Anticoagulation Failure in Stroke: Causes, Risk Factors, and Treatment

Non-adherence

Studies indicate that up to 40% of patients report issues with adhering to their anticoagulant drug regimens due to unreliability. This inability to adhere is often caused by ignorance, exploitation, or fear of the side effects such as bleeding [5,6]. Regular monitoring and dietary restrictions make patients even more resistant to VKAs intake. Poor access to healthcare institutions for follow-up visits or international normalized ratio (INR) measurements leads to non-adherence. Inadequate education on the risks and advantages of anticoagulation is worrying [7]. Patients may not realize the severity of the disease or the necessity of treatment. Medical terminology or instructions that are difficult to understand can further confuse patients and hinder compliance [8].

Renal or hepatic dysfunction

Poor renal and liver function has critical consequences on the pharmacokinetic and pharmacodynamic profiles of anticoagulants, and their safety and efficacy can vary widely [9]. Severe renal impairment decreases DOAC excretion, which raises drug levels and increases the risk of toxicity. In addition, liver disease disrupts the metabolism of anticoagulants, leading to inconsistencies in their efficacy [10]. Renal or hepatic dysfunction further impacts the patient’s condition. Chronic fatigue, weakness, and systemic complications can reduce a patient’s ability to engage in their care actively [11].

Obesity and age-related factors

Obesity impacts the effectiveness and safety of anticoagulation therapy by altering drug pharmacokinetics and leading to relative underdosing [12]. As patients age, increased frailty, polypharmacy, and a lack of physiological reserve raise the likelihood of anticoagulation failure. Older patients may have difficulty in taking their medications regularly, which can dramatically reduce treatment effectiveness. For example, they may fall asleep before taking medications that are scheduled for the evening. This is a complex phenomenon—physiological, psychological, and social—unique to the elderly [13].

Malabsorption syndromes

Inflammatory bowel disease (IBD) or post-bariatric surgery can disrupt drug absorption and decrease the blood levels of anticoagulants. Patients with chronic diarrhea often face significant challenges in medication absorption, which can reduce the effectiveness of treatments and complicate disease management [14].

Food interaction

Warfarin function decreases when consumed with foods containing high levels of vitamin K, leading to INR changes. Vitamin K is found in various foods, including kale, spinach, broccoli, cabbage, romaine lettuce, and arugula [15].

Subtherapeutic dosing

The administration of inappropriately low medication doses is a common issue in clinical practice, potentially leading to suboptimal therapeutic effects. Low INR is a common problem with VKAs. A time in therapeutic range of less than 60% increases the risk of thromboembolic complications [16]. Physicians may reduce the dosage of medications, particularly in elderly or frail patients, to avoid potential adverse effects such as drug toxicity or organ dysfunction. In the case of DOACs, standardized doses may not consider individual patient variables such as body weight, renal function, or age [17]. When DOAC doses are reduced, they are sometimes based on misunderstandings or incorrect interpretations of clinical reasoning [18].

Drug-drug interactions

Drugs like rifampin and amiodarone, for example, work on the cytochrome enzymes or P-glycoprotein networks that can affect the effectiveness of anticoagulants. VKAs such as warfarin can be impacted by interactions with other drugs in several ways, primarily by altering the activity of cytochrome P450 enzymes. Enzyme stimulants such as rifampin and carbamazepine, for example, accelerate warfarin’s metabolism, resulting in reduced levels of the drug in the blood [19]. In contrast, enzyme inhibitors like amiodarone and fluconazole slow warfarin’s metabolism, which may result in excessive accumulation of the drug in the blood [20]. DOACs such as apixaban and rivaroxaban are also subject to interactions with P-glycoprotein and cytochrome P450 3A4 enzymes. Depending on the composition of the drug, these interactions can boost or decrease the drug’s activity. Drugs such as ketoconazole (an antifungal) and ritonavir (an antiretroviral), for instance, inhibit cytochrome P450 enzymes and can raise the levels of co-administered drugs. Inducers like phenytoin and St. John’s wort, in contrast, increase the activity of these enzymes, accelerating the breakdown of drugs and lowering the activity of anticoagulants [21]. Such interactions are more common in patients taking multiple medications [22]. Polypharmacy alters drug metabolism at an accelerated rate, especially in the elderly or those with chronic illness [23].

DOAC-specific limitations

DOACs such as apixaban, rivaroxaban, dabigatran, and edoxaban have become the preferred alternative to VKAs for stroke prevention and venous thromboembolism [24]. DOACs, with their benefits of fixed dosing, reduced drug-food interaction, and a lack of frequent monitoring in most contexts, are not free from problems. Absorption syndromes (IBD, celiac disease, bariatric surgery) can seriously impair DOAC absorption [25]. Further, because dabigatran depends on an acidic gastric environment to absorb it, it is sensitive to proton pump inhibitors that could impair its bioavailability and efficacy [26]. Fixed dosing makes DOAC administration easier but may not adequately address patient variation. Standard dosing thus stresses the need for tailored interventions in at-risk groups [27]. The lack of routine monitoring of DOAC levels makes it difficult to identify subtherapeutic or supratherapeutic levels, particularly in patients with unstable renal function or excessive body weight [28]. The fear of lack of an antidote or specific hemostatic agents to counter bleeding complications is a significant concern when using certain DOACs [29].

Hypercoagulable states in CE stroke

In some patients with CE stroke, underlying hypercoagulable states such as antiphospholipid syndrome (APS) may contribute to thromboembolic recurrence despite adequate anticoagulation [30]. APS is characterized by autoantibodies that enhance thrombin generation and impair natural anticoagulant pathways [31]. In patients with both AF and APS, anticoagulation failure may occur even under appropriate VKA therapy [32]. Although some early studies suggested that DOACs—particularly factor Xa inhibitors—might provide enhanced protection against arterial thrombosis due to platelet-rich clot formation, more recent evidence indicates that DOACs are inferior to VKAs in high-risk APS patients, especially those with triple-positive antibody profiles. Thus, warfarin remains the preferred agent in this subgroup [33].

Genetic prothrombotic conditions, such as factor V Leiden mutation or protein C/S deficiency, may also coexist in CE stroke patients and reduce the effectiveness of standard anticoagulation therapies. These inherited conditions promote persistent thrombin generation and platelet activation, possibly contributing to recurrent embolic events despite therapeutic anticoagulation levels [34].

Cancer-associated thrombosis in CE stroke patients

Cancer-associated thrombosis represents another significant challenge in CE stroke patients. Malignancy can amplify thromboembolic risk through tumor-derived procoagulants, endothelial injury, and inflammation [35]. In CE stroke patients with active cancer, anticoagulation may be less effective due to increased baseline coagulability and altered drug pharmacokinetics [36]. Furthermore, physical frailty and treatment-related toxicity in cancer patients may limit the tolerability of oral anticoagulants, necessitating individualized approaches such as low-molecular-weight heparin or close INR monitoring in VKA therapy [37]. In both APS and cancer, adjunctive strategies including reassessment of anticoagulant selection, dosing, and comorbidity-specific risk profiling may be necessary to prevent recurrence in CE stroke patients with coexisting hypercoagulable states [38].

Device-associated thrombosis

Patients face particular difficulties with mechanical heart valves, left ventricular assist devices, or left atrial appendage occlusion (LAAO) devices. Such devices serve as clot-provoking surfaces, even in the face of anticoagulation therapy. Warfarin is the anticoagulant of choice in such patients because it has proven effective in avoiding valve-associated thrombi. Heparinoids can be used in patients who require temporary interruption of warfarin therapy for surgery or invasive procedures. DOACs, by contrast, are found to be less effective in these situations [39].

Persistent intracardiac thrombus

Intracardiac thrombi, especially in the left atrium or ventricle, may remain resistant to anticoagulation, which may result in systemic embolization. Chronic thrombi could require increasing the dose of anticoagulation or other therapeutic interventions to decrease the embolic risk [40].

Chronic inflammatory conditions

Chronic inflammations, such as IBD or rheumatoid arthritis, creates a hypercoagulable landscape by activating platelets and ramping up thrombin production. Other common chronic inflammation, such as gingivitis, sinusitis, periodontitis, and chronic osteomyelitis, can elevate systemic inflammatory response. They also diminish the effectiveness of anticoagulants because chronic inflammation undermines their therapeutic effectiveness [41].

Key points summarizing the causes of anticoagulation failure are consolidated in Table 1.

Table 1.

Summary of causes of anticoagulation failure

CHA₂DS₂-VASc score

An elevated CHA₂DS₂-VASc score is an important stroke risk marker for AF, even in those receiving anticoagulation. Patients with a CHA₂DS₂-VASc score greater than 6 are at the highest risk, as such a high score indicates a significantly increased probability of recurrent thromboembolism [42].

Comorbidities

Renal failure significantly alters the pharmacokinetics of anticoagulants, especially DOACs [43]. In addition to contributing to increased thrombotic risk, diabetes mellitus contributes to chronic vascular inflammation and increases platelet activation, lowering the effectiveness of anticoagulants [44]. Chronic vascular injury caused by hypertension is a chronic condition of endothelial dysfunction and arterial stiffness [45]. Diabetes mellitus leads to increased levels of procoagulant factors like fibrinogen and plasminogen activator inhibitor-1, contributing to a hypercoagulable state [46]. Hypertension is associated with increased levels of oxidative stress and inflammatory mediators, both of which contribute to thrombogenesis [47]. Such changes increase atherothrombotic plaque generation and increase the risk of clot formation, making anticoagulation treatments less effective [48].

Lifestyle factors

Smoking and heavy drinking may increase vascular inflammation and interfere with anticoagulant metabolism. These issues, taken together, contribute to increased thrombotic risk and the difficulty of obtaining and maintaining therapeutic levels of anticoagulants [49].

Silent infarcts

On-screen silent cerebral infarction, especially cortical infarction, despite vigorous anticoagulant treatment, is an alarming result that points to anticoagulant failure. This is a clinical issue that brings important questions as to whether the current anticoagulation treatment is effective or requires reevaluation [50].

Atherosclerotic plaques in large arteries

Plaques of atherosclerosis in major arteries, particularly the carotid and aortic ones, pose major risk factors for embolization and stroke. Broken or weak plaques release thromboembolic fluid into the bloodstream, rendering anticoagulation less effective at preventing ischemic strokes [51].

Hemorrhagic transformation of ischemic stroke

The hemorrhagic transformation of an ischemic stroke can be a major challenge for anticoagulation therapy because it increases the risk of treatment failure and side effects [52].

Aortic atheromas

The presence of aortic atheromas necessitates an update on the current anticoagulation regimen. Aortic atheromas—mobile or irregular, and greater than 4 mm thick—constitute major sources of emboli in patients with AF [53]. The presence of significant aortic atheromas adds another layer of embolic risk, as emboli can originate from the aorta itself, independent of atrial thrombi. Identification of high-risk aortic atheromas may warrant more aggressive anticoagulation or antiplatelet therapy to mitigate embolic risks [54].

D-dimer level

Chronically elevated D-dimer in patients receiving anticoagulation may indicate ongoing thrombotic activity and suggest a current anticoagulant regimen deficiency. This is particularly concerning in populations at high risk, including those with AF, venous thromboembolism, or hypercoagulable conditions such as cancer or APS [55]. Consistent D-dimer elevation also increases the risk of thromboembolic events and adverse clinical outcomes [56].

Drug levels

Anticoagulant doses below the recommended levels are a leading cause of treatment failure, whether due to adherence, altered metabolism, or misdosing. Underdosing—whether from physician misjudgment, patient characteristics, or adherence issues—is associated with increased risks of stroke and mortality, reflecting anticoagulation treatment failure [18].

Hypercoagulable state markers

Hypercoagulable disorders such as APS and inherited thrombophilia have the potential to diminish the efficacy of routine anticoagulation [57]. APS markers include lupus anticoagulant, anticardiolipin, and anti-2-glycoprotein I antibodies. Genetic tests can be utilized to detect the factor V Leiden mutation, the prothrombin G20210A mutation, as well as deficiencies in protein C, protein S, and antithrombin [58,59].

Table 2 summarizes the predictors of anticoagulation failure for ease of reference.

Table 2.

Summary of predictors of anticoagulation failure

Therapeutic drug monitoring

For patients on VKAs such as warfarin, routine INR monitoring is essential to ensure therapeutic efficacy and minimize bleeding risk. The target INR is typically 2.0–3.0 for most indications and 2.5–3.5 in high-risk conditions such as mechanical heart valves. INR levels are influenced by various factors, including diet, drug interactions, and liver function, necessitating frequent monitoring and dose adjustments [60].

In contrast, DOACs generally do not require routine therapeutic drug monitoring due to their predictable pharmacokinetics. However, plasma level assessment may be considered in special clinical settings such as major bleeding, renal impairment, urgent surgery, or suspected overdose. Drug-specific assays are available [61].

• Rivaroxaban and apixaban: Levels can be measured dusing anti-factor Xa activity assays, calibrated to the specific DOAC. These tests can quantify drug concentration, though they lack established therapeutic ranges [62].

• Dabigatran: Levels can be assessed using diluted thrombin time (dTT) or ecarin clotting time. dTT correlates linearly with plasma drug concentration [63].

• Edoxaban: Anti-factor Xa assays may be used but are less commonly available and not routinely employed [64].

Although DOAC level testing is available, it is infrequently used in everyday practice and is generally reserved for specialized or emergency scenarios.

Switching anticoagulants

Anticoagulant therapy is often adjusted when the current regimen presents concerns related to efficacy, safety, or patient preference. In clinical practice, DOACs are generally preferred due to their predictable pharmacokinetics, fixed dosing, and minimal monitoring requirements [65]. Switching from warfarin to a DOAC may be appropriate in patients who experience poor INR control (i.e., time-in-therapeutic range <60%) or who prefer a more convenient regimen that does not require frequent blood testing [66]. Conversely, there remain specific indications where warfarin is favored or necessary. These include patients with mechanical heart valves, those with APS, and clinical scenarios requiring high-intensity anticoagulation (target INR 3.0–4.0), for which DOACs are either ineffective or contraindicated [67].

Low molecular weight heparin is preferred over warfarin in certain clinical settings, such as cancer-associated thrombosis, pregnancy, and perioperative bridging, where studies have demonstrated superior efficacy and/or safety profiles [68]. However, we also acknowledge that warfarin remains the anticoagulant of choice in specific scenarios, such as in patients with mechanical heart valves, APS, or where cost and accessibility are key considerations [69].

Dual antithrombotic therapy

Dual antithrombotic therapy, which combines an anticoagulant with an antiplatelet agent such as aspirin, may be considered in high-risk patients who have overlapping indications—particularly those with AF and coexisting atherosclerotic cardiovascular disease, such as coronary artery disease or a recent stent placement [70,71]. However, the benefit must be weighed carefully against the increased risk of bleeding. Multiple randomized controlled trials —including the PIONEER AF-PCI (The Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), AUGUSTUS (An Open-label, 2x2 Factorial, Randomized Controlled Trial to Evaluate the Safety of Apixaban Compared to a Vitamin K Antagonist and Aspirin Compared to Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Undergoing Percutaneous Coronary Intervention), and RE-DUAL PCI (The Randomized Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention)—have evaluated dual antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI), and have generally favored short-term dual therapy (e.g., 1–6 months) followed by anticoagulant monotherapy for long-term management [72-74].

In general, indications include AF with recent PCI or acute coronary syndrome, as well as patients with high thromboembolic risk—such as those with a history of stroke and significant atherosclerotic disease.

The typical durations of therapy are as follows:

• Triple therapy (anticoagulant + dual antiplatelet agents) is typically limited to ≤1 week.

• Dual therapy (anticoagulant + a single antiplatelet agent) is generally recommended for 1 to 6 months.

• Anticoagulant monotherapy is continued thereafter, guided by a balance between ischemic and bleeding risk.

Careful monitoring is essential, and treatment decisions should be individualized based on factors such as the CHA₂DS₂-VASc score, HAS-BLED score, type of stent placed, and recent vascular events [70,72-74].

Left atrial appendage occlusion

LAAO is a catheter-based procedure that serves as an alternative stroke prevention strategy in patients with non-valvular AF (NVAF), particularly when oral anticoagulation is contraindicated or ineffective [75]. Left atrial appendage is the origin of over 90% of thrombi in patients with NVAF, and its occlusion significantly reduces the risk of CE stroke [76].

While LAAO is most often used in patients who are unsuitable for long-term anticoagulation, its role has expanded. The PRAGUE-17 trial, a randomized controlled study, demonstrated that LAAO was non-inferior to DOAC therapy in preventing a composite outcome of stroke, systemic embolism, cardiovascular death, and major bleeding in high-risk patients with AF. These findings support the broader use of LAAO, even in some patients eligible for anticoagulation, especially when bleeding risk is high [77]. Indications for LAAO include: absolute contraindication to anticoagulation (e.g., prior intracranial hemorrhage); high bleeding risk (e.g., HAS-BLED ≥3); recurrent thromboembolic events despite therapeutic anticoagulation; inability to maintain consistent anticoagulation due to adherence or tolerance issues; and patient preference, following shared decision-making [78]. LAAO is increasingly recognized as a viable option for selected patients at high thromboembolic and bleeding risk, following careful evaluation by a multidisciplinary team.

Cancer-associated thrombosis

When a tumor is eradicated by chemotherapy, radiation, or surgery, the production of procoagulant factors (both tissue factors and cancer procoagulants) is reduced. This retards the coagulation process, and thus prevents thrombus formation. Cancer therapy also minimizes the body’s inflammatory reaction that leads to excessive clotting. Lowering inflammatory mediators such as interleukin-6 and tumor necrosis factor-alpha can rebalance endothelial function and block clotting [79].

APS management

Management of APS typically requires VKA therapy, such as warfarin, with a target INR of 2.0–3.0. In refractory or high-risk cases, such as patients with recurrent thrombotic events despite adequate INR or those with triple-positive antibodies (i.e., positive lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I), a higher-intensity anticoagulation target (INR 3.0–4.0) may be considered [21]. However, this is individualized and not standard for all APS patients [31-33]. Recent evidence has shown that DOACs such as rivaroxaban are less effective than warfarin in high-risk APS, particularly in patients with triple antibody positivity, and are therefore not recommended in this population. Conversely, in patients with non-APS-related atherosclerotic vascular disease, DOACs remain a suitable option due to their favorable safety profile and ease of use [33].

Table 3 provides a detailed summary of the management of anticoagulation failure for comparison.

Table 3.

Summary of management of anticoagulation failure