Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access
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Review

Volume 17, Number 6, December 2026, pages 577-586

Warfarin After Seven Decades: Persistent Value and the Contemporary Role of Vitamin K Antagonism

Figures

↓  Figure 1. The warfarin paradox in contemporary cardiology. Despite the widespread adoption of direct oral anticoagulants, warfarin retains an essential role in patients with mechanical heart valves and in those with atrial fibrillation associated with clinically significant rheumatic mitral stenosis. The illustration summarizes the thrombotic substrates encountered in these conditions and the reduction of functional vitamin K-dependent coagulation factors II, VII, IX, and X by warfarin. Its contemporary relevance also reflects affordability and availability, balanced against the requirements for INR monitoring and management of food and drug interactions. The biological pathways shown are conceptual and should not be interpreted as proven explanations for the clinical differences between anticoagulant classes. DOAC: direct oral anticoagulant; INR: international normalized ratio.
Figure 1.
↓  Figure 2. Why thrombotic biology matters in anticoagulant selection. (a) Atrial fibrillation: atrial cardiomyopathy and blood stasis, particularly within the left atrial appendage, contribute to thrombus formation. Direct oral anticoagulants inhibit factor Xa or thrombin and are preferred in eligible patients. (b) Mechanical heart valves and rheumatic mitral stenosis: artificial surfaces, disturbed flow, contact and platelet activation, atrial stasis, inflammation, and endothelial injury illustrate potential contributors to thrombogenesis. Warfarin reduces the functional activity of vitamin K-dependent coagulation factors II, VII, IX, and X. Clinical evidence supports vitamin K antagonist therapy for mechanical heart valves and for atrial fibrillation associated with clinically significant rheumatic mitral stenosis; however, broader coagulation-factor suppression has not been established as the causal explanation for its clinical advantage in these settings. AF: atrial fibrillation; DOAC: direct oral anticoagulant; VKA: vitamin K antagonist.
Figure 2.
↓  Figure 3. Real-world transition from warfarin to DOACs in (a) the United States and (b) England. United States: the displayed estimates illustrate the decline in warfarin prescribing after the introduction of direct oral anticoagulants, alongside its continued use in a substantial patient population. England: the illustration depicts the transition from warfarin-dominant to DOAC-dominant prescribing. These trends reflect the increasingly selective role of warfarin, particularly in mechanical heart valves, atrial fibrillation associated with clinically significant rheumatic mitral stenosis, and settings where access influences treatment choices. Prescription counts and numbers of treated patients represent different measures and should not be directly equated. Bars and timelines are schematic and do not represent a common quantitative scale across countries. DOACs: direct oral anticoagulants; VKA: vitamin K antagonist.
Figure 3.

Tables

↓  Table 1. Contemporary Hierarchy of Vitamin K Antagonist Therapy
 
Clinical settingContemporary role of VKAEvidence-based interpretationPractical implication
AF: atrial fibrillation; APS: antiphospholipid syndrome; CKD: chronic kidney disease; DOAC: direct oral anticoagulant; INR: international normalized ratio; LVT: left ventricular thrombus; post-MI: post-myocardial infarction; RHD: rheumatic heart disease; VKA: vitamin K antagonist.
Mechanical heart valveNecessary/established standardRE-ALIGN and PROACT Xa failed to establish effective DOAC alternativesLifelong INR-guided VKA therapy
RHD-associated AF with clinically significant mitral stenosisPreferredINVICTUS favored VKA over rivaroxabanDo not extrapolate conventional AF DOAC evidence
High-risk thrombotic APS, particularly triple-positive APSPreferredTRAPS demonstrated excess events with rivaroxabanVKA remains preferred
Left ventricular thrombusEstablished; alternatives emergingRandomized evidence supports rivaroxaban as a potential alternative in selected acute post-MI LVTIndividualize therapy and repeat imaging; avoid extrapolation to all LVT phenotypes
Pregnancy with mechanical valveDynamic/potentially essentialVKA offers strong maternal protection but creates fetal riskTrimester-, dose-, valve-, and monitoring-dependent strategy
AF with severe CKD or dialysisIndividualized/uncertainLimited randomized evidence and high competing risksDecide whether to anticoagulate before selecting agent
AF eligible for DOAC therapyGenerally replacedDOACs provide favorable efficacy-safety balanceDOAC generally preferred
Limited or unstable DOAC accessPotentially necessary for feasibilityAccess advantage, not biological superiorityRequires sustainable INR-monitoring infrastructure

 

↓  Table 2. Randomized Evidence Defining Contemporary Boundaries of DOAC and VKA Therapy
 
TrialPopulationComparisonPrincipal findingInterpretation
APS: antiphospholipid syndrome; DOAC: direct oral anticoagulant; LVT: left ventricular thrombus; post-MI: post-myocardial infarction; RHD: rheumatic heart disease; VKA: vitamin K antagonist.
RE-ALIGN [11]Mechanical aortic/mitral valvesDabigatran vs. warfarinExcess thromboembolism and bleeding with dabigatranDabigatran should not be used for mechanical valves
RIWA [12]Mechanical valvesRivaroxaban vs. warfarinSmall proof-of-concept studyInsufficient to alter standard care
PROACT Xa [13]On-X mechanical aortic valveApixaban vs. warfarinInadequate protection with apixaban; trial stopped earlyVKA remains standard
INVICTUS [16]RHD-associated AFRivaroxaban vs. VKAPrimary cardiovascular outcome favored VKASupports VKA class, not warfarin specifically
TRAPS [18, 19]High-risk triple-positive APSRivaroxaban vs. warfarinExcess thrombotic/adverse events with rivaroxabanVKA preferred in high-risk APS
RIVAWAR [21]Acute post-MI LVTRivaroxaban vs. warfarinNon-inferior 12-week thrombus resolution; earlier resolution at 4 weeksPotential alternative for selected acute post-MI LVT; broader generalization requires caution
OCEANIC-AF [30]AFAsundexian vs. apixabanLess major bleeding but substantially more stroke/systemic embolismSafety advantage cannot compensate for inadequate efficacy
AZALEA-TIMI 71 [31]AFAbelacimab vs. rivaroxabanMarkedly lower major/CRNM bleedingStrong safety signal; efficacy equivalence not established

 

↓  Table 3. The True Cost and Feasibility of Anticoagulation
 
DimensionVKA/warfarinDOACClinical relevance
CKD: chronic kidney disease; DOAC: direct oral anticoagulant; FFP: fresh frozen plasma; 4F-PCC: four-factor prothrombin complex concentrate; INR: international normalized ratio; TTR: time in therapeutic range.
Acquisition costGenerally lowUsually higherDrug price alone is incomplete
Routine coagulation monitoringINR requiredNo routine INRMajor logistical distinction
Dose adjustmentFrequent/variableUsually fixed; renal/clinical criteria applyInfluences workload and adherence
Travel and patient timePotentially substantialGenerally lowerImportant hidden cost
Food/drug interactionsNumerousFewer, but clinically relevant interactions remainRequires medication review
Renal considerationsNot primarily renally clearedDrug-specific renal restrictionsParticularly relevant in CKD
ReversalVitamin K + 4F-PCC; FFP selectedDrug-specific or PCC-based strategiesAvailability differs geographically
Continuity of supplyGenerally broadMay be limited by reimbursement/costCritical global-health consideration
Quality metricTTR/INR stabilityCorrect dose, adherence, renal surveillanceBoth strategies require quality control