Stable Anticoagulation Research Articles

Letter to the Editor Unexplained thrombosis of the aortic arch with distal embolization in a patient with altered fibrin clot properties

Letter to the Editor Unexplained thrombosis of the aortic arch with distal embolization in a patient with altered fibrin clot properties

Pharmacological basis and clinical evidence of dabigatran therapy

Dabigatran is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. It has been approved in the European Union and the United States of America for the prevention of thrombosis after major orthopedic surgery. It has also been approved by the American Food and Drug Administration and the European Medicines Agency for the prevention of stroke in chronic atrial fibrillation. Dabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, dabigatran may suppose a revolution in oral anticoagulation. However, two important limitations remain. First, it is contraindicated in patients with end-stage renal disease. Second, there is no evidence of the prevention of thrombosis in mechanical heart valves.

The VKORC1 and CYP2C9 Genotypes Significantly Affect Vitamin K Antagonist Dosing Only in Patients Aged 20 Years or Older

Abstract 1243 INTRODUCTION:Anticoagulation with Vitamin K antagonists (VKA) is problematic due to difficulties in safely managing dosing. Polymorphisms in cytochrome P450 C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. Recently we reported that, in children, the VKORC1 and CYP2C9 genotypes play insignificant roles in explaining variation in VKA dosing (Nowak-Gottl et al. Blood 2010 116:61–1–6105). Given the qualitative differences in the role these polymorphisms play in VKA dosing variation between adults and children, we were interested in determining at what age these polymorphism begin to play a role in variation in VKA dosing. Understanding at which age these genotypes begin to play a significant role will lead to only screening patients in whom there would be potential benefit from the knowledge of their VKA dose related genotypes. METHODS:We performed a prospective cohort study of patient’s 1–30 years of age, who were receiving VKA and were considered to be on stable anticoagulation. Stable anticoagulation was defined as a VKA requirement remaining constant for 3 consecutive measurements after achieving the target INR (target INR 2.0–3.0). Blood samples were collected for DNA with which VKORC1 and CYP2C9 genotyping were performed. Patient demographics and data on VKA dose (mg/kg) were collected. The VKA dose (mg/kg) was transformed by taking the square root of the dose values to produce an approximate symmetric distribution. Multiple linear regression of the transformed VKA dose was used to assess its relationship with genetic and clinical/demographic variables. VKORC1 genotypes were categorized into three groups (AA, GA, and GG) and CYP2C9 genotype into two groups (any mutation 1.2, 1.3 or 2.2, and wild type 1.1). Gender and INR were not associated with VKA dose and were removed from the model. The final model used weight, VKORC1 and CYP2C9 genotypes as explanatory variables which were fit for the following age groups: 1– 13 years, 14–19 years, 20–30 years. Weight was used in the model but was highly positively correlated with age and body mass index. A summary of the fitted models (partial R2 and p value) is reported in Table I.TABLE I:Summary of Fitted Models in the Three Age GroupsVariable1–13 years Partial R2(p value)14–19 years Partial R2(p value)20–30 years Partial R2(p value)Weight*41.0% (p=0.014)*15.9% (p=0.01)3.2% (p=0.51)VKORC1 (AA,GA)12.6% (p=0.12)4.8% (p=0.29)**29.8% (p=0.038)CYP2C9 (1.2, 1.3, 2.2,3.3)0.1% (p=0.6)1.1% (p=0.53)**12.7% (p=0.018)NOTE: The value for the partial R2 indicates the percent of the variation in the VKA dosing associated with the individual variables in the model. For example: Weight explains 41.0% of the variation in VKA dosing in patients aged 1–13 years. RESULTS:A total of 91 patients were recruited (1–13 years n=18, 14–19 years n=44, 20–30 years n=29). The distribution of genotypes in the study population were consistent with previous reports in the literature (VKORC1 AA (12%) GA (43%) GG (45%); CYP2C9 1.1 (68%), 1.2 (20%), 1.3 (14%) 2.2/2.2/3.3 (2%). In the regression model in patients 1–13 years of age and 14–19 years of age, *weight explained the dosing variation significantly and far more than the two genes. The polymorphisms in VKORC1 or CYP2C9 were not significantly associated with VKA dosing in this age range and there was no significant difference in dosing among differing genotypes. In contrast, in the age group 20–30 years, weight was no longer significantly associated with variation in VKA dosing. However, ** VKORC1 and **CYP2C9 were significantly associated with variation in VKA dosing in patients over the age of 20 years. Also, in the 20–30 year age group carriers of VKORC1 AA genotype required significantly lower daily doses than GG genotypes (p-value=0.036). CONCLUSION:Assessing genotypes in patients under the age of 20 has little clinical relevance explaining no more than 12.7% of variation in VKA dosing. Weight or age have a far greater effect on dosing variation under the age of 20 years. However, in patients 20 years of age or older, the VKORC1 and CYP2C9 genotypes play a significant role, explaining 42.5% of the variation in VKA dosing. Designing models based on the differences in the various age groups is important for optimizing VKA dosing. Disclosures:No relevant conflicts of interest to declare.

Therapie der Beinvenenthrombose und der Lungenembolie

Deep vein thrombosis and pulmonary embolism may be considered as different manifestations of the same disease: venous thromboembolism. Under the condition of entirely stable hemodynamics, treatment follows exactly the same principles. The phase of initial therapy has a duration of 5-10 days and has remained so far a domain of parenteral anticoagulants (low molecular weight heparin, fondaparinux). The phase of early maintenance therapy is instituted with an overlap and has a duration of 3-6 months; vitamin K antagonists with a target INR of 2.0-3.0 are the standard. Patients with a high risk of recurrence and a low risk of bleeding will enter a phase of prolonged or even indefinite maintenance therapy. Again, vitamin K antagonists with a target INR of 2.0-3.0 are the standard. A target INR of 1.5-2.0 may be considered an alternative for patients in whom a very stable anticoagulation with less frequent INR testing is desirable. Clear recommendations can be made for venous thromboembolism treatment in pregnancy, in the post partum and lactation periods, as well as for patients with severe renal impairment. New anticoagulants (thrombin inhibitors, factor Xa inhibitors) have made significant progress in their clinical development and will soon become available as an alternative for all three phases of therapy.

Establishment of pharmacogenomic algorithm for predicting stable warfarin dose in Chinese patients

BackgroundGenetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated....

Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy

AbstractSingle-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P = .52, P = .28) and risk of overanticoagulation (P = .64, P = .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.

Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and pharmacodynamic substudy

Establishing factor IX inhibition in patients with acute coronary syndrome/non-ST-elevation myocardial infarction (ACS/NSTEMI), a setting characterized by increased factor IX activity, is critical to investigate the REG1 system in this target population. The REG1 system (Regado Biosciences, Basking Ridge, NJ) consists of pegnivacogin (RB006), an RNA aptamer that directly inhibits factor IXa, and anivamersen (RB007), its complementary control agent. RADAR is a Phase 2b study investigating the use of pegnivacogin in patients (n = 800) with ACS undergoing planned early cardiac catheterization. To validate dose selection and stability of anticoagulation throughout the time of cardiac catheterization at an early stage of the clinical trial, 33 patients, 22 of whom had not received recent prior heparin, underwent thorough pharmacokinetic and pharmacodynamic assessment. Fold prolongation of activated partial thromboplastin time (aPTT) was used to impute factor IX inhibition. Pegnivacogin 1 mg/kg rapidly achieved a high pegnivacogin plasma concentration (26.1 ± 4.6 µg/mL), prolonged the aPTT (mean aPTT 93.0 ± 9.5 s), and approached near complete factor IX inhibition (mean fold increase from baseline 2.9 ± 0.3). These levels remained stable from the time of drug administration through completion of the catheterization. Pegnivacogin administered at a weight-adjusted dose of 1 mg/kg consistently achieves a high level of factor IX activity inhibition among patients with ACS and provides stable anticoagulation during cardiac catheterization. These findings support the dose of pegnivacogin selected for the RADAR study.

Guidelines on oral anticoagulation with warfarin – fourth edition

Guidelines on oral anticoagulation with warfarin – fourth edition

Extreme sensitivity to acenocoumarol therapy in patient with both VKORC.-1639 A/A and CYP2C9*1/*3 genotypes

The initiation phase of vitamin K antagonist (VKA) is a challenging and demanding process that can result in adverse event such as bleeding. Dosing is influenced by a variety of acquired factors, while another factor that is associated with the optimal dose is the presence of certain genetic variants. We describe a 73years old male who required extremely low dose of acenocoumarol (0.33mg/day) to reach the target INR of 2-2.5. During initiation of VKA he started with usually recommended doses of acenocoumarol: 4mg/day for the first 2 days and 3mg/day during next 2 days. On fifth day of initiation, massive haematuria occurred and INR level of 10.5 was recorded. Patient was transfused with three doses of fresh frozen plasma in order to stop the bleeding. Acenocoumarol dose was gradually reduced after every INR laboratory monitoring and finally a dose of 0.33mg/day was required for maintain stable anticoagulation. The genotyping results performed after introducing of VKA showed the patient was homozygous for vitamin K epoxide reductase (VKORC1) c.-1639 G>A, and heterozygous for cytochrome P450 2C9 (CYP2C9)*3 which pointed to extreme sensitivity to acenocoumarol. Our case supports the need for prospective genotyping of CYP2C9 and VKORC1 prior to initiation of VKA where pharmacogenetics, as a good predictor of extreme sensitivity to VKA, could help to tailor optimal VKA dose.

Recombinant Thromboplastins vs Tissue-Extract Thromboplastins in Patients on Unstable Oral Anticoagulant Therapy

To the Editor: In a previous report in Clinical Chemistry , we described much higher international normalized ratios (INRs)1 with recombinant Neoplastin R (Roche Diagnostics) than with tissue-extract Neoplastin Plus (Roche Diagnostics) in patients initiating oral anticoagulant therapy (1). For patients on stable oral anticoagulation, we observed no significant differences in INRs between the thromboplastins. The increased INR values with Neoplastin R during unstable anticoagulation, such as in the initial phase of oral anticoagulation treatment, could be explained by fluctuations in coagulation factor VII (FVII) concentrations owing to the low half-life of FVII. Recombinant thromboplastin exhibits an increased sensitivity for FVII compared with tissue-derived thromboplastin (2, 3). The difference in sensitivity between Neoplastin R and Neoplastin Plus for FVII could implicate alterations in anticoagulation dosage and time period in obtaining stable anticoagulation. We investigated whether our findings could be extrapolated to other recombinant thromboplastins. We collected and citrate-treated blood samples from 20 patients in the initial phase of …

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P=0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (P<0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R(2)=0.3499; P<0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients.

Miconazole and nystatin used as topical antifungal drugs interact equally strongly with warfarin

Medline search disclosed 10 case reports of interactions between oral anticoagulants and miconazole oral gel, but none so far between nystatin solution and anticoagulants. We report on change in anticoagulant activity with use of different topical antifungal drugs, miconazole oral gel and vaginal suppositories, and nystatin solution. We conducted a retrospective study that included 43 patients on stable anticoagulation before the introduction of topical antifungal drugs. Miconazole oral gel was prescribed for 32 patients, nystatin solution for eight patients and miconazole vaginal suppositories for three patients. Nineteen (44·2%) of the patients reported bleeding complications and some of these were severe. Fifteen of 32 who used miconazole oral gel and four of 8 of those who used nystatin solution were affected. Before use of the antifungal drugs, the mean weekly warfarin dose in the nystatin group was 14·5 mg, and after antifungal drugs, 9 mg, P = 0·038, while the mean international normalized ratio (INR) before antifungal drugs was 2·5 (range 1·9-3·5) and afterwards it was 10·6 (range 4·5-19·3), P = 0·0001. In the miconazole oral gel group the mean weekly warfarin dose was 15·7 mg, and after 10·8 mg, P = 0·008, while the mean INR before antifungal drugs was 2·44 (range 1·92-3·18) and afterwards it was 8·8 (range 4·9-16·9), P < 0·0001. Miconazole oral gel and topically applied nystatin solution have equally strong effects on warfarin activity and can provoke major bleeding. Prospective evaluation of this effect is called for. However, based on our results the warfarin dose adjustment appears necessary when the anticoagulant is used concomitantly with those topical antifungals.

Effect of the VKORC1 Genotype on Warfarin Dose Requirements in Japanese Pediatric Patients

The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.

Clinical study of anticoagulation with warfarin and heparin in patients after mechanical valve replacement

To investigate the effect of different methods of anticoagulation after mechanical valve replacement. Totally 172 cases of mechanical valve replacement performed from October 2005 to June 2008 were divided into two groups and then analyzed retrospectively. Patients on warfarin and heparin were classified as the heparin group while those on warfarin alone were classified as the warfarin group. The operation, anticoagulation, anticoagulation index and associated complications were recorded to compare the effect of anticoagulation between two groups. warfarin group: the overall anticoagulation effect was satisfactory except for cerebral embolism (n=1, 1.1%) and lower gastrointestinal hemorrhage (n=1, 1.1%) during hospitalization. Heparin group: no anticoagulation-related complication was found. The time to reach stable warfarin anticoagulation was shorter than the warfarin group and difference was of significance (8 d±3 d vs 11 d±4 d, P<0.01). After adjustment of potential confounding factors such as age, gender, weight by linear regression analysis, the result showed that, the time to reach stable warfarin anticoagulation was shortened than the warfarin group by 2.11 days. Statistical significance of difference was observed between two groups (P<0.01). It is both safe and effective to anticoagulated the patients after mechanical valve replacement with warfarin and heparin.

Factores genéticos y ambientales asociados con la respuesta a warfarina en pacientes colombianos

Warfarin is an anticoagulant that is difficult to administer because of its narrow therapeutic margin and the numerous factors that influence patient response. Demographic, clinical and genetic variables were characterized to establish the appropriate maintenance dosages of warfarin. The Colombian patients consisted of 145 adults of both sexes. They were in stable anticoagulation status with international normalized ratio between 2 and 3 for at least two months, and without changes in the warfarin commercial preparation or in the dosage. After signing the informed consent, the following data was recorded for each volunteer: age, gender, weight, height, smoker status, co-morbidity, co-medication, International Normalized Ratio (INR), warfarin dose, and commercial brand. Each patient was typed for genes CYP2C9, VKORC1, CYP4F2 and PROC; for 59 patients, the serum levels of warfarin were quantified. The genotyping and the blood quantification were performed by mini-sequencing and HPLC methods, respectively. Age, co-medication with enzymatic inhibitors (amiodarone, sertraline, fluoxetine) or inducers (phenytoin, carbamazepine), and the alleles rs1799853 (*2) and rs1057910 (*3) of the CYP2C9 gene, as well as rs9923231 of the VKORC1 gene were associated with warfarin dose required to achieve anticoagulation with INR of 2-3. These variables were included in a multiple linear regression model for predicting the optimum dose/week of warfarin. This resulted in an algorithm that explained 47.4% of the variability in the dose responses. Clinical and pharmacogenetic variables provided a basis for improving the safety and effective dosage of warfarin; however, the use of a pharmacogenetic algorithm will require patient data obtained during clinical trials.

The c.-1639G&gt;A polymorphism of the VKORC1 gene in Serbian population: retrospective study of the variability in response to oral anticoagulant therapy

A single nucleotide polymorphism c.-1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral vitamin K antagonist (VKA). Our aim was to study the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in a group of patients under stable anticoagulation, and to estimate the variability in response to VKA. We conducted a retrospective cohort analysis of 200 stable anticoagulation patients followed from the initiation of VKA. Out of 43 low-dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high VKA dose; among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. Patients with GG genotype required 2.6 times higher dose than patients carriers of AA genotype (P < 0.0001). Carriers of AA genotype were more likely to be overanticoagulated during follow-up after initiation of VKA when compared with carriers of the GA and GG genotypes (P < 0.0001). Patients with GG genotype spent more time below therapeutic range compared with patients carriers of AA (P = 0.0328) and GA genotype (P < 0.0001). VKORC1 c.-1639G>A polymorphism significantly influenced VKA dose and represented a good predictor of individuals predisposed to unstable anticoagulation. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients, carriers of AA genotype, before the initiation of anticoagulation.

Compartment syndrome of the thigh. A case report with delayed onset after stable pelvic ring fracture and chronic anticoagulation therapie

Compartment syndrome of the thigh is a rare occurrence potentially leading to devastating functional restrictions. There is a wide spectrum of reported conditions leading to increased tissue pressure in the thigh possibly resulting in a compartment syndrome, ranging from deep venous thrombosis to blunt injuries and femoral fractures. We report a case of a delayed development of a compartment syndrome of the thigh secondary to an undisplaced anterior pelvic ring fracture and chronic anticoagulation therapy in a 94-year-old woman. Regarding anticoagulation therapy there are numerous reports about the spectrum of bleeding complications during therapy, however this severe complication has to our knowledge not been reported previously. Treatment consisted in immediate fasciotomy and subsequently secondary wound closure.

Improved Stability in INR with Coumadin for a Patient Requiring Very Low Warfarin Doses

Objective: To describe a patient who required very low doses of warfarin but who could not achieve therapeutically stable anticoagulation until treatment was switched from generic to branded warfarin. Case Summary: A 53-year-old male with a history of hypertension, coronary artery disease, heart failure, and mild renal insufficiency was diagnosed with atrial fibrillation during a routine examination. Anticoagulation was started with warfarin 5 mg daily. The patient presented to the anticoagulation clinic 2 days later with an international normalized ratio (INR) of 5.4 and no signs or symptoms of bleeding. Warfarin was held for 3 days until the INR was &lt;3. Warfarin was then restarted at 2.5 mg daily. Over the next week his INR rose to 4.8; warfarin was again held and restarted at 1.5 mg/day. Although the warfarin dose was eventually titrated to 6.5 mg/wk, the INR never stabilized and the patient only had consecutive therapeutic INRs twice in 1 year and only one 3-month period with therapeutic INRs not requiring any dosage adjustments. The decision was made to switch from the generic product to Coumadin to try to improve stability. Several dosage adjustments were made over the 6 weeks following the switch before the INR was stabilized with 7 mg/wk. Subsequent INRs ranged from 2.0 to 2.2 in the 3 months after the switch, during which time INRs were measured at least weekly. Over 14 months after the switch, the patient did not have an INR outside of the therapeutic range. Discussion: Many patients are able to take generic warfarin without problems. However, case reports have documented occasional patients who have had problems after switching to a generic product. Large cohorts have been switched to generic warfarin without experiencing significant changes in therapeutic control. However, 1 cohort study found that patients who required very low warfarin dosages had significant changes in their INR after switching to a generic product. Conclusions: Patients who require very low warfarin dosages to consistently maintain therapeutic anticoagulation may experience less therapeutic stability while on a generic product.

A Novel, Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an “acenocoumarol-dose genotype score” (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (>28mg/week) compared with the low-dose (<7mg/week) group (mean(SEM) of 84.1±3.4 vs. 62.2±4.8, P = 0.008). An AGS>70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112–10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation.

Abstract LB-77: A randomized double-blind placebo-controlled phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small cell lung cancer: Correlative analyses

Abstract Background: Sorafenib is an oral multikinase inhibitor of angiogenesis and cellular proliferation which has shown preliminary activity in non-small-cell lung cancer (NSCLC). We conducted a multicenter phase II trial of erlotinib +/− sorafenib in 2nd/3rd line NSCLC. Methods: Patients with previously treated stage IIIB/IV NSCLC were eligible (1-2 prior regimens). Additional eligibility criteria included: ECOG performance status 0-2, all NSCLC histologies, measurable disease, adequate organ function, and the absence of major cardiovascular disease. Patients with treated brain metastases and/or on stable anticoagulation were eligible. Patients were stratified according to squamous/non-squamous histology, prior bevacizumab use, and line of therapy and were randomized 2:1 to receive erlotinib 150mg orally once daily and sorafenib 400mg orally twice daily, or erlotinib and placebo. Patients were also consented for biomarker testing for epidermal growth factor receptor (EGFR) mutations, EGFR amplification, and K-ras mutations. The primary endpoint was to assess the efficacy of each arm in terms of objective response rate (ORR) and progression-free survival (PFS). The trial was designed to enroll 168 patients to demonstrate a 40% improvement on an historical 2.2 month PFS (&amp;gt; 80%, 1-sided 0.1). Results: 168 patients were enrolled from February 2008 to February 2009. Baseline characteristics were well-matched between cohorts (median age, 65 years; 3rd line therapy, 39%; prior bevacizumab, 36%; squamous histology, 30%). The ORRs for the sorafenib/erlotinib and erlotinib/placebo cohorts were 8.1% v. 10.9%, respectively (p=.55). However, the disease control rates (ORR + proportion of patients with stable disease) were 54.1% (sorafenib/erlotinib) v. 38.2% (erlotinib/placebo) (p=.06). The median PFS was 3.25 months (sorafenib/erlotinib) v. 1.87 months (erlotinib/placebo) (HR 0.86 [95% CI 0.60, 1.22], p=.20). 72 (44%) patients had material assessable for EGFR mutation analysis. Among the 67 patients who were found to have EGFR wild-type (WT) tumors, the median PFS was 3.25 months (sorafenib/erlotinib) v. 1.71 months (erlotinib/placebo) (HR 0.55 [95% CI 0.32, 0.96], p=.02). Conclusions: Additional preplanned subset analyses based on histology, EGFR amplification, K-ras mutation, prior bevacizumab treatment, and line of therapy will be presented, as well as updated overall response, PFS, survival, and toxicity data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-77.