodynamics, and pharmacokinetics. While warfarin inhibits multiple vitamin K–dependent clotting factors (II, VII, IX, X), DOACs exert selective inhibition at a single point in the coagulation cascade. Dabigatran directly inhibits thrombin (factor IIa), while apixaban, rivaroxaban, and edoxaban inhibit activated factor X (factor Xa). These targeted mechanisms enable fast onset of action, predictable-anticoagulation levels, and reduced need for routine coagulation testing. ^[1][2][3][4] The absorption, bioavailability, route of elimination, hepatic metabolism, and half-life differ substantially among DOACs, influencing their safety in organ dysfunction, drug interaction potential, and suitability in complex patient populations. For example, dabigatran is approximately 80% renally cleared, making renal impairment a major determinant of drug accumulation and bleeding risk. In contrast, apixaban has the lowest renal clearance (~27%), offering greater stability and safety in patients with deteriorating kidney function. ^[5][6] Dabigatran undergoes hepatic activation from its prodrug form and is a substrate for P-glycoprotein (P-gp). Rivaroxaban and apixaban undergo varying levels of hepatic metabolism via CYP3A4, meaning co-administration with strong inhibitors or inducers of CYP3A4 or P-gp can significantly affect serum concentrations.^[18][19]  Edoxaban is minimally metabolized by CYP enzymes and is also influenced by renal clearance, although its unique profile includes reduced efficacy at higher creatinine clearance (>95 mL/min), potentially due to insufficient drug exposure at very efficient renal filtration rates.^[4]  These pharmacokinetic variations are essential to clinical decision-making. In patients with severe renal impairment—including dialysis—dabigatran is generally contraindicated, while apixaban may be used with caution and dose reductions based on established criteria. In hepatic impairment, rivaroxaban is unsuitable in moderate to severe dysfunction, while apixaban may be used in mild impairment. In addition, food effects must be considered: rivaroxaban doses of 15–20 mg should be administered with food to ensure adequate absorption, while apixaban and dabigatran absorption are not significantly affected by meals. Beyond individual drug characteristics, DOACs offer advantages over VKAs due to: Rapid onset and offset of action, No routine INR monitoring, Lower rates of intracranial hemorrhage, Predictable dose-response relationships and Fewer dietary restrictions. However, their selectivity and reliance on renal or hepatic pathways also make them more sensitive to organ dysfunction, polypharmacy, and physiologic extremes, particularly among populations excluded from initial trials. Understanding each agent’s pharmacology is therefore a prerequisite to interpreting clinical data in these special settings.

Table 1. Pharmacokinetic Characteristics of Direct Oral Anticoagulants

Clinical Interpretation of Pharmacologic Differences:

Renal Implications

Dabigatran is largely renally cleared, making it high-risk in chronic kidney disease (CKD), with drug accumulation leading to increased bleeding potential. ^[5][6] Apixaban’s lower renal clearance makes it preferable in advanced CKD, including dialysis, where observational studies show lower bleeding compared to warfarin. ^[6] Rivaroxaban and edoxaban require caution but may be used in moderate kidney impairment with dose modifications.

Hepatic Metabolism

Apixaban and rivaroxaban are affected by CYP3A4 and P-gp activity, making them sensitive to strong inhibitors such as ketoconazole or ritonavir, and inducers such as rifampin. In hepatic dysfunction, reduced metabolism may heighten bleeding risk, meaning rivaroxaban should be avoided in Child–Pugh B and C disease, while apixaban may be used cautiously in Child–Pugh B.

Food Interactions

Rivaroxaban requires meal-time dosing at higher strengths, which can influence adherence. The other DOACs are food-independent.

Dosing Frequency and Adherence

Once-daily regimens (rivaroxaban, edoxaban) may improve adherence in some patients; however, twice-daily dosing (apixaban, dabigatran) may offer steadier pharmacodynamic exposure and lower peak–trough variability.

Drug–Drug Interactions

The primary interaction mechanisms involve CYP3A4 and P-gp. Apixaban generally has the fewest clinically significant interaction complications, making it preferred in patients with extensive polypharmacy.

Individualized Selection

Apixaban’s balanced clearance, safety profile, and robust clinical data make it the most versatile DOAC across special populations. Dabigatran may be avoided in patients with renal impairment or gastrointestinal sensitivity due to higher GI bleeding risk. Edoxaban’s unique reduced efficacy in high CrCl (>95 mL/min) is a distinguishing limitation. Rivaroxaban’s reliance on food coadministration and hepatic metabolism make its use more sensitive to adherence and hepatic status.

Role of Reversal Agents

All DOACs now have FDA- or conditionally-approved reversal pathways:

• Dabigatran: Idarucizumab (Praxbind) provides immediate factor IIa reversal.
• Factor Xa inhibitors: Andexanet alfa reverses apixaban and rivaroxaban, though availability and cost may limit use.
• Non-specific reversal options such as four-factor PCC remain valuable in many emergency settings.

These agents provide clinicians and pharmacists with greater confidence in DOAC selection, particularly among high bleeding risk populations.

Pharmacology of DOACs:

Direct oral anticoagulants selectively inhibit specific coagulation pathway targets and differ considerably in absorption, bioavailability, onset, metabolism, elimination, and drug–drug interaction profiles. Understanding these characteristics is critical for choosing the appropriate agent in special populations where physiologic changes may significantly alter drug exposure and safety.

Mechanism of Action

DOACs are divided into two categories:

1. Direct Thrombin Inhibitor (Dabigatran): Inhibits factor IIa (thrombin), preventing conversion of fibrinogen to fibrin and blocking thrombus propagation.
2. Direct Factor Xa Inhibitors (Apixaban, Rivaroxaban, Edoxaban): These drugs directly inhibit free and clot-bound factor Xa, reducing thrombin generation and fibrin formation.

Unlike warfarin, DOACs do not affect synthesis of clotting factors, allowing for rapid onset and offset of action.

Absorption and Bioavailability

• Dabigatran is administered as a prodrug requiring acidic gastric environment for absorption. Bioavailability is ~6–7%, making it more susceptible to absorption changes with proton pump inhibitors or gastric surgeries.
• Rivaroxaban has dose-dependent absorption; 15 mg and 20 mg doses require food to achieve adequate bioavailability.
• Apixaban maintains stable absorption independent of food intake.
• Edoxaban demonstrates consistent linear pharmacokinetics.

Protein Binding

High protein binding influences tissue distribution and dialyzability:

• Dabigatran: ~35%
• Rivaroxaban, apixaban, edoxaban: >85%

Consequently, dabigatran is the only DOAC that can be partially removed by dialysis.

Metabolism and Elimination

This variation greatly influences safety and dosing, particularly in Chronic kidney disease, Acute kidney injury, Cirrhosis or hepatic impairment and Drug–drug interaction risk.

Table 2. Key pharmacologic differences among DOACs

Clinical Implications

Why pharmacology matters in special populations

• Renal impairment: Dabigatran and edoxaban accumulate most quickly.
• Hepatic impairment: Rivaroxaban and apixaban may show altered metabolism.
• Elderly: Reduced volume of distribution and renal clearance increase exposure.
• Obesity: Larger distribution volume may decrease exposure; impact varies by agent.
• Pediatrics: Developmental physiology requires specialized dosing studies.
• Cancer patients: Polypharmacy and mucosal lesions affect both bleeding and efficacy.
• Pregnancy: Teratogenic concerns preclude use of DOACs due to placental transfer.

DOAC Use in Renal Impairment:

Chronic kidney disease (CKD) affects both thrombotic and bleeding risk due to changes in platelet function, uremic toxins, endothelial dysfunction, and reduced clearance of anticoagulants. Because renal excretion varies widely among DOACs, kidney function is one of the most important considerations when choosing and dosing therapy.

Impact of Renal Function on DOAC Pharmacokinetics

Renal clearance percentages: Dabigatran: ~80%, Edoxaban: ~50%, Rivaroxaban: ~35% and Apixaban: ~25%. Dabigatran shows the greatest accumulation in renal impairment. Apixaban is generally considered the preferred DOAC for most patients with moderate to severe CKD due to the smallest renal contribution.

Renal Assessment Methods

Dosing recommendations are typically based on Cockcroft–Gault creatinine clearance (CrCl), not eGFR. This distinction matters because of eGFR may overestimate kidney function in older adults and those with low muscle mass, Most FDA labeling, pivotal trials, and guideline recommendations use CrCl.

DOAC Use by CKD Stage:

CKD Stage 2–3 (CrCl 30–90 mL/min)

Most DOACs can be used with standard or slightly reduced dosing: Apixaban and rivaroxaban have strong clinical trial and real-world evidence in mild-to-moderate CKD, Dabigatran and edoxaban require dose reduction at the lower end of this range due to renal dependence. Randomized trials including RE-LY, ARISTOTLE, ENGAGE-AF, and ROCKET-AF consistently found: DOACs maintain comparable or improved efficacy vs. Warfarin, Major bleeding is generally lower with apixaban and edoxaban.

CKD Stage 4 (CrCl 15–29 mL/min)

This is where greater caution is required.

• Apixaban: Has the strongest support in Stage 4 CKD based on real-world studies showing similar stroke prevention and lower bleeding than warfarin. U.S. labeling allows reduced-dose apixaban (2.5 mg BID) in patients meeting dose-reduction criteria (age ≥80, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL).
• Rivaroxaban: May be used at reduced dosing (commonly 15 mg daily), but bleeding risk is higher compared to apixaban in several observational studies.
• Dabigatran: Usually avoided because of marked drug accumulation.
• Edoxaban: Reduced dosing permitted, though evidence is limited.

CKD Stage 5/Dialysis

This is the most controversial population because of Major clinical trials excluded end-stage renal disease (ESRD) patients. Warfarin has long been used but increases vascular calcification and intracranial bleeding risk.

• Apixaban: U.S. labeling allows use in dialysis patients. Several U.S. Medicare studies shows Standard dosing (5 mg BID) reduces stroke/systemic embolism more than reduced dosing. Lower rates of major bleeding vs. warfarin. As a result, apixaban is increasingly used for dialysis patients, but international guidelines differ.
• Rivaroxaban: Has limited evidence and is used less often.
• Dabigatran & edoxaban: Not recommended in ESRD because of high renal clearance.

Acute Kidney Injury (AKI):

AKI presents unique challenges because of DOAC accumulation can occur rapidly. Creatinine changes often lag behind real-time renal function. Patients may be receiving nephrotoxic medications or contrast dye. In AKI Switching temporarily to parenteral anticoagulation (e.g., unfractionated heparin) is common. Resuming DOAC therapy only after renal function stabilizes is preferred.

Monitoring in CKD

Although routine coagulation monitoring is not required, periodic lab assessment becomes essential in renal impairment, including Serum creatinine and CrCl (every 3–6 months, or more often if unstable), Haemoglobin/hematocrit for occult bleeding and Medication review for interacting agents For high-risk situations (e.g., overdose, emergency surgery), specialized tests may be used a Dabigatran: dilute thrombin time or ecarin clotting time and Xa inhibitors: calibrated anti–factor Xa activity assay. However, availability varies widely.

Reversal in CKD

• Dabigatran: Idarucizumab provides rapid reversal. Hemodialysis can also remove 50–60% of drug.
• Apixaban/rivaroxaban/edoxaban: Andexanet alfa is the specific reversal agent. Prothrombin complex concentrates (PCCs) may be used off-label.

Table 3. Summary of Recommendations in CKD

Hepatic Impairment:

Pathophysiology and Clinical Relevance

Liver disease causes complex hemostatic changes: reduced synthesis of both procoagulant and anticoagulant proteins, thrombocytopenia from splenic sequestration, and portal hypertension–related bleeding risks. Conventional laboratory tests (INR, PT) poorly reflect net bleeding/thrombotic balance in cirrhosis, complicating anticoagulant decisions. DOACs undergo varying degrees of hepatic metabolism and are therefore differentially affected by hepatic impairment both in exposure (drug levels) and bleeding risk. Clinical guidance typically stratifies recommendations by Child–Pugh class (A–C) because this correlates with metabolic capacity and clinical severity. ^[7][8]

Pharmacokinetic Considerations by Agent

• Apixaban: Partial hepatic metabolism (CYP3A4) but relatively low renal clearance (~27%), with favorable safety data in mild–moderate hepatic impairment. Studies suggest that apixaban exposure increases modestly in Child–Pugh A/B but remains within therapeutic range for many patients; caution is advised in Child–Pugh B and use is generally contraindicated in Child–Pugh C. ^[7][8]
• Rivaroxaban: Substantial hepatic metabolism; Child–Pugh B and C patients are at increased risk for elevated drug exposure and bleeding. Most guidelines advise avoiding rivaroxaban in Child–Pugh B and C. ^[7][8]
• Dabigatran: Minimal CYP metabolism; however, coexisting portal hypertension and impaired clearance (via renal rather than hepatic pathways) combined with mucosal fragility in cirrhotics may increase bleeding; use with caution in Child–Pugh A–B and avoid in C. ^[7][8]
• Edoxaban: Limited hepatic metabolism but insufficient safety data in moderate–severe hepatic impairment; generally, not recommended in Child–Pugh C. ^[7][8]

Evidence and Outcomes

High-quality randomized trials of DOACs largely excluded patients with advanced hepatic dysfunction. Observational and pharmacokinetic studies provide most current evidence:

• Pharmacokinetic analyses indicate dose-dependent increases in apixaban and rivaroxaban exposure in patients with impaired hepatic metabolism. ^[7]
• Real-world registry data suggest apixaban may be associated with a more favorable bleeding profile compared with warfarin in patients with compensated cirrhosis, though absolute bleeding risk remains elevated compared with non-cirrhotic populations. ^[8]
• A recent multi-center cohort study reported that DOACs (particularly apixaban) had similar thromboembolic protection and lower intracranial hemorrhage than warfarin in Child–Pugh A patients, but bleeding rates rose in Child–Pugh B and were highest in Child–Pugh C patients. ^[8]

Practical Recommendations

• Child–Pugh A (mild): DOACs may be used, with clinical vigilance and close monitoring of liver function and bleeding signs. Apixaban and rivaroxaban are acceptable options.
• Child–Pugh B (moderate): Apixaban can be considered with caution; rivaroxaban is typically avoided. Dose reduction is not well-established clinical judgment, consultation with hepatology, and individualized risk assessment are essential.
• Child–Pugh C (severe): DOACs are generally contraindicated due to unpredictable metabolism and high bleeding risk; VKA or parenteral anticoagulation with specialist input may be alternatives depending on indication.

Table 4. DOAC Suitability in Hepatic Impairment

Elderly Patients:

Why the Elderly Are a Special Population

Aging is accompanied by physiologic changes (reduced renal function, decreased hepatic mass and blood flow, altered body composition) and higher prevalence of comorbidities and polypharmacy that influence DOAC pharmacokinetics and pharmacodynamics. Frailty, fall risk, and dysphagia may also affect adherence and safety. Given that stroke risk attributable to AF increases sharply with age, anticoagulation decisions in older adults balance stroke prevention against bleeding risk. ^{[9] [11]}

Evidence Base

• Large trials and post-hoc analyses (e.g., ARISTOTLE for apixaban, RE-LY for dabigatran, ROCKET-AF for rivaroxaban, ENGAGE-AF for edoxaban) included older adults but were often underpowered for frail subgroups. ^[1][2][3][4]
• Observational cohorts and Medicare-based analyses indicate that apixaban offers a favorable net clinical benefit in older adults with lower rates of major bleeding and intracranial hemorrhage compared with warfarin; dabigatran showed higher GI bleeding in some elderly cohorts. ^[9]
• Dose reduction strategies (e.g., apixaban 2.5 mg BID when ≥80 years plus low weight or elevated creatinine) are evidence-based and reduce bleeding without compromising efficacy when criteria are applied correctly. ^{[9] [11]}

Practical Considerations

• Renal function: Use Cockcroft–Gault to guide dosing. Age-related decline in creatinine production may mask reduced renal function if relying solely on eGFR.
• Polypharmacy: Screen for interacting drugs (strong P-gp/CYP3A4 inhibitors and inducers).
• Falls and frailty: A history of falls alone is insufficient to withhold anticoagulation for most patients; the absolute stroke prevention benefit often outweighs fall-related hemorrhage risk. Shared decision-making is crucial.
• Adherence and dosing: Twice daily regimens may improve steady-state levels but may be harder for some patients to adhere to; tailor selection to patient capacity and caregiver support.

Clinical Recommendations

• Apixaban is generally preferred in the elderly due to lower intracranial hemorrhage and better overall safety.
• Dose reductions should follow product labeling and patient characteristics (age, weight, renal function).
• Close follow-up (clinical and laboratory) within 1–3 months of initiation is recommended to reassess renal function, adherence, and bleeding signs.

Cancer-Associated Thrombosis (CAT):

Clinical Complexity in Cancer

Cancer creates a prothrombotic milieu through tumor cell procoagulant release, endothelial activation, immobility, central venous catheters, and systemic therapies. Conversely, bleeding risk increases due to tumor invasion of mucosa, thrombocytopenia from chemotherapy, and concurrent procedures. Historically, LMWH (dalteparin, enoxaparin) was the standard of care for CAT because trials demonstrated superiority to VKAs. However, more recent randomized studies have evaluated DOACs versus LMWH, expanding options for many patients. ^{[10] [11][12]}

Key Trials and Outcomes

• Hokusai-VTE Cancer (edoxaban vs dalteparin) ^[10]: Edoxaban demonstrated non-inferiority to dalteparin for recurrent VTE but had higher rates of major bleeding—particularly in patients with gastrointestinal (GI) cancers. Clinical implication: edoxaban is an option but caution is required in GI malignancies due to mucosal bleeding risk.
• SELECT-D (rivaroxaban vs dalteparin) ^[11]: Rivaroxaban reduced recurrent VTE but showed increased clinically relevant non-major bleeding and GI bleeding in patients with GI tumors. Clinical implication: rivaroxaban can be considered, especially in lower-bleeding-risk malignancies, but avoid in active GI lesions.
• ADAM-VTE & CARAVAGGIO (apixaban vs dalteparin) ^[12]: ADAM-VTE and CARAVAGGIO showed low major bleeding rates with apixaban and non-inferior efficacy compared with dalteparin; apixaban performed particularly well in non–GI cancers. Clinical implication: apixaban has emerged as a preferred DOAC in many non-GI cancer patients with VTE due to favorable bleeding profile.

Practical Application and Guidelines

• Non-GI cancers: Apixaban (and in some contexts rivaroxaban/edoxaban) represent reasonable alternatives to LMWH for treatment of CAT. Apixaban often favored for its lower bleeding signal.
• GI or genitourinary cancers: Use DOACs cautiously. Many guidelines advise LMWH as first-line in active mucosal tumors or when the bleeding risk is high. If DOACs are used, close surveillance and shared decision-making are essential.
• Thrombocytopenia: For platelet counts <50 ×10^9/L, anticoagulation strategy should be individualized; temporary dose reductions or holding therapy may be required.
• Drug–drug interactions: Cancer therapies (e.g., tyrosine kinase inhibitors, certain chemotherapeutics) frequently interact with CYP3A4 or P-gp pathways; pharmacy review is mandatory.

Duration of Therapy

For most cancer-associated VTE events, at least 6 months of anticoagulation is recommended, with continuation beyond 6 months considered while cancer is active or ongoing treatment persists. Decisions should reflect bleeding risk, cancer status, and patient preference.

Special Considerations

• Drug absorption: GI surgeries, mucositis, vomiting, or malabsorption can affect oral DOAC levels; LMWH may be preferred if absorption is unreliable.
• Renal/hepatic impairment: Coexisting organ dysfunction requires dose adjustments or alternative agents.
• Use in central venous catheter thrombosis: LMWH or DOACs may be used; data are limited and individualized strategies required.

Obesity and Extremes of Body Weight:

Background and Rationale

Obesity and extremes of body weight present important pharmacokinetic and pharmacodynamic challenges for DOAC therapy. Increased body mass can expand the volume of distribution and increase renal clearance relative to lean body weight, potentially reducing plasma concentrations and therapeutic exposure. Conversely, very low body weight can increase exposure and bleeding risk. Landmark DOAC trials included relatively few patients at weight extremes, prompting guideline statements and registry analyses to guide practice. ^{[13] [14]}

Evidence Summary

• Pharmacokinetic studies show that apixaban and rivaroxaban retain acceptable trough and peak concentrations in many obese patients, whereas dabigatran and edoxaban may have reduced exposure or variable outcomes in extreme obesity. Based on pooled data and pharmacokinetic modeling, international consensus (ISTH) has advised caution for DOACs in patients with BMI >40 kg/m² or weight >120 kg, recommending preferential use of apixaban or rivaroxaban when a DOAC is chosen. ^[13]
• Observational and registry studies generally report comparable efficacy (prevention of stroke or VTE recurrence) with apixaban and rivaroxaban versus VKAs in obese patients, although the evidence remains less robust than for normal-weight cohorts. ^[14]
• Anti–factor Xa levels calibrated to each DOAC may be used in selected situations to confirm therapeutic exposure, but target ranges are incompletely standardized and assay availability varies.

Practical Recommendations

• BMI ≤40 kg/m² / weight ≤120 kg: Standard DOAC dosing per indication is generally acceptable.
• BMI >40 kg/m² or weight >120 kg: Prefer apixaban (favored overall) or rivaroxaban if a DOAC is selected; avoid routine use of dabigatran or edoxaban unless therapeutic drug monitoring is available and interpreted by an experienced anticoagulation specialist.
• Consider measuring calibrated anti–Xa levels (for factor Xa inhibitors) in patients with extreme body weight when clinical concern exists (e.g., recurrent thrombosis while on therapy or major bleeding with no clear cause). Interpret results cautiously and with pharmacology consult input.
• Review adherence and absorption factors (e.g., bariatric surgery can alter absorption of oral drugs, favoring parenteral anticoagulation or careful monitoring).

Pregnancy and Lactation:

Pregnancy is a hypercoagulable state with increased venous thromboembolism risk, but fetal safety is paramount. DOACs cross the placenta to varying degrees and lack comprehensive teratogenicity data; thus, they are not recommended for routine use in pregnancy. Low-molecular-weight heparin (LMWH) remains the standard of care for VTE treatment and prophylaxis during pregnancy due to its safety profile (does not cross the placenta) and extensive human experience. ^[15]

Evidence and Safety Concerns

• Case reports and small retrospective series have documented fetal exposure with DOACs and occasional adverse outcomes; however, data are insufficient to establish safety. ^[15] DOACs are currently categorized as contraindicated or not recommended in pregnancy by most expert bodies.
• Breastfeeding data are limited; some DOACs appear in breast milk at low levels, but safety for neonates is not well established. LMWH is preferred during lactation when anticoagulation is required.

Practical Recommendations

• Pregnancy: Avoid DOACs. Use LMWH for prophylaxis and treatment of VTE. Transition women on DOACs to LMWH prior to conception or upon pregnancy confirmation. If an unplanned DOAC exposure occurs in early pregnancy, involve maternal-fetal medicine and hematology for individualized counseling and risk assessment.
• Breastfeeding: Prefer LMWH or warfarin if oral therapy is required and breastfeeding will continue; warfarin is compatible with breastfeeding in many cases under specialist guidance.

PEDIATRICS:

Overview and Evidence

Pediatric hemostasis differs from adults; developmental pharmacokinetics necessitate age- and weight-appropriate dosing studies. Recent trials have begun to evaluate DOACs in children most notably EINSTEIN Jr for rivaroxaban demonstrating acceptable safety and efficacy in selected pediatric populations, but DOAC use in children should be guided by pediatric hematology expertise. ^[16]

Practical Recommendations

• Use pediatric-specific trial data and dosing algorithms when available (e.g., rivaroxaban dosing by weight bands from EINSTEIN Jr).
• In neonates and very young infants, LMWH remains a common standard due to extensive experience and predictable dosing via weight-based protocols.
• Follow-up in pediatric anticoagulation clinics is essential to monitor growth-related dose adjustments, adherence, and bleeding complications.

Perioperative and Periprocedural Management:

General Principles

DOACs simplify perioperative management relative to warfarin due to rapid onset/offset and predictable pharmacokinetics. Key considerations include procedural bleeding risk, renal function, DOAC half-life, and urgency of the procedure. ^[17]

Interruption Timing Based on Bleeding Risk and Renal Function

• Low bleeding-risk procedures: Hold DOACs for 24 hours prior to the procedure if renal function is normal.
• High bleeding-risk procedures: Hold DOACs 48–72 hours prior, with longer interruption for impaired renal function or dabigatran due to renal clearance.
• Renal impairment: Extend interruption interval proportionally (e.g., dabigatran in CrCl <50 mL/min may require 48–72 hours).
• Urgent procedures: Use reversal agents where indicated (idarucizumab for dabigatran; andexanet alfa for factor Xa inhibitors when available) or employ non-specific reversal (PCC) as per institutional protocols.

Bridging Anticoagulation

Routine bridging with heparin is not required for most patients on DOACs. Bridging may be considered in circumstances with very high thromboembolic risk (e.g., mechanical heart valves though DOACs are contraindicated in mechanical valves) or recent VTE in the first month after event, but such decisions should be individualized and involve multidisciplinary input.

Restarting Anticoagulation

• Low bleeding-risk procedures: Resume DOACs 24 hours post-procedure if hemostasis is secure.
• High bleeding-risk procedures: Resume 48–72 hours post-procedure, assessing hemostasis and ongoing bleeding risk.
• Gastrointestinal or neurosurgical procedures: Resume only after multidisciplinary agreement on acceptable bleeding risk.

Drug–Drug Interactions:

Mechanisms and High-Risk Interactions

DOACs are primarily subject to interactions via P-glycoprotein (P-gp) transport and CYP3A4 metabolism (apixaban and rivaroxaban most affected). Clinically significant interactions fall into two categories:

1. Inhibitors that increase DOAC exposure (↑ bleeding risk): Strong dual CYP3A4/P-gp inhibitors: ketoconazole, itraconazole, ritonavir, cobicistat. Certain macrolide antibiotics (clarithromycin). Amiodarone and verapamil (P-gp inhibitors) may increase levels dose adjustments or caution advised.
2. Inducers that decrease DOAC exposure (↑ thrombotic risk): Rifampin, carbamazepine, phenytoin, phenobarbital.

Cancer therapies, antiretrovirals, and antifungal agents are particular concerns. Antiplatelet agents (aspirin, P2Y12 inhibitors) and NSAIDs increase bleeding risk when combined with DOACs, though combinations may be clinically necessary (e.g., post-PCI in AF). In these cases, multidisciplinary balancing of bleeding versus ischemic risk and use of the shortest effective duration of combination therapy is recommended. ^{[18] [19]}

Practical Management Strategies

• Medication reconciliation at every clinical encounter identify strong inhibitors/inducers and modify therapy where possible.
• Dose adjustments according to product labeling when co-administered with interacting agents. For example, concomitant use of strong P-gp inhibitors with dabigatran may require dose reductions or avoidance.
• Alternative strategies such as switching to an agent with less interaction potential (e.g., apixaban) or using LMWH in patients on potent interacting therapies.
• Therapeutic drug monitoring (anti–Xa assays) may be helpful in certain complex interaction scenarios but is not standardized.

Table 5. Preferred DOACs by Special Population