Acenocoumarol (DB01418): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Acenocoumarol is a potent, orally administered anticoagulant belonging to the 4-hydroxycoumarin class of Vitamin K antagonists (VKAs). Structurally a nitro-derivative of warfarin, it functions through the competitive inhibition of the Vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby impairing the synthesis of active coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S. This monograph provides an exhaustive analysis of its chemical properties, pharmacology, pharmacokinetics, clinical applications, and safety profile.

Characterized by rapid absorption and a short elimination half-life of 8 to 11 hours, Acenocoumarol presents a distinct pharmacokinetic profile compared to other VKAs, notably warfarin. Its administration as a racemic mixture of R(+) and S(-) enantiomers, which undergo highly stereoselective metabolism primarily via the cytochrome P450 2C9 (CYP2C9) enzyme, introduces significant complexity. This metabolic pathway is the foundation for its narrow therapeutic index and the substantial inter-individual variability in dose response. This variability is largely attributable to common genetic polymorphisms in the CYP2C9 and VKORC1 genes, which profoundly alter drug clearance and sensitivity, respectively, and form a strong basis for pharmacogenomic-guided dosing strategies to mitigate the high risk of hemorrhagic complications.

Clinical management of Acenocoumarol therapy is critically dependent on frequent and regular monitoring of the International Normalized Ratio (INR) to maintain the delicate balance between therapeutic efficacy and the risk of bleeding. The primary adverse effect is hemorrhage, which can range from minor to life-threatening. The drug is contraindicated in pregnancy due to established teratogenicity.

Comparative clinical data challenge long-held assumptions regarding VKA therapy. Recent, large-scale real-world evidence suggests Acenocoumarol may possess a more favorable efficacy and safety profile than warfarin. When compared to Direct Oral Anticoagulants (DOACs), Acenocoumarol presents a nuanced risk-benefit profile. While DOACs offer a clear and significant advantage in reducing the risk of intracranial hemorrhage, they do not demonstrate uniform superiority in preventing thromboembolic events and are associated with a lower risk of all-cause mortality. This positions Acenocoumarol as a clinically relevant anticoagulant whose selection requires a personalized assessment of a patient's specific thrombotic and hemorrhagic risk profile, genetic makeup, and capacity for adherence to a rigorous monitoring regimen.

Section 1: Chemical Identity and Physicochemical Properties

1.1 Nomenclature and Identifiers

The definitive identification of a pharmaceutical substance is foundational to its study and safe clinical use, enabling precise cross-referencing across global chemical, pharmacological, and regulatory databases. Acenocoumarol is recognized by a standardized set of names and unique identifiers.[1]

• Generic Name: Acenocoumarol [1]
• Systematic (IUPAC) Name: (RS)-4-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-chromen-2-one [1]
• Chemical Abstracts Service (CAS) Number: 152-72-7 [1]
• DrugBank Accession Number: DB01418 [1]
• Anatomical Therapeutic Chemical (ATC) Code: B01AA07 [1]

In addition to these primary identifiers, Acenocoumarol is cataloged in numerous other databases, including PubChem (CID: 9052), UNII (I6WP63U32H), KEGG (D07064), and ChEBI (CHEBI:53766).[1]

The drug is marketed globally under a wide array of brand names and synonyms. The most common synonyms are Nicoumalone and Acenocoumarin.[2] Prominent brand names include Sintrom and Sinthrome, which are widely recognized in European and other international markets.[2] Other notable brand names include Acitrom (India), Trombostop (Romania), and Syncumar (Russian Federation), reflecting its generic availability and widespread use.[2]

1.2 Chemical Structure and Stereochemistry

The pharmacological properties of Acenocoumarol are a direct consequence of its molecular structure and stereochemistry.

• Molecular Formula: C19​H15​NO6​ [1]
• Molar Mass: 353.330 g·mol⁻¹ [1]

Structurally, Acenocoumarol is a 4-hydroxycoumarin derivative. Its chemical definition provides a crucial comparative anchor: it is warfarin in which the hydrogen atom at the para (4') position of the phenyl substituent is replaced by a nitro group (NO2​).[2] This single, specific modification is the origin of the distinct pharmacokinetic and, to some extent, pharmacodynamic properties that differentiate Acenocoumarol from its parent compound, warfarin. Its synthesis is analogous to that of warfarin, utilizing 4-nitrobenzalacetone in place of benzalacetone as a key reactant with 4-hydroxycoumarin.[11]

Standardized textual representations of its structure include:

• SMILES: CC(=O)CC(C1=CC=C(C=C1)[N+](=O)[O-])C2=C(OC3=CC=CC=C3C2=O)O [1]
• InChIKey: VABCILAOYCMVPS-UHFFFAOYSA-N [1]

A critical structural feature of Acenocoumarol is its chirality. The molecule possesses a single stereocenter at the benzylic carbon of the side chain, meaning it exists as a pair of enantiomers. Clinically, Acenocoumarol is manufactured and administered as a racemic mixture of the R(+) and S(-) enantiomers.[1] This is not a trivial characteristic; the body interacts with these two enantiomers as distinct chemical entities, each with its own metabolic fate and, importantly, differing anticoagulant potency.[13] This stereoisomerism is a fundamental source of the drug's complex pharmacokinetic profile and a key factor in the clinical impact of pharmacogenomic variations, as will be detailed in subsequent sections.

1.3 Physicochemical Characteristics

The physical and chemical properties of Acenocoumarol influence its formulation as an oral solid dosage form, its behavior in biological systems, and its handling in laboratory settings.

• Appearance: It is a white to tan crystalline solid or powder.[5]
• Melting Point: The melting point is in the range of 196 to 199 °C.[1]
• Solubility: Acenocoumarol is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), but is sparingly soluble in aqueous buffers.[11] This property necessitates the use of organic solvents for preparing stock solutions for in vitro research.
• Drug-Likeness Profile: An analysis of its physicochemical properties in the context of Lipinski's Rule-of-Five, a predictor of oral bioavailability, is favorable. With a molecular weight of 353.09, one hydrogen bond donor, two hydrogen bond acceptors, five rotatable bonds, and an XLogP of 3.49, it meets the criteria for a "drug-like" molecule with good potential for oral absorption and membrane permeability.[6] This theoretical profile is consistent with the observed rapid oral absorption and high bioavailability in clinical practice.

The following table provides a consolidated summary of the key identifiers and physicochemical properties of Acenocoumarol.

Property	Value	Source(s)
IUPAC Name	(RS)-4-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-chromen-2-one	1
CAS Number	152-72-7	1
DrugBank ID	DB01418	1
Molecular Formula	C19​H15​NO6​	1
Molar Mass	353.330 g·mol⁻¹	1
Chirality	Racemic Mixture (R/S)	1
Appearance	White to tan crystalline solid	11
Melting Point	196 - 199 °C	1
SMILES	CC(=O)CC(C1=CC=C(C=C1)[N+](=O)[O-])C2=C(OC3=CC=CC=C3C2=O)O	1
InChIKey	VABCILAOYCMVPS-UHFFFAOYSA-N	1

Section 2: Pharmacology and Mechanism of Action

2.1 Drug Classification and Therapeutic Category

Acenocoumarol is classified pharmacologically as an anticoagulant agent.[1] It belongs to the chemical class of coumarin derivatives, specifically the 4-hydroxycoumarins.[2] Its mechanism of action places it in the therapeutic sub-category of Vitamin K antagonists (VKAs).[1] Within the World Health Organization's Anatomical Therapeutic Chemical (ATC) classification system, it is assigned the code B01AA07, under the parent group B01AA (Vitamin K antagonists).[1]

2.2 Primary Molecular Target: Vitamin K Epoxide Reductase (VKORC1)

The therapeutic effect of Acenocoumarol is mediated through its specific interaction with a single primary molecular target. This target is the Vitamin K epoxide reductase complex subunit 1 (VKORC1), an integral membrane protein located in the endoplasmic reticulum.[12] Acenocoumarol functions as a potent, competitive inhibitor of this enzyme.[12] In vitro studies have quantified this inhibitory activity, demonstrating a half-maximal inhibitory concentration (

IC50​) of 1.5 nM for VKORC1, indicating high-affinity binding.[18] The structural similarity between the coumarin core of Acenocoumarol and Vitamin K allows it to bind to the enzyme's active site, thereby preventing the enzyme from performing its physiological function.[12]

2.3 Pharmacodynamics: Inhibition of the Vitamin K Cycle and Coagulation Cascade

The inhibition of VKORC1 by Acenocoumarol initiates a cascade of downstream pharmacodynamic effects that culminate in systemic anticoagulation. The mechanism is centered on the disruption of the Vitamin K cycle, a critical metabolic pathway for hemostasis.

VKORC1 is responsible for the regeneration of the active, reduced form of Vitamin K (Vitamin K hydroquinone, KH2​) from its inactive, oxidized form (Vitamin K epoxide).[21] By inhibiting VKORC1, Acenocoumarol leads to a progressive depletion of the intracellular pool of

KH2​.[11]

This depletion of active Vitamin K has a profound impact because KH2​ is an essential cofactor for the enzyme gamma-glutamyl carboxylase.[21] This enzyme catalyzes a crucial post-translational modification: the gamma-carboxylation of specific glutamate (Glu) residues near the N-terminus of several key proteins, converting them to gamma-carboxyglutamate (Gla) residues.[2]

The proteins dependent on this modification include the pro-coagulant clotting factors II (prothrombin), VII, IX, and X.[2] The Gla residues act as calcium-binding sites, which are necessary for the factors to adopt their correct conformation, bind to phospholipid surfaces (such as on activated platelets), and participate effectively in the coagulation cascade.[21] Without adequate gamma-carboxylation, the liver continues to synthesize these protein precursors, but they are biologically inactive or have severely impaired function. These are often referred to as PIVKAs (Proteins Induced by Vitamin K Absence or Antagonism).

This blockade of coagulation factor activation ultimately leads to a dose-dependent decrease in prothrombin levels, a reduction in the rate and amount of thrombin generation, and the formation of a less stable fibrin clot, thereby reducing the thrombogenicity of blood.[11]

This mechanism inherently explains the characteristic delay in the onset of Acenocoumarol's therapeutic effect. The drug does not inactivate or destroy existing, fully carboxylated clotting factors already present in the circulation. Instead, it prevents the synthesis of new, functional ones. The clinical anticoagulant effect only becomes apparent as the pre-existing factors are naturally cleared from the plasma, a process governed by their respective biological half-lives. Factor VII has the shortest half-life (approx. 4-6 hours), while Factor II (prothrombin) has the longest (approx. 60-72 hours). Consequently, the full anticoagulant effect of Acenocoumarol is not immediate, becoming apparent within 24 to 48 hours and reaching its maximum effect within 36 to 72 hours.[17] This delay has a critical clinical implication: for patients requiring immediate anticoagulation for acute thromboembolic events, therapy must be initiated with a rapid-acting parenteral anticoagulant, such as heparin or low-molecular-weight heparin. This "bridging" therapy provides immediate protection while the oral VKA's effect gradually develops until the INR reaches the therapeutic target.[17]

Furthermore, the mechanism of action extends to Vitamin K-dependent anticoagulant proteins, namely Protein C and Protein S.[2] The synthesis of these natural inhibitors of coagulation is also impaired by Acenocoumarol. This creates a complex and clinically significant phenomenon at the initiation of therapy. Protein C has a relatively short half-life (approx. 6-8 hours), shorter than most of the pro-coagulant factors it regulates (especially Factor II). As a result, upon starting Acenocoumarol, the levels of anticoagulant Protein C can fall more rapidly than the levels of pro-coagulant factors. This can lead to a transient, paradoxical prothrombotic or hypercoagulable state in the first few days of treatment, before the full anticoagulant effect is established. This transient imbalance is the underlying pathophysiological mechanism for the rare but severe adverse reaction of coumarin-induced skin necrosis, which involves microthrombosis in the dermal capillaries. The risk is significantly elevated in patients with an underlying, often undiagnosed, hereditary deficiency of Protein C or Protein S.[29] This phenomenon further underscores the importance of heparin bridging, which provides continuous anticoagulation during this vulnerable initial period.

Section 3: Pharmacokinetics and Metabolism

The clinical utility and challenges of Acenocoumarol are largely dictated by its pharmacokinetic profile, which governs its absorption, distribution, metabolism, and excretion (ADME).

3.1 Absorption, Distribution, and Protein Binding

Acenocoumarol is formulated for oral administration and exhibits favorable absorption characteristics.

• Absorption and Bioavailability: It is rapidly absorbed from the gastrointestinal tract following oral intake, with a systemic bioavailability of at least 60%.[13]
• Time to Peak Concentration (Tmax​): Peak plasma concentrations are typically reached within 1 to 3 hours after a single oral dose, indicating a rapid onset of absorption.[13]
• Distribution: The apparent volume of distribution (Vd​) at steady-state has been noted to be dose-dependent, though it is generally small, consistent with a drug that is largely confined to the vascular compartment.[21]
• Protein Binding: Acenocoumarol is extensively bound to plasma proteins, with a bound fraction of 98% to 98.7%.[13] The primary binding protein is albumin.[21]

This high degree of protein binding is a critical pharmacokinetic feature. Only the small, unbound (free) fraction of the drug is pharmacologically active and available to diffuse into hepatocytes to exert its effect on VKORC1. This creates a high potential for clinically significant drug-drug interactions based on protein binding displacement. When another drug that also binds strongly to albumin is co-administered, it can compete for binding sites and displace Acenocoumarol. This displacement increases the free fraction of Acenocoumarol in the plasma. Even a minor change in the bound percentage (e.g., from 98.7% to 97.4%) can result in a doubling of the free, active drug concentration (from 1.3% to 2.6%), leading to a sudden and potentially dangerous potentiation of the anticoagulant effect and an increase in the INR, without any change in the total measured drug concentration.

3.2 Metabolism: The Central Role of CYP2C9 and Stereoselective Biotransformation

The elimination of Acenocoumarol from the body is almost entirely dependent on hepatic metabolism.[1]

• Site and Pathways: It is extensively biotransformed in the liver into pharmacologically inactive metabolites.[1] The major metabolic pathways include oxidation to form hydroxy metabolites (6- and 7-hydroxylation of both enantiomers) and keto reduction of the side chain to produce two alcohol metabolites.[13]
• Primary Enzyme System: The cytochrome P450 (CYP) enzyme system is responsible for this metabolism. Specifically, CYP2C9 has been unequivocally identified as the predominant isoenzyme involved in the clearance of Acenocoumarol.[12]
• Minor Enzyme Contributions: Other CYP isoenzymes, including CYP1A2 and CYP2C19, play minor roles in its metabolism.[12] Acenocoumarol is thus considered a substrate for CYP2C9 (major), CYP1A2 (minor), and CYP2C19 (minor).[12]

The metabolism of Acenocoumarol is highly stereoselective, a direct consequence of its administration as a racemic mixture. The two enantiomers, R(+) and S(-), are handled very differently by the hepatic enzymes. Studies have shown that the total plasma clearance of the S(-) enantiomer is approximately 10 times greater than that of the R(+) enantiomer.[15] This differential clearance is primarily driven by CYP2C9, which is the principal catalyst for the metabolism of the S-enantiomer.[30] In contrast, the pharmacokinetics of the R-enantiomer are not significantly affected by variations in CYP2C9 activity.[33] This stereoselectivity is of paramount clinical importance because the enantiomers also differ in potency, and any factor affecting CYP2C9 will disproportionately impact the clearance of the more potent enantiomer.

3.3 Elimination and Half-Life

The metabolic processes described above lead to the elimination of the drug from the body.

• Elimination Half-Life (t1/2​): Acenocoumarol is characterized by a short elimination half-life, which for the racemate ranges from 8 to 11 hours.[1]
• Enantiomer-Specific Half-Lives: Reflecting the differences in clearance, the apparent elimination half-life of the rapidly cleared S(-) enantiomer is much shorter than that of the R(+) enantiomer.[15] For example, in individuals with normal CYP2C9 function, the half-life of the S-enantiomer can be as short as 1.0 hour, whereas this can be prolonged to 2.0 hours in individuals with a reduced-function CYP2C9*3 variant.[33]
• Excretion: Following extensive metabolism, the inactive metabolites are excreted from the body. Approximately 60% of an administered dose is recovered in the urine, and about 29% is excreted in the feces.[13]

The combination of a short overall half-life and highly variable, enantiomer-specific metabolic clearance creates a "brittle" pharmacokinetic profile. This means that plasma concentrations of the active drug can fluctuate significantly within a 24-hour dosing interval and are highly sensitive to factors such as missed doses, interacting medications, or genetic variations in metabolism. This inherent pharmacokinetic instability is a key mechanistic explanation for the clinical challenges associated with maintaining a stable INR in some patients treated with Acenocoumarol, and it contrasts sharply with the more buffered, stable plasma concentrations provided by longer-acting VKAs like warfarin.

3.4 Dose-Proportionality and Linearity

Despite its complex metabolism, the pharmacokinetics of Acenocoumarol behave in a predictable, linear fashion across the clinically relevant dose range. Studies have demonstrated that the drug exhibits dose-proportional pharmacokinetics, meaning that key exposure parameters, such as the area under the plasma concentration-time curve (AUC), increase proportionally with the administered dose. This linearity has been confirmed for doses ranging from 1 mg to 16 mg.[13]

The table below summarizes the key pharmacokinetic parameters for Acenocoumarol.

Parameter	Value / Description	Source(s)
Bioavailability	≥ 60%	13
Time to Peak (Tmax​)	1 - 3 hours	13
Protein Binding	98 - 98.7% (to albumin)	13
Volume of Distribution (Vd​)	Dose-dependent, small	21
Primary Metabolizing Enzyme	Cytochrome P450 2C9 (CYP2C9)	30
Minor Metabolizing Enzymes	CYP1A2, CYP2C19	12
Elimination Half-life (t1/2​)	8 - 11 hours (racemate)	1
Excretion	~60% in urine, ~29% in feces (as metabolites)	13

Section 4: Clinical Pharmacology and Therapeutic Use

4.1 Approved Clinical Indications

Acenocoumarol is a cornerstone therapy for the management of conditions where pathological thrombosis is a primary concern. Its approved clinical indications are centered on the treatment and prevention of thromboembolic diseases.[21] Specific, well-established uses include:

• Venous Thromboembolism (VTE): For the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the secondary prevention (prophylaxis) of their recurrence.[17]
• Atrial Fibrillation (AF): For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation who are at an increased risk of thromboembolic events.[17]
• Other Cardiovascular Conditions: As an adjunctive therapy in the treatment of coronary occlusion (myocardial infarction) and for the prevention of thromboembolism associated with transient ischemic attacks (TIAs).[17] It is also used for long-term anticoagulation in patients with mechanical prosthetic heart valves.[36]

The use of Acenocoumarol in these conditions is supported by data from clinical trials, including completed Phase 3 trials for pulmonary embolism and atrial fibrillation, and Phase 4 trials for coagulation disorders.[37]

4.2 Dosing and Administration

The clinical management of Acenocoumarol therapy is a highly individualized process, dictated by the drug's narrow therapeutic index and the wide inter-patient variability in dose response. The guiding principle is to titrate the dose based on frequent monitoring of its anticoagulant effect.[17]

4.2.1 Initiation and Loading Dose Regimens

The initiation of therapy requires careful consideration of the patient's baseline coagulation status and clinical characteristics.

• Standard Initiation: If the patient's pre-treatment prothrombin time (PT) or International Normalized Ratio (INR) is within the normal range, the usual starting dose is 2 mg to 4 mg per day, administered without a loading dose.[27]
• Loading Dose Regimen: An alternative approach, particularly in a hospital setting, is to initiate therapy with a loading dose, typically 6 mg on the first day followed by 4 mg on the second day, to more rapidly achieve a therapeutic level of anticoagulation.[27]
• Special Populations: Dose adjustments are critical in certain populations. Elderly patients (≥65 years), patients with hepatic impairment, severe heart failure with hepatic congestion, or those who are malnourished are often more sensitive to the effects of Acenocoumarol. In these individuals, therapy should be initiated with lower doses and managed with increased caution.[19]

4.2.2 Maintenance Therapy and Dose Titration

Once initiated, the dose of Acenocoumarol must be continuously adjusted to maintain the patient's INR within a specific therapeutic range.

• Maintenance Dose: The daily maintenance dose varies widely among individuals, generally ranging from 1 mg to 8 mg.[27]
• Therapeutic Range: The target INR is determined by the clinical indication. For most conditions, such as VTE and atrial fibrillation, the therapeutic range is an INR of 2.0 to 3.0.[28] For higher-risk conditions, such as mechanical heart valves, a higher target range of 2.5 to 3.5, or even up to 4.5 in some cases, may be required.[27]
• Administration: To ensure stable plasma concentrations, the total daily dose should be taken as a single dose at the same time each day. The tablet should be swallowed whole with a glass of water and can be taken with or without food, though consistency is recommended.[27]

4.3 Patient Monitoring: The International Normalized Ratio (INR)

The entire clinical management framework for Acenocoumarol is built upon the regular and precise measurement of its anticoagulant effect using the INR. This is not merely a procedural step but a direct consequence of the drug's pharmacological properties. The narrow therapeutic window, where sub-therapeutic levels lead to thrombosis and supra-therapeutic levels lead to hemorrhage, combined with the high inter-individual variability in response, makes fixed-dose therapy impossible and dangerous. The INR provides the necessary feedback loop to navigate this challenge safely.

• Mandatory Monitoring: Regular monitoring of the PT/INR is an absolute requirement for any patient on Acenocoumarol therapy.[2]
• Frequency of Monitoring:
• Initiation Phase: During the initial phase of treatment, monitoring must be frequent, often daily or every other day, until the INR is stable within the target range.[27]
• Maintenance Phase: Once a stable maintenance dose is established, the interval between tests can be gradually extended. However, monitoring should continue at regular intervals, typically every 4-6 weeks, for the duration of therapy.[27]
• Patient Education: A critical component of successful therapy is comprehensive patient education. Patients must understand the importance of strict adherence to their prescribed dose, the necessity of regular INR testing, and the need to maintain a consistent diet, particularly with respect to Vitamin K intake. They must also be taught to recognize the signs and symptoms of both bleeding and thrombosis and to report any falls, injuries, or changes in their medications or health status to their healthcare provider immediately.[40] Patients are often provided with an "Anticoagulant Alert Card" to carry at all times, which informs emergency medical personnel of their treatment status.[42]

The recommendation for lower starting doses in elderly patients or those with hepatic impairment is a direct application of pharmacokinetic and pharmacodynamic principles. The aging process is often associated with reduced hepatic mass and blood flow, leading to decreased metabolic clearance of drugs like Acenocoumarol. In patients with liver disease, this is compounded. The liver is the site of both the drug's metabolism (clearance) and the synthesis of its target proteins (clotting factors).[1] Hepatic impairment can therefore lead to a "double-hit": reduced drug clearance causes higher plasma concentrations and an exaggerated effect, while the baseline production of clotting factors is already diminished, making the patient exquisitely sensitive to further inhibition. This dual sensitization dramatically increases the risk of bleeding and necessitates a highly cautious and conservative approach to dosing.

Section 5: Safety Profile, Contraindications, and Toxicology

The primary limitation and principal risk associated with Acenocoumarol therapy is its potential to cause bleeding. A thorough understanding of its adverse effect profile, contraindications, and the management of toxicity is essential for its safe clinical use.

5.1 Adverse Drug Reactions

5.1.1 Hemorrhagic Complications

Bleeding is the most common and most serious adverse effect of Acenocoumarol and is a direct extension of its therapeutic action.[21] Hemorrhage can occur at virtually any site in the body and its severity can range from minor to life-threatening.

• Minor Bleeding: Common manifestations include easy bruising (ecchymosis), prolonged bleeding from minor cuts, nosebleeds (epistaxis), bleeding gums, and heavier menstrual periods.[43]
• Major and Fatal Bleeding: Severe hemorrhagic events are a significant risk, particularly when the INR is supra-therapeutic. These include gastrointestinal bleeding (manifesting as hematemesis or melena), hematuria (blood in the urine), and intracranial hemorrhage, which is the most feared and often fatal complication.[19]
• Risk Factors: The risk of bleeding is increased by several factors, including a high intensity of anticoagulation (INR >4.0), advanced age (>65 years), a history of gastrointestinal bleeding, uncontrolled hypertension, cerebrovascular disease, severe heart disease, and renal insufficiency.[29]

5.1.2 Non-Hemorrhagic Adverse Effects

While less common than bleeding, Acenocoumarol is associated with a range of other adverse effects.

• Gastrointestinal: Nausea, vomiting, diarrhea, and loss of appetite may occur.[19]
• Dermatological: Skin reactions such as rash and urticaria can occur.[43] Alopecia (hair loss) has also been reported.[19]
• Hepatic: Hepatic dysfunction and elevated liver enzymes may be observed.[28]
• Rare but Serious Reactions:
• Coumarin-Induced Skin Necrosis: A rare but devastating complication that typically occurs within the first few days of therapy. It is caused by extensive thrombosis of the microvasculature within the subcutaneous fat and is linked to the transient hypercoagulable state induced by the rapid fall in Protein C levels. It presents as painful, erythematous lesions that progress to hemorrhagic bullae and necrotic eschars.[29]
• "Purple Toe" Syndrome: This is another rare complication, believed to be caused by cholesterol microembolization from atherosclerotic plaques, which may be dislodged as a result of anticoagulant therapy. It presents as painful, purplish discoloration of the toes.[29]
• Calciphylaxis: A very rare and often fatal syndrome involving calcification of small and medium-sized blood vessels in the skin and subcutaneous tissue, leading to ischemia and painful necrotic ulcers. It has been reported in patients on VKA therapy, including those with and without end-stage renal disease.[40]

5.2 Contraindications and High-Risk Populations

The use of Acenocoumarol is contraindicated in situations where the risk of hemorrhage is judged to be greater than the potential therapeutic benefit. This list of contraindications serves as a critical clinical risk assessment framework, identifying patient populations and clinical scenarios where the risk-benefit balance is inherently unfavorable.

• Absolute Contraindications:
• Pregnancy: Acenocoumarol is classified as Pregnancy Category X. It crosses the placenta and is a known teratogen, capable of causing a characteristic pattern of birth defects (fetal warfarin syndrome), particularly with first-trimester exposure. It can also cause fetal hemorrhage. Therefore, its use is absolutely contraindicated during pregnancy.[1]
• Active Bleeding and High-Risk Conditions: Any active, clinically significant bleeding; hemorrhagic diathesis or blood dyscrasias (e.g., hemophilia); severe, uncontrolled hypertension; acute pericarditis; infective endocarditis; and cerebrovascular hemorrhage.[17]
• Recent or Contemplated Surgery: Surgery of the central nervous system or eye, or any traumatic surgery resulting in large open surfaces, where even minor bleeding could be catastrophic.[17]
• High-Risk Populations (Use with Caution):
• Hepatic or Renal Impairment: Both conditions can alter the pharmacokinetics and pharmacodynamics of the drug, increasing bleeding risk.[19]
• Elderly Patients: Often more sensitive to the anticoagulant effect and at a higher risk of falls and co-morbidities.[29]
• Uncooperative or Unreliable Patients: Patients who cannot adhere to the strict dosing and monitoring schedule (e.g., due to dementia, alcoholism, or psychosis) are poor candidates for therapy.[47]

5.3 Management of Overdosage and Reversal Strategies

Overdosage with Acenocoumarol manifests as an elevated INR and, potentially, hemorrhage.[21] The management strategy is dictated by the INR level and the presence and severity of bleeding. This involves a two-tiered approach: reversing the drug's mechanism and, if necessary, immediately replacing the deficient clotting factors.

• Minor Over-anticoagulation (High INR without significant bleeding): Management typically involves withholding one or more doses of Acenocoumarol and re-checking the INR more frequently until it returns to the therapeutic range. A small oral dose of Vitamin K1 (phytonadione) may be considered for higher INR values.
• Major or Life-Threatening Bleeding: This is a medical emergency requiring immediate intervention.
• Vitamin K1 Administration: The specific antidote for VKA toxicity is Vitamin K1. Administering a high dose of Vitamin K1 overcomes the enzymatic block by VKORC1, allowing the liver to resume synthesis of functional clotting factors.[11] However, this process is not immediate; it takes several hours for new factors to be synthesized and released into the circulation.
• Factor Replacement: For immediate hemostasis in a life-threatening bleed, waiting for new factor synthesis is not viable. Therefore, the definitive treatment is the rapid replacement of the deficient clotting factors. This is achieved by administering blood products such as Fresh Frozen Plasma (FFP), Prothrombin Complex Concentrates (PCCs), or, in some cases, recombinant Factor VIIa.[19] These products provide an immediate, albeit temporary, restoration of clotting ability, bridging the time until the administered Vitamin K1 takes effect.

Section 6: Clinically Significant Interactions

The efficacy and safety of Acenocoumarol therapy are profoundly influenced by interactions with co-administered drugs, foods, and herbal supplements. These interactions can be pharmacodynamic (affecting hemostasis) or pharmacokinetic (affecting drug metabolism) and necessitate vigilant clinical management.

6.1 Pharmacodynamic Interactions Increasing Hemorrhagic Risk

These interactions increase the risk of bleeding without necessarily altering the INR. They occur when Acenocoumarol is combined with other drugs that independently impair hemostasis, leading to an additive or synergistic anti-hemostatic effect.

• Antiplatelet Agents: Drugs such as aspirin and clopidogrel inhibit platelet function. When used with Acenocoumarol, they impair both the coagulation cascade and primary hemostasis (platelet plug formation), significantly increasing the risk of bleeding, particularly gastrointestinal bleeding.[28]
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Drugs like ibuprofen, diclofenac, and naproxen have a dual effect. They inhibit platelet aggregation and can also cause direct gastrointestinal mucosal injury, increasing the risk of GI bleeding. Some NSAIDs may also have a minor pharmacokinetic interaction, but the primary concern is pharmacodynamic.[28]

6.2 Pharmacokinetic Interactions via Cytochrome P450 Pathways

Given that Acenocoumarol clearance is almost entirely dependent on CYP2C9, this enzyme represents the focal point for the majority of clinically significant pharmacokinetic interactions. Any substance that inhibits or induces CYP2C9 activity can dramatically alter Acenocoumarol plasma concentrations and its anticoagulant effect.

• CYP2C9 Inhibitors (Potentiate Effect, Increase INR): These drugs decrease the metabolism of Acenocoumarol, leading to its accumulation and an increased risk of over-anticoagulation and bleeding. Numerous commonly prescribed drugs are potent CYP2C9 inhibitors. Key examples include:
• Antifungals: Fluconazole, miconazole, voriconazole.[20]
• Antibiotics: Metronidazole, trimethoprim/sulfamethoxazole, ciprofloxacin, erythromycin, clarithromycin.[20]
• Cardiovascular Drugs: Amiodarone is a particularly potent and long-acting inhibitor.[9]
• Other: Cimetidine, allopurinol.[9]
• CYP2C9 Inducers (Inhibit Effect, Decrease INR): These drugs increase the synthesis of CYP2C9 enzymes, accelerating the metabolism of Acenocoumarol. This leads to lower plasma concentrations and a reduced anticoagulant effect, increasing the risk of sub-therapeutic anticoagulation and thrombosis. Key examples include:
• Anticonvulsants: Carbamazepine, phenytoin, barbiturates.[20]
• Antimicrobials: Rifampicin (a very potent inducer).[50]
• Other: Bosentan.[20]

6.3 Drug-Food and Drug-Herb Interactions

Patient diet and use of supplements can also significantly impact the stability of Acenocoumarol therapy.

• Vitamin K-Rich Foods: The interaction with dietary Vitamin K is a classic example of competitive antagonism. Acenocoumarol's effect is a balance between its dose and the patient's Vitamin K intake. A sudden, large increase in the consumption of Vitamin K-rich foods (e.g., leafy green vegetables like spinach and kale, broccoli, liver) can overcome the drug's effect, leading to a decrease in the INR.[23] Conversely, a sudden decrease in Vitamin K intake (e.g., due to illness) can potentiate the drug's effect and increase the INR. Therefore, the clinical advice is not to avoid Vitamin K, but to maintain a consistent and stable daily intake.[40]
• Cranberry Juice: Evidence suggests that cranberry products can interfere with the metabolism of coumarins and potentiate their effect, leading to an increased INR. It is generally recommended that patients on Acenocoumarol avoid consuming cranberry juice and other cranberry products.[40]
• Herbal Supplements: Several herbal products can interact with Acenocoumarol. St. John's Wort is a potent inducer of CYP enzymes and can significantly reduce the drug's effectiveness. Others, such as garlic, ginkgo biloba, and ginseng, may have antiplatelet effects or other mechanisms that can increase bleeding risk.[28]
• Alcohol: The interaction with alcohol is complex. Acute, binge drinking can inhibit hepatic metabolism and transiently increase the INR. In contrast, chronic heavy alcohol consumption can induce hepatic enzymes, potentially increasing Acenocoumarol clearance and decreasing the INR.[29]

The following table summarizes key clinically significant interactions with Acenocoumarol.

Interacting Agent/Class	Effect on INR / Bleeding Risk	Mechanism
CYP2C9 Inhibitors
Amiodarone, Fluconazole, Metronidazole	↑ INR, ↑ Bleeding Risk	Inhibition of CYP2C9-mediated metabolism
CYP2C9 Inducers
Rifampicin, Carbamazepine	↓ INR, ↑ Thrombotic Risk	Induction of CYP2C9-mediated metabolism
Pharmacodynamic Interactions
Antiplatelet Agents (Aspirin, Clopidogrel)	↑ Bleeding Risk (INR may be unchanged)	Inhibition of platelet aggregation
NSAIDs (Ibuprofen, Diclofenac)	↑ Bleeding Risk (INR may be unchanged)	Inhibition of platelet aggregation, GI mucosal injury
Food/Herbal Interactions
High Vitamin K Foods (inconsistent intake)	Variable INR (↓ with increased intake)	Competitive antagonism at VKORC1
Cranberry Juice	↑ INR, ↑ Bleeding Risk	Potential inhibition of metabolism
St. John's Wort	↓ INR, ↑ Thrombotic Risk	Induction of CYP enzymes

Section 7: Pharmacogenomics and Personalized Dosing

The marked inter-individual variability in the dose of Acenocoumarol required to achieve a therapeutic INR, long a challenge in clinical practice, is now largely understood to be driven by common genetic variations. Pharmacogenomics provides a molecular basis for this variability and offers the potential for a more personalized and safer approach to dosing. Two genes are of primary importance: CYP2C9, which governs drug metabolism, and VKORC1, which encodes the drug's target.

7.1 Impact of CYP2C9 Polymorphisms on Acenocoumarol Clearance

The gene encoding the primary metabolizing enzyme, CYP2C9, is highly polymorphic. Several variant alleles have been identified that result in the production of enzymes with decreased catalytic activity. The two most common and clinically significant variants in Caucasian populations are CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu).[33]

• Functional Impact: The CYP2C9*2 allele results in an enzyme with moderately reduced activity (approximately 50% of wild-type).[33] The CYP2C9*3 allele has a more profound effect, reducing the enzyme's intrinsic activity by as much as 85-95% for most substrates.[33]
• Clinical Consequences: Since CYP2C9 is the primary route of elimination, individuals who are heterozygous or homozygous for these variant alleles are "poor metabolizers" of Acenocoumarol. This leads to reduced drug clearance, higher plasma concentrations, and an exaggerated anticoagulant response to a standard dose. Consequently, patients carrying the CYP2C9*2 or, more dramatically, the CYP2C9*3 allele require significantly lower maintenance doses to achieve a therapeutic INR.[34] They are also at a substantially higher risk of over-anticoagulation (dangerously high INR) during the initiation phase of therapy and tend to have less stable anticoagulation control over time.[34]

The clinical impact of these polymorphisms is magnified by the stereoselective metabolism of Acenocoumarol. As established, CYP2C9 is primarily responsible for clearing the more potent S-enantiomer of the drug.[30] Therefore, a genetic defect in CYP2C9 function leads to a disproportionate accumulation of the enantiomer that contributes most to the anticoagulant effect. This elegant convergence of stereochemistry, metabolism, and genetics provides a complete molecular explanation for why the

CYP2C9 genotype is such a powerful predictor of both dose requirement and bleeding risk.

7.2 Influence of VKORC1 Variants on Dose Requirements

Genetic variations in the gene encoding the drug's molecular target, VKORC1, also play a crucial role in determining dose requirements. Polymorphisms in the promoter region of the VKORC1 gene can lead to lower expression of the VKORC1 enzyme.[21]

• Functional Impact: Individuals with these variants produce less VKORC1 protein in their hepatocytes. This means there is less target enzyme that needs to be inhibited to achieve an anticoagulant effect.
• Clinical Consequences: These individuals are more sensitive to the effects of Acenocoumarol and require significantly lower doses to achieve the target INR.[21]

Combined, genetic variations in CYP2C9 (pharmacokinetic effect) and VKORC1 (pharmacodynamic effect) are estimated to account for 30% to 40% of the total variability in VKA dose requirements among patients.[36]

7.3 Implications for Genotype-Guided Therapy

The strong association between CYP2C9 and VKORC1 genotypes and Acenocoumarol dose response provides a compelling rationale for personalized, genotype-guided therapy. By identifying a patient's genetic makeup before initiating treatment, clinicians can more accurately predict their dose requirement and sensitivity.

• Dose Prediction: Pharmacogenetic dosing algorithms, which incorporate a patient's genetic information along with clinical factors like age and weight, have been developed to predict the optimal starting and maintenance dose. While these are more established for warfarin, similar principles apply to Acenocoumarol.[36]
• Improving Safety: Pre-emptive genotyping has the potential to significantly improve the safety of therapy initiation. By identifying "poor metabolizers" (CYP2C9 variants) or "highly sensitive" individuals (VKORC1 variants) in advance, clinicians can start with a much lower, more appropriate dose, thereby mitigating the high risk of early over-anticoagulation and major bleeding that these patients face with standard dosing regimens.[54] While the clinical actionability is still under evaluation by some pharmacogenetics working groups, the evidence strongly supports the role of these genes in Acenocoumarol response.[31]

Section 8: Comparative Clinical Efficacy and Safety

The position of Acenocoumarol in the therapeutic armamentarium is best understood through its comparison with the other major oral anticoagulants: the older VKA, warfarin, and the newer class of Direct Oral Anticoagulants (DOACs).

8.1 Acenocoumarol versus Warfarin: A Comparative Analysis of Vitamin K Antagonists

For decades, warfarin has been the most widely used oral anticoagulant globally. The choice between Acenocoumarol and warfarin is often influenced by local prescribing habits and long-held clinical beliefs, primarily centered on their differing pharmacokinetic profiles.

• Pharmacokinetic Differences: The most significant difference is the elimination half-life. Warfarin has a long half-life of approximately 36-42 hours, whereas Acenocoumarol has a much shorter half-life of 8-11 hours.[55]
• Stability of Anticoagulation: The conventional wisdom has been that warfarin's longer half-life provides a more stable level of anticoagulation, buffering against minor daily variations and leading to a higher Time in Therapeutic Range (TiTR). However, the clinical evidence is mixed. One crossover study in a general anticoagulant clinic population found no statistically significant difference in the percentage of INR values within the therapeutic range between the two drugs (59% for Acenocoumarol vs. 62% for warfarin).[55] In contrast, a study focused on a high-risk population of patients with mechanical heart valves found that anticoagulation quality was consistently lower in patients on Acenocoumarol compared to those on warfarin (mean TiTR 56.1% vs. 61.6%).[58]
• Factor VII Fluctuation: The concern that Acenocoumarol's short half-life could lead to clinically significant daily fluctuations in the level of Factor VII was not supported by one study, which found that these fluctuations were independent of the specific drug used and appeared to be more influenced by dietary Vitamin K intake.[55]
• Real-World Efficacy and Safety: A large-scale, real-world data analysis from a cohort of over 150,000 patients with atrial fibrillation directly challenged the presumed superiority of warfarin. In this study, when compared directly to Acenocoumarol, warfarin was found to be both less effective and less safe. Warfarin was associated with a higher risk of systemic embolism, a higher risk of all-cause mortality, and a significantly higher risk of both gastrointestinal and intracranial bleeding.[59]

This recent evidence suggests that the simple pharmacokinetic argument of "longer half-life is better" may be an oversimplification. The clinical reality appears to be far more complex, with factors other than half-life potentially playing a more significant role in overall outcomes. In the context of this large observational dataset, Acenocoumarol holds a surprisingly favorable position relative to warfarin.

8.2 Acenocoumarol versus Direct Oral Anticoagulants (DOACs): An Evaluation of Real-World Evidence

The introduction of DOACs—including the direct thrombin inhibitor dabigatran and the Factor Xa inhibitors rivaroxaban, apixaban, and edoxaban—has revolutionized oral anticoagulation. DOACs offer significant practical advantages, including fixed-dose regimens without the need for routine INR monitoring and fewer drug and food interactions.[62] The comparison between Acenocoumarol and DOACs reveals a crucial and nuanced trade-off between safety, efficacy, and mortality.

• Safety (Bleeding Risk): The most consistent and clinically profound advantage of DOACs over VKAs is in safety, specifically the risk of intracranial hemorrhage. In a large real-world analysis comparing various anticoagulants to Acenocoumarol, all four major DOACs were associated with a significantly lower risk of intracranial bleeding.[59] This represents a major advance in patient safety. The risk of gastrointestinal bleeding, however, was more varied: dabigatran was associated with a higher risk, rivaroxaban with a lower risk, and apixaban with a similar risk compared to Acenocoumarol.[59]
• Efficacy (Thromboembolic Events): Contrary to the safety profile, the real-world data did not demonstrate a clear superiority of DOACs over Acenocoumarol in preventing ischemic events. In the same large cohort study, dabigatran and rivaroxaban were associated with a statistically significant higher risk of the combined endpoint of ischemic events compared to Acenocoumarol. Apixaban showed a lower risk of ischemic stroke but a higher risk of TIA.[59] Another study in the setting of atrial fibrillation catheter ablation found similar rates of thromboembolic complications between patients treated with DOACs and those treated with Acenocoumarol.[67]
• All-Cause Mortality: Despite the mixed efficacy results for thromboembolic events, the data showed a clear mortality benefit for DOACs. Dabigatran, rivaroxaban, and apixaban were all associated with a significantly lower risk of all-cause mortality compared to Acenocoumarol.[59]

This complex dataset suggests that the choice of anticoagulant is not a simple matter of "old versus new." DOACs offer a clear and compelling advantage in reducing the risk of the most feared complication, intracranial bleeding, which likely drives their observed benefit in all-cause mortality. However, this safety advantage does not appear to translate into a uniform improvement in preventing thromboembolic events when Acenocoumarol is the comparator. This positions the clinical decision as a nuanced balancing act, weighing a patient's individual risk profile for ischemic stroke against their specific risks for different types of bleeding (e.g., intracranial versus gastrointestinal).

The table below provides a high-level comparative summary of Acenocoumarol, warfarin, and the DOAC class based on the available evidence.

Parameter	Acenocoumarol	Warfarin	DOACs (Class)
Half-Life	Short (~8-11 h)	Long (~36-42 h)	Short to Intermediate
Monitoring Required	Yes (Frequent INR)	Yes (Frequent INR)	No (Routine)
Reversal Agent	Vitamin K, PCCs/FFP	Vitamin K, PCCs/FFP	Specific Agents (e.g., Idarucizumab, Andexanet alfa)
Risk of Intracranial Bleeding	Baseline Risk	Higher vs. Acenocoumarol	Significantly Lower vs. VKAs
Risk of GI Bleeding	Baseline Risk	Higher vs. Acenocoumarol	Variable (some higher, some lower vs. Acenocoumarol)
Risk of Ischemic Events	Baseline Risk	Higher vs. Acenocoumarol	No clear benefit vs. Acenocoumarol; some may be higher
All-Cause Mortality	Baseline Risk	Higher vs. Acenocoumarol	Lower vs. Acenocoumarol

Section 9: Concluding Analysis and Clinical Recommendations

Acenocoumarol is a clinically effective Vitamin K antagonist whose utility is defined by a dynamic interplay between its potent anticoagulant effect, its challenging pharmacokinetic and pharmacogenomic profile, and its evolving position in a therapeutic landscape that now includes both another VKA (warfarin) and the newer class of DOACs.

The analysis of its fundamental properties reveals a drug whose clinical behavior is a direct consequence of its chemical structure. As a nitro-derivative of warfarin, it shares the same mechanism of action—inhibition of VKORC1—but its shorter half-life and stereoselective metabolism via CYP2C9 create a more "brittle" pharmacokinetic profile. This profile necessitates a rigorous and highly individualized management strategy centered on frequent INR monitoring. The discovery of the profound impact of CYP2C9 and VKORC1 polymorphisms has transformed our understanding of the wide inter-patient variability in dose response, moving it from an empirical observation to a predictable, genetically determined phenomenon. This provides a strong scientific foundation for the implementation of pharmacogenomic-guided dosing to enhance the safety of therapy initiation.

Recent, large-scale comparative evidence has challenged established clinical dogma. The long-held belief in the inherent superiority of warfarin due to its longer half-life is not consistently supported and, in some real-world analyses, is directly contradicted, with Acenocoumarol demonstrating a more favorable safety and efficacy profile. This suggests that factors beyond simple half-life are critical determinants of clinical outcomes in VKA therapy.

The comparison with DOACs illuminates the primary trade-off in modern anticoagulation. DOACs provide a clear, significant, and life-saving reduction in the risk of intracranial hemorrhage, a benefit that likely drives their observed superiority in reducing all-cause mortality. However, this critical safety advantage does not extend to a uniform improvement in preventing thromboembolic events when compared directly against Acenocoumarol in real-world settings.

Based on this comprehensive analysis, the following clinical recommendations can be made:

1. Advocacy for Personalized Anticoagulation: The choice of oral anticoagulant should not be based on a rigid hierarchy but on a personalized assessment of the individual patient. This assessment must weigh the patient's absolute risk of ischemic stroke against their absolute risk of major bleeding, with particular attention to the specific type of bleeding risk (intracranial vs. gastrointestinal).
2. Positioning of Acenocoumarol: Acenocoumarol remains a viable and important therapeutic option. In health systems where cost is a major consideration or in patients who are well-managed and stable on VKA therapy, it may be a suitable choice. The evidence suggests it may be preferable to warfarin in terms of both safety and efficacy.
3. Consideration of Genotyping: For patients being initiated on Acenocoumarol, pre-emptive genotyping for CYP2C9 and VKORC1 variants should be strongly considered. This information can guide initial dosing, reduce the risk of early over-anticoagulation, and improve the overall safety of the therapy.
4. Prioritization of DOACs in High-Risk Patients: In patients with a high risk of intracranial hemorrhage (e.g., history of falls, previous intracranial bleed, uncontrolled hypertension), DOACs should be considered the first-line therapy due to their demonstrated superiority in reducing this specific, devastating complication.
5. Continued Research: The surprising findings from recent real-world evidence underscore the need for further research, including prospective, randomized controlled trials that directly compare Acenocoumarol to individual DOACs, to definitively clarify their relative merits and solidify their place in clinical practice guidelines.

Works cited

1. Acenocoumarol - Wikipedia, accessed September 8, 2025, https://en.wikipedia.org/wiki/Acenocoumarol
2. Acenocoumarol | C19H15NO6 | CID 54676537 - PubChem, accessed September 8, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Acenocoumarol
3. Acenocoumarol - Drugs.com, accessed September 8, 2025, https://www.drugs.com/international/acenocoumarol.html
4. Gene Set - Acenocoumarol, accessed September 8, 2025, https://maayanlab.cloud/Harmonizome/gene_set/Acenocoumarol/DrugBank+Drug+Targets
5. CAS 152-72-7 Acenocoumarol - Alfa Chemistry, accessed September 8, 2025, https://www.alfa-chemistry.com/product/acenocoumarol-cas-152-72-7-290414.html
6. acenocoumarol | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 8, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=9015
7. acenocoumarol | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 8, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9015
8. Information for the user Sinthrome® 1 mg Tablets Acenocoumarol Read all of this leaflet carefully before you s, accessed September 8, 2025, https://www.medicines.org.uk/emc/files/pil.2058.pdf
9. Acenocoumarol drug interactions | Litt's Drug Eruption and Reaction Database, accessed September 8, 2025, http://www.drugeruptiondata.com/drug/id/1276
10. Acenocoumarol | CAS 152-72-7 | SCBT - Santa Cruz Biotechnology, accessed September 8, 2025, https://www.scbt.com/p/acenocoumarol-152-72-7
11. ACENOCOUMAROL | 152-72-7 - ChemicalBook, accessed September 8, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9114003.htm
12. ACENOCOUMAROL - Inxight Drugs, accessed September 8, 2025, https://drugs.ncats.io/substance/I6WP63U32H
13. Acenocoumarol's pharmacokinetic: linear or not? - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6785764/
14. Letter to the editor: ACENOCOUMAROL'S PHARMACOKINETIC: LINEAR OR NOT? - ResearchGate, accessed September 8, 2025, https://www.researchgate.net/publication/336589174_Acenocoumarol's_pharmacokinetic_linear_or_not/fulltext/5da7458692851caa1baa4ef0/Acenocoumarols-pharmacokinetic-linear-or-not.pdf
15. Pharmacokinetics of the enantiomers of acenocoumarol in man, accessed September 8, 2025, https://www.bps.ac.uk/publishing/our-journals/british-journal-of-clinical-pharmacology/volume-12/issue-5/pharmacokinetics-of-the-enantiomers-of-acenocoumar?y=1981&v=12&i=5
16. Acenocoumarol - Product Information, accessed September 8, 2025, https://fnkprddata.blob.core.windows.net/domestic/data/datasheet/CAY/10010569.pdf
17. Prescribing Information SINTROM 1 mg and 4 mg tablets Oral ..., accessed September 8, 2025, https://pdf.hres.ca/dpd_pm/00008015.PDF
18. www.caymanchem.com, accessed September 8, 2025, https://www.caymanchem.com/product/10010569/acenocoumarol#:~:text=Acenocoumarol%20is%20an%20anticoagulant%20and%20vitamin%20K%20antagonist.&text=It%20inhibits%20the%20reduction%20of,VKORC1%20and%20VKORC1L1%2C%20respectively)..&sa=D&source=editors&ust=1757322956009136&usg=AOvVaw0IlvIpFq9uCf7cmYDveMYs)
19. Acenocoumarol - Uses, Dosage, Side Effects, Price, Composition | Practo, accessed September 8, 2025, https://www.practo.com/medicine-info/acenocoumarol-785-api
20. Showing BioInteractions for Acenocoumarol (DB01418) | DrugBank Online, accessed September 8, 2025, https://go.drugbank.com/drugs/DB01418/biointeractions
21. Acenocoumarol: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 8, 2025, https://go.drugbank.com/drugs/DB01418
22. Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition | Blood | American Society of Hematology, accessed September 8, 2025, https://ashpublications.org/blood/article-abstract/132/6/647/39443
23. What is the mechanism of Acenocoumarol? - Patsnap Synapse, accessed September 8, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-acenocoumarol
24. Evaluation of oral anticoagulants with vitamin K epoxide reductase in its native milieu - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6213321/
25. Antagonists of Vitamin K—Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives - MDPI, accessed September 8, 2025, https://www.mdpi.com/1420-3049/25/6/1465
26. SINTROM 1 mg and 4 mg tablets Oral Anticoagulant - Paladin Labs Inc., accessed September 8, 2025, https://www.paladin-pharma.com/our_products/Sintrom_en.pdf
27. Sinthrome 1 mg Tablets - Summary of Product Characteristics ..., accessed September 8, 2025, https://www.medicines.org.uk/emc/product/2058/smpc
28. What is Acenocoumarol used for? - Patsnap Synapse, accessed September 8, 2025, https://synapse.patsnap.com/article/what-is-acenocoumarol-used-for
29. Acenocoumarol (United States: Not available): Drug information - sniv3r2.github.io, accessed September 8, 2025, https://sniv3r2.github.io/d/topic.htm?path=acenocoumarol-united-states-not-available-drug-information
30. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. - PharmGKB, accessed September 8, 2025, https://www.clinpgx.org/literature/15121703
31. Acenocoumarol Pathway, Pharmacokinetics - ClinPGx, accessed September 8, 2025, https://www.clinpgx.org/pathway/PA166247041
32. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. | DrugBank Online, accessed September 8, 2025, https://go.drugbank.com/articles/A2460
33. Acenocoumarol Pharmacokinetics in Relation to Cytochrome P450 2C9 Genotype, accessed September 8, 2025, https://www.researchgate.net/publication/10675997_Acenocoumarol_Pharmacokinetics_in_Relation_to_Cytochrome_P450_2C9_Genotype
34. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/12414349/
35. Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/12844136/
36. Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial - PMC - PubMed Central, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3543328/
37. Acenocoumarol Completed Phase 4 Trials for Coagulation Disorder Treatment - DrugBank, accessed September 8, 2025, https://go.drugbank.com/drugs/DB01418/clinical_trials?conditions=DBCOND0057118&phase=4&purpose=treatment&status=completed
38. Acenocoumarol Completed Phase 3 Trials for Pulmonary Embolism Treatment - DrugBank, accessed September 8, 2025, https://go.drugbank.com/drugs/DB01418/clinical_trials?conditions=DBCOND0027915&phase=3&purpose=treatment&status=completed
39. Acenocoumarol Completed Phase 3 Trials for Atrial Fibrillation Treatment | DrugBank Online, accessed September 8, 2025, https://go.drugbank.com/drugs/DB01418/clinical_trials?conditions=DBCOND0000503&phase=3&purpose=treatment&status=completed
40. Acenocoumarol - Memorial Sloan Kettering Cancer Center, accessed September 8, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/acenocoumarol
41. Acenocoumarol | Memorial Sloan Kettering Cancer Center, accessed September 8, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/acenocoumarol?mode=large&msk_tools_print=pdf
42. Acenocoumarol - an anticoagulant. Side effects and information - Patient.info, accessed September 8, 2025, https://patient.info/medicine/acenocoumarol-an-anticoagulant-sinthrome
43. What are the side effects of Acenocoumarol?, accessed September 8, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-acenocoumarol
44. www.apollopharmacy.in, accessed September 8, 2025, https://www.apollopharmacy.in/salt/Acenocoumarol#:~:text=Drug%20Warnings&text=Prolonged%20use%20of%20Acenocoumarol%20can,five%20days%20before%20the%20surgery.
45. Side effects: Anticoagulant medicines - NHS, accessed September 8, 2025, https://www.nhs.uk/medicines/anticoagulants/side-effects/
46. Acenocoumarol: Uses, Side Effects and Medicines | Apollo Pharmacy, accessed September 8, 2025, https://www.apollopharmacy.in/salt/Acenocoumarol
47. NICOUMALONE/ ACENOCOUMAROL Indications/Uses Thromboembolic disorders. Dosage/Direction for Use Adult : PO Initial, accessed September 8, 2025, https://simsrc.edu.in/pdf_df/N-drugs/Nicoumalone.pdf
48. Acenocoumarol | Uses, Side Effects & Medicines - Truemeds, accessed September 8, 2025, https://www.truemeds.in/drug-salts/acenocoumarol-10115
49. Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/14691574/
50. Clinically significant interactions with VKAs (acenocoumarol, warfarin) - McMaster Textbook of Internal Medicine - empendium.com, accessed September 8, 2025, https://empendium.com/mcmtextbook/table/B31.2.34-3.
51. DI-084 Acenocoumarol drug interactions in hospitalised patients, accessed September 8, 2025, https://ejhp.bmj.com/content/21/Suppl_1/A104.1
52. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations - MDPI, accessed September 8, 2025, https://www.mdpi.com/2075-4426/8/1/1
53. Cytochrome P450 2C9 polymorphism and acenocoumarol therapy. - SciSpace, accessed September 8, 2025, https://scispace.com/pdf/cytochrome-p450-2c9-polymorphism-and-acenocoumarol-therapy-3ao50fzfkz.pdf
54. Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers., accessed September 8, 2025, https://www.clinpgx.org/literature/6449061/overview
55. Warfarin or Acenocoumarol: Which Is better in the ... - Thieme Connect, accessed September 8, 2025, https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0037-1615385.pdf
56. ACENOCOUMAROL OR WARFARIN: WHICH IS THE CLINICIAN'S ALLY? - ResearchGate, accessed September 8, 2025, https://www.researchgate.net/profile/Navin-Patil/publication/297007525_Acenocoumarol_or_warfarin_Which_is_the_clinician's_ally/links/56dc74f408aebe4638c030ae/Acenocoumarol-or-warfarin-Which-is-the-clinicians-ally.pdf
57. Warfarin or acenocoumarol: which is better in the management of oral anticoagulants? - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/9869157/
58. Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study - MDPI, accessed September 8, 2025, https://www.mdpi.com/1420-3049/26/5/1425
59. Comparative clinical outcomes of acenocoumarol versus direct oral anticoagulants (DOACs) and warfarin in patients with atrial fibrillation: real-world-evidence (SIESTA-A study) - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/40822463/
60. Comparative clinical outcomes of acenocoumarol versus ... - Frontiers, accessed September 8, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1548298/full
61. Matched group comparisons of each anticoagulant versus acenocoumarol... | Download Scientific Diagram - ResearchGate, accessed September 8, 2025, https://www.researchgate.net/figure/Matched-group-comparisons-of-each-anticoagulant-versus-acenocoumarol-propensity-score_tbl3_394214117
62. What are Direct-Acting Oral Anticoagulants (DOACs)? - American Heart Association, accessed September 8, 2025, https://www.heart.org/-/media/files/health-topics/answers-by-heart/what-are-doacs.pdf
63. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation | Blood Advances | American Society of Hematology, accessed September 8, 2025, https://ashpublications.org/bloodadvances/article/2/3/200/15767/Comparative-effectiveness-of-direct-oral
64. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care | The BMJ, accessed September 8, 2025, https://www.bmj.com/content/362/bmj.k2505
65. Oral Anticoagulants Beyond Warfarin - Annual Reviews, accessed September 8, 2025, https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-032823-122811
66. Oral anticoagulants: a systematic overview of reviews on efficacy and safety, genotyping, self-monitoring, and stakeholder experiences, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9615370/
67. Safety and efficacy of DOACs vs acenocoumarol in patients undergoing catheter ablation of atrial fibrillation - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6490606/