Therapeutic Warfarin Research Articles

Laboratory characteristics of ischemic stroke patients with atrial fibrillation on or off therapeutic warfarin.

In patients with atrial fibrillation (AF), despite adequate anticoagulation, ischemic stroke (IS) is an uncommon yet concerning occurrence. Specific laboratory parameters may affect the efficacy of warfarin despite therapeutic international normalized ratio (INR) in patient with AF who present with IS. We used the database from a multicenter clinical trial to identify AF patients who presented with IS. We trichotomized the cohort into patients with therapeutic INR on warfarin, subtherapeutic INR on warfarin, and on no anticoagulants. We then compared baseline laboratory characteristics and other baseline features among the groups. Patients with therapeutic INR presented with higher serum creatinine (P = 0.01) and blood urea nitrogen (P = 0.02) and lower glomerular filtration rates (P = 0.001) compared with other groups. Other laboratory parameters were not different among the 3 groups. Patients with therapeutic INR also presented with milder stroke symptoms (P = 0.01). Medical history of the 3 groups was not different, except for history of valvular heart disease, which was more prevalent in patients with therapeutic INR (P = 0.004). In-hospital mortality rates and 90-day disability were not different among the 3 groups. AF patients who presented with IS on therapeutic warfarin had higher average serum creatinine and blood urea nitrogen, and lower glomerular filtration rates, compared with others. Impaired renal function may be a factor contributing to occurrence of IS in AF patients despite adequate anticoagulation. Larger, targeted studies are needed to confirm these findings.

Left Atrial Enlargement and Anticoagulation Status in Patients with Acute Ischemic Stroke and Atrial Fibrillation

Despite anticoagulation therapy, ischemic stroke risk in atrial fibrillation (AF) remains substantial. We hypothesize that left atrial enlargement (LAE) is more prevalent in AF patients admitted with ischemic stroke who are therapeutic, as opposed to nontherapeutic, on anticoagulation. We included consecutive patients with AF admitted with ischemic stroke between April 1, 2015, and December 31, 2016. Patients were divided into two groups based on whether they were therapeutic (warfarin with an international normalized ratio ≥ 2.0 or non-vitamin K oral anticoagulant with uninterrupted use in the prior 2 weeks) versus nontherapeutic on anticoagulation. Univariable and multivariable models were used to estimate associations between therapeutic anticoagulation and clinical factors, including CHADS2 score and LAE (none/mild versus moderate/severe). We identified 225 patients during the study period; 52 (23.1%) were therapeutic on anticoagulation. Patients therapeutic on anticoagulation were more likely to have a larger left atrial diameter in millimeters (45.6 ± 9.2 versus 42.3 ± 8.6, P = .032) and a higher CHADS2 score (2.9 ± 1.1 versus 2.4 ± 1.1, P = .03). After adjusting for the CHADS2 score, patients who had a stroke despite therapeutic anticoagulation were more likely to have moderate to severe LAE (odds ratio, 2.05; 95% confidence interval, 1.01-4.16). LAE is associated with anticoagulation failure in AF patients admitted with an ischemic stroke. This provides indirect evidence that LAE may portend failure of anticoagulation therapy in patients with AF; further studies are needed to delineate the significance of this association and improve stroke prevention strategies.

Association of Preceding Antithrombotic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation

Antithrombotic therapies are known to prevent stroke for patients with atrial fibrillation (AF) but are often underused in community practice. To examine the prevalence of patients with acute ischemic stroke with known history of AF who were not receiving guideline-recommended antithrombotic treatment before stroke and to determine the association of preceding antithrombotic therapy with stroke severity and in-hospital outcomes. Retrospective observational study of 94 474 patients with acute ischemic stroke and known history of AF admitted from October 2012 through March 2015 to 1622 hospitals participating in the Get With the Guidelines-Stroke program. Antithrombotic therapy before stroke. Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS; range of 0-42, with a higher score indicating greater stroke severity and a score ≥16 indicating moderate or severe stroke), and in-hospital mortality. Of 94 474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7176 (7.6%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥2) and 8290 (8.8%) were receiving non-vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79 008 patients (83.6%) were not receiving therapeutic anticoagulation; 12 751 (13.5%) had subtherapeutic warfarin anticoagulation (INR <2) at the time of stroke, 37 674 (39.9%) were receiving antiplatelet therapy only, and 28 583 (30.3%) were not receiving any antithrombotic treatment. Among 91 155 high-risk patients (prestroke CHA2DS2-VASc score ≥2), 76 071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeutic warfarin (15.8% [95% CI, 14.8%-16.7%]) and NOACs (17.5% [95% CI, 16.6%-18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI, 26.6%-27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%-25.3%]), or subtherapeutic warfarin (25.8% [95% CI, 25.0%-26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%-7.0%]) and NOACs (6.3% [95% CI, 5.7%-6.8%]) compared with those receiving no antithrombotic therapy (9.3% [95% CI, 8.9%-9.6%]), antiplatelet therapy only (8.1% [95% CI, 7.8%-8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%-9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51-0.60], 0.65 [0.61-0.71], and 0.88 [0.84-0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67-0.85], 0.79 [0.72-0.88], and 0.83 [0.78-0.88], respectively). Among patients with atrial fibrillation who had experienced an acute ischemic stroke, inadequate therapeutic anticoagulation preceding the stroke was prevalent. Therapeutic anticoagulation was associated with lower odds of moderate or severe stroke and lower odds of in-hospital mortality.

Figure-of-eight suture for venous hemostasis in fully anticoagulated patients after atrial fibrillation catheter ablation

IntroductionLimited data exists for types of venous closure and its associated complications in patients after atrial fibrillation (AF) catheter ablation. We evaluated the subcutaneous figure-of-eight closure (FO8) for achieving venous hemostasis after AF catheter ablation compared to manual pressure. Methods284 consecutive patients that underwent AF catheter ablation by two operators were included. All patients received continuous therapeutic warfarin or interrupted novel oral anticoagulants (NOAC) and heparin (ACT300-400 s) without reversal. Patients were divided into two groups: 1) sheaths were left in place and pulled once ACT < 180 s, with hemostasis being achieved with manual pressure (MP); and 2) a subcutaneous FO8 suture closed the venous access site immediately after the ablation on each groin site and sheaths were removed immediately after the ablation despite full anticoagulation with heparin and warfarin or interrupted NOAC. Sutures were removed after four hours, and the patients laid flat for an additional two hours. ResultsThe MP group (n = 105) was similar to the FO8 group (n = 179). Time in bed was 573 ± 80 min for MP group vs. 373 ± 49 min for FO8 group (p < 0.0001). Eleven hematomas were seen in the MP group compared to seven in the FO8 group (P = 0.041). ConclusionsIn fully anticoagulated patients undergoing AF catheter ablation, excellent hemostasis was achieved with figure-of-eight sutures, with no major vascular complications, a lower hematoma rate, and a significantly shorter flat-time-in-bed compared to manual pressure.

Abstract TP118: Recanalization After Extracranial Dissection Stratified by Medical Treatment: Antiplatelets versus Anticoagulation

Objective: Dissection is a leading cause of stroke in young adults, though optimal antithrombotic management with either anticoagulation or antiplatelet therapy remains controversial. Existing data have focused on recurrent stroke but these studies have been underpowered. We aimed to assess recanalization rates for patients treated with anticoagulants compared to those treated with antiplatelet agents and to identify factors associated with vessel recanalization. Methods: We performed a retrospective, single center, cohort study, identifying patients with extracranial carotid or vertebral dissection, with acute and follow up imaging, over a 15 year period. Vessel stenosis was measured using NASCET methodology. Anticoagulation was defined as treatment with therapeutic Heparin or warfarin for greater than 50% of the first month. Univariable and multivariable analyses were performed to determine clinical, demographic, and radiographic factors associated with ≥ 50% relative recanalization at follow up. Results: We identified 75 patients with 84 dissections, mean age 47± SD 15, 43% female, 39% non-white. The rate of recurrent strokes was 2.7% in the entire cohort, which was not significantly different between treatment arms (p=0.35). Median time from symptom onset to first vessel imaging was 1 day (interquartile range [IQR] 0-6) and median time to follow up imaging was 4 months (IQR 3-7) after symptoms. Patients with higher percent stenosis at baseline were more likely to be treated with anticoagulation (median 99% vs. 50%, p=0.02). Comparing anticoagulation to antiplatelet therapy, there was no difference in the rates of ≥50% relative recanalization (50% vs 48%, p=0.84), nor in the absolute change (median 16% vs 7%, p=0.34) nor relative change (median 48% vs 43%, p=0.92) from baseline. In a multivariable model, antithrombotic therapy was not significantly associated with ≥ 50% recanalization. Hypertension was the only significant variable and was negatively associated with the outcome (OR 0.26, 95% confidence interval 0.09 - 0.72, p=0.009). Conclusions: Use of anticoagulation did not result in higher rates of recanalization, suggesting antiplatelet therapy is sufficient for the majority of patients with acute extracranial dissection.

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice

BackgroundPeople infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims...

Safety of continuing warfarin therapy in patients undergoing cardiac resynchronization therapy device implantation

Background: Continuing warfarin therapy is considered safe for patient undergoing pacemaker or implantable cardioverter defibrillator procedures, but less evidence exists for patients undergoing cardiac resynchronization therapy (CRT) device implantation. Subjects and Methods: We retrospectively evaluated 136 consecutive patients who received a CRT device. Three periprocedural anticoagulation strategies were utilized: Group 1, continuation of therapeutic warfarin; Group 2, cessation of warfarin with heparin bridging; and Group 3, cessation of anticoagulation temporarily. Groups were compared on the incidence of complications. Results: Of the 136 patients, 87 (64%) were in Group 1, 18 (13%) were in Group 2, and 31 (23%) were in Group 3. Group 1 patients had an international normalized ratio of 2.3 ± 0.5, which was significantly higher than the other two groups. Coronary sinus dissection occurred in four patients: Three in Group 1 and one in Group 2, but no patient experienced pericardial effusion or tamponade. Group 2 experienced a higher incidence of pocket hematoma (P = 0.0065) and a longer length of hospital stay (P = 0.0069) than Group 1. Transient ischemic attack occurred in one patient in Group 3. Conclusion: Continuing warfarin with therapeutic international normalized ratio seems to be safe in individuals undergoing CRT device implantation.

Use of Direct Oral Anticoagulants in Patients on Immunomodulatory Agents

The risk of venous thromboembolism (VTE) is increased in individuals with cancer, particularly in those with multiple myeloma. The immunomodulatory agents (IMiDs) thalidomide, lenalidomide and pomalidomide are commonly used to treat multiple myeloma and other hematologic malignancies and are associated with increased risk of VTE. Current National Comprehensive Cancer Network (NCCN) guidelines (v.1.2016) on cancer-associated VTE utilize a risk assessment model based on a few small studies to guide VTE prophylaxis for multiple myeloma patients being treated with an IMiD (Palumbo, et al. Leukemia, 2008). Aspirin is recommended for lower risk patients while prophylactic-dose low molecular weight heparin or therapeutic warfarin are recommended for higher risk patients.The use of direct oral anticoagulants (DOACs) for cancer-associated VTE is currently under investigation (Raskob, et al. Lancet Haematol, 2016). Little is known about their role in VTE prophylaxis in patients on IMiDs. The purpose of this study was to explore the use of DOACs in patients receiving IMiDs. We performed a retrospective chart review of all patients at the University of Virginia Health System who received an IMiD and who were taking either a DOAC or warfarin between January 1, 2010 and December 31, 2015. DOACs included dabigatran, rivaroxaban, and apixaban. IMiDs included lenalidomide, thalidomide, and pomalidomide. The primary endpoint was to assess the safety of DOACs as compared to warfarin, and the secondary endpoint was to assess their efficacy.We collected baseline patient information, as well as diagnosis, IMiD, anticoagulant, antiplatelet agent and dose, duration of treatment, concurrent antineoplastic therapies, and thrombotic risk factors. We utilized the NCCN definitions of individual and myeloma-related thrombotic risk factors. Many patients had changes in their IMiD or anticoagulation. Thus, separate encounters were collected, where an encounter was the combination of an IMiD agent and dose, the anticoagulant, the antiplatelet agent (if any), and the thrombotic risk profile for that time period. Descriptive analyses were performed on all encounters in both groups. Rates of bleeding and thrombotic events were calculated.There were 21 discrete patients in the DOAC group and 16 in the warfarin group. Characteristics and outcomes are described in Table 1. There were four non-major bleeding events in the DOAC group; two of the four bleeding events occurred while on concomitant aspirin therapy. The patient with hematuria stopped anticoagulation and cystoscopy revealed bladder cancer. The other patients did not change or stop therapy. There were six bleeding events in the warfarin group: two were major and four were non-major. The two major events were gastrointestinal bleeding (GIB) and a subarachnoid hemorrhage (SAH). Neither event occurred while on concomitant antiplatelet therapy. The GIB required cessation of therapy, hospitalization, and transfusions. The INR at the time is unknown. The SAH was preceded by a fall while INR was in therapeutic range. Both major and two of the non-major bleeding events occurred in the same patient at different time points and accounted for most of the warfarin-related bleeding events. There was one thrombotic event in the DOAC group. The patient had a non-ST segment elevation myocardial infarction (NSTEMI) while on prophylactic-dose rivaroxaban. She was not on concomitant antiplatelet therapy. Arterial thrombotic events are not typically seen with IMiDs, and the NSTEMI was thought to be related to the recent initiation of carfilzomib. There were no thrombotic events in the warfarin group.This was a retrospective, single-institution study assessing the safety and efficacy of DOACs as compared to warfarin in patients on IMiDs. In our study, all bleeding events in the DOAC group were non-major, while patients on warfarin experienced both major and non-major bleeds. Only one thrombotic event was recorded in the DOAC group. DOACs may represent an attractive alternative to warfarin for VTE prophylaxis in these patients, given no need for routine monitoring and fewer dietary restrictions. Prospective studies in this population are warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Immunizations in Children Requiring Warfarin Therapy.

Children with conditions requiring chronic warfarin therapy have increased. The importance of receiving immunizations in this population is magnified due to potential weakness in their immune response. There is concern about immunizing on therapeutic anticoagulation due to risk of hematomas and the influence of vaccine on warfarin metabolism. This study evaluated the influence of vaccines on warfarin effect as measured by the International Normalized Ratio and the clinically relevant hematomas or bruising postimmunization. There were no clinically relevant negative outcomes postimmunizations. This study demonstrates that immunizations may be safely administered to children receiving therapeutic warfarin therapy.

Abstract 10: Pre-stroke Antithrombotic Therapy and Stroke Severity in Acute Ischemic Stroke Patients with Atrial Fibrillation

Background: Antithrombotic therapies are known to prevent thromboembolic events and stroke for patients with atrial fibrillation (AF). Despite this, it is unclear in contemporary practice what percentage of AF patients presenting with acute ischemic stroke (AIS) receive antithrombotic therapy prior to stroke and how pre-stroke antithrombotic therapy affects stroke severity, particularly in the era of non-vitamin K antagonist oral anticoagulants (NOACs). Methods: We analyzed data from 1625 Get With The Guidelines-Stroke hospitals between October 2012 and March 2015. Multivariable logistic regression was performed to evaluate the association between antithrombotic therapy and stroke severity according to NIHSS. Results: Of 103,327AIS patients with pre-stroke AF, 28,583 (28%) were not on any home antithrombotics prior to their stroke, and another 30,149 (29%) were receiving aspirin alone; followed by warfarin alone (18,532, 18%) with only a quarter (4705/18,532) in the therapeutic range, aspirin and warfarin (7130, 7%), and NOACs alone (5803, 6%) ( Figure ). Even among patients with a CHA2DS2-VASc score≥2, only one third of them (34,145/99,807) were receiving some form of oral anticoagulant. Stroke severity was associated with home antithrombotic use ( Figure ). Compared with those receiving aspirin alone, warfarin with INR≥2 (adjusted odds ratio [aOR], 0.72, 95% CI 0.66-0.79), aspirin and warfarin (aOR 0.83, 95% CI 0.77-0.90), NOACs alone (aOR 0.83, 95% CI 0.77-0.91), NOACs with aspirin or clopidogrel (aOR 0.69, 95% 0.60-0.79), aspirin and clopidogrel (aOR 0.90, 95% CI 0.83-0.99), or triple antithrombotic therapy (aOR 0.64, 95% 0.49-0.84) were associated with a lower likelihood of severe stroke (NIHSS≥16). In contrast, patients subtherapeutic (INR&lt;2 or INR missing) on warfarin (aOR 1.07, 95% 1.01-1.13) and those not receiving any antithrombotic treatment (aOR 1.10, 95% 1.05-1.15) were more likely to present with more severe stroke. Conclusions: A majority of AF patients presenting with AIS are not on guideline recommended anticoagulation or are not therapeutic on their anticoagulation. Even when strokes occurred on therapeutic warfarin or a NOAC, the strokes were less severe. These findings highlight the huge opportunities to further improve proper use of oral anticoagulants in eligible AF patients.

Artificial neural network-based pharmacogenomic algorithm for warfarin dose optimization.

To develop more precise pharmacogenomic algorithm for prediction of safe and effective dose of warfarin. An artificial neural network (ANN) algorithm was developed by using age, gender, BMI, plasma vitamin K levels, thyroid status and ten genetic variables as the inputs and therapeutic warfarin dose as the output. Hyperbolic tangent function was used to build an ANN architecture. This model explained 93.5% variability in warfarin dosing and predicted warfarin dose accurately in 74.5% patients whose international normalized ratio (INR) was less than 2.0 and in 83.3% patients whose INR was more than 3.5. This algorithm reduced the out-of-range INRs (odds ratio [OR]: 0.49; 95% CI: 0.30-0.79; p = 0.003), the rate of adverse drug reactions (OR: 0.00; 95% CI: 0.00-1.21; p = 0.06) and time to reach first therapeutic INR (OR: 6.73; 95% CI: 2.17-22.31; p < 0.0001). This algorithm was found to be applicable in both euthyroid and hypothyroid status. S-warfarin/7-hydroxywarfarin ratio was found to increase in subjects with CYP2C9*2 and CYP2C9*3 justifying the warfarin sensitivity attributed to these variants. An application of ANN for warfarin dosing improves predictability and provides safe and effective dosing.

Use of Rivaroxaban for Prophylaxis of Superficial Venous Thrombosis in Klippel-Trenaunay- Weber Syndrome - Case Report and Systematic Review

INTRODUCTIONWe present a case of a young man with Klippel Trenaunay Weber Syndrome (KTWS) characterized by recurrent superficial vein thrombosis (SVT) complicated by an episode of disseminated intravascular coagulation (DIC) who ultimately was maintained on prophylactic rivaroxaban to prevent recurrent thrombotic events. We performed a literature search to identify similar cases and to summarize common presenting features and attempted treatment modalities. CASE DESCRIPTIONAn 18 year old man with KTWS presented with a large vascular malformation over his left chest and arm developed acute worsening SVT post sodium tetradecyl injection. Further investigation revealed a severe DIC was also present. On exam, the venous malformation and left arm were extremely tender with significant bruising. Presenting labs: Hg 24, platelet 98, bilirubin 588 (unconjugated 212), LDH 1597, PTT 32, INR 1.9, fibrinogen 1.1, Ddimer >20. He was treated with aggressive supportive care for DIC and routine deep vein thrombosis (DVT) prophylaxis with low-molecular-weight heparin (LMWH). Symptoms improved after anticoagulation was started. Ultrasound of his left arm revealed old SVT with recanulization within the venous malformation. He subsequently developed recurrent painful crises in his arm secondary to recurrent SVT. These were usually treated with short term LMWH. Imaging studies ruled out any deep vein thrombotic events. We eventually elected to commence indefinite duration anticoagulation with rivaroxaban 10mg daily with significant decrease in further acute flares. METHODSTo review how thrombotic manifestations of KTWS are managed, we performed a comprehensive literature search on PubMed using MESH terms: Klippel Trenaunay Weber Syndrome, Thrombosis, DIC and Kasabach-Merritt coagulopathy. RESULTSWe found 99 abstracts. 87 were excluded for non thrombotic complications of KTWS. 13 case reports focusing on treatment of thrombotic manifestations of KTWS were analyzed further. These included 12 case reports reviewing management of DVT in KTWS and 1 case report reviewing management of SVT in KTWS however with no DIC. 3 of these abstracts also reviewed management of coagulopathy (DIC or local intravascular coagulopathy). Of the 12 case reports, 5 described patients with deep vein thrombosis in KTWS treated with therapeutic warfarin; 4 patients improved however 1 died of cor pulmonale. An additional 5 cases of DVT in KTWS were successfully managed with therapeutic LMWH. 2 of these cases were also complicated by DIC. One case report described use of therapeutic rivaroxaban (20mg daily) to manage DVT in KTWS. This case was also complicated by DIC. There were no case reports describing the prevention of SVT in KTWS. CONCLUSIONTo our knowledge this is the first case report to describe successful off-label use of prophylactic rivaroxaban to prevent further thrombotic events in a patient with KTWS. DisclosuresOff Label Use: RIVAROXABAN -- PROPHYLACTIC ANTI-THROMBOSIS FOR SUPERFICIAL VEIN THROMBOSIS. Wu:Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

International warfarin genotype-guided dosing algorithms in the Turkish population and their preventive effects on major and life-threatening hemorrhagic events.

To determine the accuracy of international warfarin pharmacogenetic algorithms developed on large multiethnic cohorts (comprising more than 1000 subjects) to predict therapeutic warfarin doses in Turkish patients. We investigated two Turkish warfarin-treated cohorts: patients with no history of hemorrhagic or thromboembolic event and patients with major and life-threatening hemorrhagic events. International pharmacogenetic algorithms showed good performances in predicting the therapeutic dose of patients with no history of bleedings, but they did not significantly detect the incorrect warfarin dose of patients with major and life-threatening hemorrhagic events. Although genetic information can predict the therapeutic warfarin dose, the accuracy of the international pharmacogenetic algorithms is not sufficient to be used for warfarin screening in Turkish patients.

Abstract T P137: Cerebral Ischemic Events In Patients With Therapeutic Warfarin Treatment

Background: Patients on long term warfarin treatment can have cerebral ischemic events despite therapeutic levels. We sought to determine unique patient attributes that result in ischemic events on therapeutic warfarin treatment. Methods: We reviewed the medical records and imaging data of consecutive patients with cerebral ischemic events who were on long term warfarin treatment over a 4 year period. We stratified the patients based on international normalized ratio (2.0-3.0 versus &lt;2.0) and compared the demographic and clinical characteristics between the two groups of patients. Results: A total of 163 patients (mean age±SD; 77.3 ± 11.2) on long term warfarin treatment were admitted with cerebral ischemic events (97 ischemic strokes and 40 transient ischemic attacks). The mean age was not different between patients who were sub therapeutic and therapeutic on warfarin (78.2 ±11.6 versus 77.5±10.5, p=0.7). The proportion of patients with hypertension (87.2% versus 84.0%, p=0.6), diabetes mellitus (44.2% versus 50.0 %, p=0.5), and cigarette smoking (7.0% versus 6.0%, p=0.8), was similar between the two groups. Patients who were therapeutic on warfarin were more likely to have large vessel atherosclerosis (8.0% versus 2.3 %, p=0.1) and small vessel disease (2.0% versus 1.2 %, p=0.6) and less likely to have atrial fibrillation (66.0% versus 77.5%, p=0.2) as the underlying etiologies for ischemic events. IV alteplase was used in 5 and none of patients who were sub therapeutic and therapeutic on warfarin, respectively. Conclusions: Patients who have concurrent predisposing factors appear to be at risk for cerebral ischemic events despite therapeutic warfarin treatment and concomitant preventive strategies should be evaluated.

Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study.

There are several pharmacogenetic algorithms to determine the warfarin doses required in patients treated for thromboembolism, but they only explain 60% of dose variation, suggesting that other genes may influence the dose required. This study aimed to evaluate the impact of clinical factors and CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, MDR1 3435C>T, APOE* ε4, and UGT1A1(TA)n polymorphisms on the warfarin dose required, especially in those individuals requiring a high warfarin dose. We studied 116 Brazilian patients who received warfarin therapy for thromboembolism. Associations between dose variability and age, body mass index (BMI), gender, use of warfarin antagonists, and genetic polymorphisms were examined. CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses. Of these subjects, 21% required a warfarin dose higher than 70 mg/week, which was associated with a BMI greater than 25 kg/m(2), use of warfarin antagonists, and the presence of the MDR1 3435T allele and UGT1A1(TA) 7 polymorphism. These individuals were considered to exhibit warfarin resistance. The individuals with the MDR1 3435TT genotype required a dose 21% higher than that required by 3435CT and 3435CC individuals. The UGT1A1(TA) 7 allele was positively correlated with the warfarin dose. CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses, while MDR1 3435C>T and UGT1A1(TA) n polymorphisms were associated with a requirement for higher doses. This is the first study to evaluate warfarin resistance, APOE *ε4 and UGT1A1(TA) n genotypes in the Brazilian population, and the association of these two genotypes with warfarin dose required.

Warfarin pharmacogenomics: recommendations with available patented clinical technologies.

Warfarin pharmacogenomic testing has become a prime example of the utility of personalized molecular testing in the modern clinical laboratory. Warfarin is a commonly used drug for the prevention and treatment of thromboembolic complications in a variety of clinical situations. However, a number of factors lead to a high interindividual variability in dose requirements. Among the primary factors in this variability are genetic polymorphisms in general patient populations, which can account for 35-50% of varying dose requirements among patients. In this review, we discuss the implications of polymorphisms in the cytochrome P-450 enzyme 2C9 (CYP2C9) and Vitamin K Epoxide Reductase Enzyme Complex subunit 1 (VKORC1) as they relate to therapeutic warfarin dosing. We discuss the clinical utility of pharmacogenomics testing as related to warfarin dosing, and propose a clinical model for the implementation of the pharmacogenomic test results. Finally, we provide a brief overview of the currently available commercial testing platforms with discussion of the complexities of utilizing patented methodologies in bringing genetic testing such as this to the clinical laboratory.

Pyrosequencing of the CYP2C9 -1766T>C polymorphism as a means of detecting the CYP2C9*8 allele.

The CYP2C9 c.449G>A (p.R150H, rs7900194) polymorphism, which confers the CYP2C9*8 allele, is common in persons of African descent and results in reduced clearance of the narrow therapeutic index drugs, warfarin and phenytoin. Because of significant homology in DNA sequence at the 449G>A locus among CYP2C genes, the 449G>A variant cannot be reliably detected via PCR-based genotyping assays that require a short PCR product, such as pyrosequencing. Herein, we propose genotyping for the CYP2C9 c.-1766T>C polymorphism via pyrosequencing as an alternative and accurate means of identifying the CYP2C9*8 allele.

Warfarin monitoring in antiphospholipid syndrome and lupus anticoagulant.

To review the available literature on international normalized ratio (INR) and chromogenic factor X (CFX) monitoring in patients with antiphospholipid syndrome (APS), specifically lupus anticoagulant (LA), and furthermore, to identify benefits of one monitoring test compared with the other in the presence of LA. A literature search was conducted through MEDLINE (1946-May 2014) utilizing the following MeSH terms chromogenic compounds, anticoagulants, and factor X. Further articles were identified from original literature citations. All English-language studies were included that involved INR and/or CFX monitoring in APS patients that focused on a therapeutic anticoagulation level with warfarin therapy. A total of 55 articles were identified, of which nine are referenced because of their relevance for this review: three articles focus on the efficacy of utilizing INR monitoring in patients with APS, five focus on CFX compared with INR for therapeutic warfarin dosing, and one compares different thromboplastins utilizing both INR and CFX monitoring. INR monitoring in patients with APS, specifically LA, was not found to be reliable because thromboplastin reagents are sensitive to LA. Furthermore, when INR was compared to CFX, patients with LA had supratherapeutic INRs despite having CFX within goal range. In a subgroup of APS patients, INR monitoring may not be safe for determining the dose of warfarin because their INR values can be falsely elevated. Although CFX monitoring is more accurate, it too comes with its own downsides. Managing warfarin therapy in the APS population needs to be individualized.

Outcomes of pharmacogenetics-guided dosing of warfarin: A systematic review and meta-analysis

Warfarin is one of the most widely used oral anticoagulants, with a narrow therapeutic window and high inter-individual variability in the dose needed to achieve target INR [1–4]. It was reported that the gene CYP2C9 and VKORC1 polymorphisms in the population may affect the therapeutic warfarin dose requirement, which could increase the risk for over anticoagulation and hemorrhage complicat ions during warfar in treatment [1–3] . A number of pharmacogenetics-based algorithms integrating patients' demographic data and different genotypes have been established to predict the dose of warfarin [1,2,4–8]. Existing clinical trials [1,2,4–8] were performed to investigate the efficacy and safety of pharmacogeneticsguided warfarin dosing, but the results were controversial. Recently, the EU-PACT study reported that pharmacogenetics-based dosing of warfarin was better than standard dosing, with higher percentage of time in the therapeutic INR range (PTTR) than that of standard clinical during the initiation of warfarin therapy [1]. However, the COAG study failed to show the advantage of pharmacogenetics compared to conventional dosing procedures [2]. To further explore this, we performed the current meta-analysis to systematically investigate it. Subgroup and meta-regression analyses were used to study potential confounding factors. We searched the Pubmed, Embase and the Cochrane Library, using the

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy.

CYP2C9 metabolizes approximately 20% of clinically used drugs, including the narrow therapeutic window drugs warfarin and phenytoin. More than 16,000 variants have been reported in the National Center for Biotechnology Information CYP2C9 database, as well as 58 alleles in the official P450 Nomenclature Committee website. Two single nucleotide polymorphisms represented by the CYP2C9*2 and CYP2C9*3 alleles have been studied extensively. However, in addition to these two alleles, other genetic factors and an individual's biological characteristics contribute to the overall drug phenotype. A major bottleneck for CYP2C9 pharmacogenomics in clinical field applications is the lack of knowledge regarding the numerous genetic polymorphisms and their molecular functionalities. An unmet gap exists between the ever-growing number of genetic variants and their molecular mechanisms. In the present review, functional changes of all known CYP2C9 protein coding alleles were predicted using in silico analyses and compared with the in vitro and in vivo data. We also summarize functional information from recently reported CYP2C9 variants. Regarding the previously known CYP2C9 variants, we provide an update on the functional information obtained from in vitro and in vitro data.