Prior Warfarin Research Articles

Evaluation of Bleeding Events Requiring Hospitalization in Patients With Atrial Fibrillation Receiving Dabigatran, Warfarin, or Antiplatelet Therapy

Objective: To determine the incidence and severity of bleeding events requiring hospitalization among patients with atrial fibrillation (AF) receiving anticoagulants (dabigatran or warfarin) or antiplatelet agents (eg, aspirin and clopidogrel). Methods: This was a single-center, retrospective cohort study involving 1494 patients with AF hospitalized from November 1, 2010, to November 1, 2011, with prior warfarin, dabigatran, or antiplatelet therapy. Results: Overall bleeding events in the dabigatran group compared to the warfarin group were 24% and 12%, respectively (P = .004). Of these events, individually, there were no significant differences in major (56% vs 58%, P = .88), life-threatening (25% vs 36%, P = .38), or minor bleeding (44% vs 42%, P = .06). Gastrointestinal (GI) bleeding occurred more in the dabigatran group compared to the warfarin group (P = .02). Intracranial bleeding occurred in 15% of patients in the warfarin group and did not occur at all in the dabigatran group. Warfarin patients had significantly more overall bleeding events compared to antiplatelet therapy (P < .001), with an increasing trend seen in major bleeding (P = .06). GI bleeding, however, favored the warfarin group over the antiplatelet group (48% vs 73%, P = .04). Conclusion: Anticoagulation with dabigatran was associated with an overall increased occurrence of bleeding requiring hospital admission compared to warfarin. GI bleeding was more prevalent with dabigatran and antiplatelets than with warfarin. There were more intracranial hemorrhages seen in the warfarin group.

PCV62 - Patterns and Predictors of Discontinuation and Switch in Atrial Fibrillation Patients Treated with Non-Vitamin K Antagonist Oral Anticoagulants

Recent clinical trials have established non-vitamin K antagonist oral anticoagulants (NOACs) as viable alternatives to warfarin in stroke prevention for atrial fibrillation. A major challenge in routine clinical practice is the high rate of medication discontinuation and switching. There are currently few large studies offering estimates of drug persistence with NOACs. Moreover, little is known about what drives patients’ choice and behavior regarding patterns of long-term medication use. Using a large heterogeneous cohort of patients, we aimed to investigate the patterns and predictors of switch and discontinuation among patients initiating NOACs. We performed a retrospective cohort analysis using a large U.S. commercial insurance database, OptumLabs Data Warehouse. We identified 10,147 privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who initiated apixaban, dabigatran and rivaroxaban in 2013 and 2014, the time period when all three NOACs had become available in the U.S. Discontinuation of anticoagulation was defined as having at least 3 months of gap in days of supply of any oral anticoagulants. Two multivariable logistic regression models were performed to assess the risk factors related switch and discontinuation, respectively. Within one year of NOACs initiation, 13% of the patients switched to another oral anticoagulant, among whom the majority (64%) switched to warfarin. Nearly 40% of patients discontinued oral anticoagulants. Patients initiating apixaban were less likely to switch or discontinue compared to those initiating dabigatran or rivaroxaban. Other risk factors for switch include high out-of-pocket costs, prior warfarin use, and a stroke during follow up. Risk factors for discontinuation include high out-of-pocket costs, no prior warfarin exposure, and a major bleeding during follow up. Medication discontinuation and switching are common among patients treated with NOACs in routine clinical practice. Medication use may be affected by the choice of initial medication, out-of-pocket costs, and clinical events occurring during follow up.

Prognostic significance of delayed intraventricular haemorrhage in the INTERACT studies

Background and purposeIntraventricular extension of intracerebral haemorrhage (ICH) predicts poor outcome, but the significance of delayed intraventricular haemorrhage (dIVH) is less well defined. We determined the prognostic significance of dIVH...

Cost-effectiveness of edoxaban vs warfarin in patients with atrial fibrillation based on results of the ENGAGE AF–TIMI 48 trial

In 21,105 patients with atrial fibrillation (AF), the ENGAGE AF-TIMI 48 trial demonstrated that both higher dose (60mg/30mg dose reduced) and lower dose (30mg/15mg dose reduced) once-daily regimens of edoxaban were non-inferior to warfarin for the prevention of stroke or systemic embolism (SE), with significantly lower rates of bleeding and cardiovascular death. Higher dose edoxaban was associated with a greater reduction in the risk of ischemic stroke than lower dose edoxaban, and the FDA approved higher dose edoxaban in patients with creatinine clearance ≤95mL/min. This study evaluated the economic value of higher dose edoxaban vs warfarin based on data from patients in ENGAGE within the FDA-approved population. We assessed the cost-effectiveness of edoxaban vs warfarin over a lifetime horizon from the US healthcare system perspective using a Markov model based on a combination of ENGAGE AF-TIMI 48 trial data, US life tables, and published literature on the costs and long-term outcomes of non-fatal cardiovascular and bleeding events. Data from the ENGAGE AF-TIMI 48 trial were used to calculate age-adjusted event rates for warfarin and hazard ratios (HRs) for the relative impact of edoxaban on embolic and bleeding complications. Based on the wholesale acquisition price, edoxaban and warfarin were assumed to cost $9.24 and $0.36/day, respectively. For edoxaban vs warfarin, lifetime incremental costs and QALYs were $16,384 and 0.444, respectively, yielding an incremental cost-effectiveness ratio (ICER) of $36,862/QALY gained, using data from patients with creatinine clearance ≤95mL/min in ENGAGE AF-TIMI 48. ICERs were more favorable for patients without compared to those with prior warfarin use; ICERs differed minimally by CHADS2 score. Despite its higher acquisition cost, edoxaban is an economically attractive alternative to warfarin for the prevention of stroke and SE in patients with atrial fibrillation and creatinine clearance ≤95mL/min. These results were robust to variation of key model parameters, including assumptions regarding the cost and quality-of-life impact of stroke and bleeding events, and were favorable across both CHADS2 score stroke-risk categories.

Impact of video technology on efficiency of pharmacist-provided anticoagulation counseling and patient comprehension.

Discharge anticoagulation counseling is important for ensuring patient comprehension and optimizing clinical outcomes. As pharmacy resources become increasingly limited, the impact of informational videos on the counseling process becomes more relevant. To evaluate differences in pharmacist time spent counseling and patient comprehension (measured by the Oral Anticoagulation Knowledge [OAK] test) between informational videos and traditional face-to-face (oral) counseling. This prospective, open, parallel-group study at an academic medical center randomized 40 individuals-17 warfarin-naïve ("New Start") and 23 with prior warfarin use ("Restart")-to receive warfarin discharge education by video or face-to-face counseling. "Teach-back" questions were used in both groups. Although overall pharmacist time was reduced in the video counseling group (P < 0.001), an interaction between prior warfarin use and counseling method (P = 0.012) suggests the difference between counseling methods was smaller in New Start participants. Following adjustment, mean total time was reduced 8.71 (95% CI = 5.15-12.26) minutes (adjusted P < 0.001) in Restart participants and 2.31 (-2.19 to 6.81) minutes (adjusted P = 0.472) in New Start participants receiving video counseling. Postcounseling OAK test scores did not differ. Age, gender, socioeconomic status, and years of education were not predictive of total time or OAK test score. Use of informational videos coupled with teach-back questions significantly reduced pharmacist time spent on anticoagulation counseling without compromising short-term patient comprehension, primarily in patients with prior warfarin use. Study results demonstrate that video technology provides an efficient method of anticoagulation counseling while achieving similar comprehension.

Abstract W P375: Prior Antithrombotic Therapy, Initial Neurological Severity And 3-month Outcome In Acute Ischemic Stroke Patients With Non-valvular Atrial Fibrillation: The Samurai-nvaf Study

Background and Purpose: We aimed to assess whether prior antithrombotic therapy affects initial neurological severity and functional outcome in acute ischemic stroke patients with non-valvular atrial fibrillation (NVAF). Methods: Patients with NVAF who were admitted within 7 days after ischemic stroke onset from 2011 to 2014 were enrolled from the register of a prospective, multicenter, observational study (the SAMURAI-NVAF study). Patients receiving novel oral anticoagulants at onset were excluded from the study. They were classified into 3 groups: the non-WF group, patients without prior warfarin; the iWF group, those on warfarin with initial PT-INR below the target range; the sWF group, those on warfarin with initial PT-INR within or above the target range. They were also divided into patients without prior antiplatelet agents (the non-AP group) and those with (the AP group). Initial neurological severity was measured by NIHSS score. Poor functional outcome was defined by mRS 3-6 at 3 months of onset. Results: Of 1000 patients studied, 713, 221 and 66 were assigned to the non-WF group, the iWF group and the sWF group, respectively. Of all, 245 were assigned to the AP group, mainly taking aspirin (202 patients). On multivariate analysis, the sWF group (vs. the non-WF group) (standardized regression coefficient [β], -0.23; p&lt;0.001) was inversely associated with initial NIHSS score, but the iWF group (vs. the non-WF group) (β, -0.03; p=0.327) and the AP group (vs. the non-AP group) (β, 0.02; p=0.580) were not. The sWF group (vs. the non-WF group) (OR, 0.41; 95% CI, 0.21-0.77; p=0.005) was inversely associated with poor functional outcome, but the iWF group (vs. the non-WF group) (OR, 0.81; 95% CI, 0.55-1.18; p=0.267) and the AP group (vs. the non-AP group) (OR, 1.17; 95% CI, 0.80-1.71; p=0.413) were not. Conclusions: Prior sufficient warfarinization was associated with mild neurological severity and favorable outcome in acute ischemic stroke patients with NVAF, whereas prior insufficient warfarinization and prior antiplatelet therapy were not.

Hematoma expansion in spontaneous intracerebral hemorrhage: predictors and outcome

Background: Hematoma growth is an independent determinant of outcome in patients with intracerebral hemorrhage (ICH). Predictors of hematoma expansion are poorly defined. Our aim is to determine predictors of hematoma expansion in patients with ICH. Methods: We reviewed our prospective database of patients with ICH between January 2009 and June 2012. Patients were divided into two groups based on the presence or absence of hematoma expansion. Hematoma volume was calculated by thin volumetric cuts using special software. Expansion was defined as 33% increase in hematoma volume over 24 hours. We compared risk factors, laboratory parameters, medications and CT findings between the two groups using Fisher's exact test. A multivariate regression analysis was performed to identify predictors of expansion. Results: We identified 200 patients with ICH. On univariate analysis, patients with hematoma expansion were more likely to have Warfarin use (37% vs. 11% p = 0.001), low admission GCS (9 ± 4, 11 ± 4, p = 0.003), intraventricular hemorrhage (IVH) (79% vs. 45% p = 0.002) and hydrocephalus (43% vs. 22% p = 0.032). On multivariate regression analysis, prior Warfarin use (OR = 3.6, 95% CI: 1.3,10.3; p = 0.016) and IVH (OR = 5.7, 95% CI: 1.5,20.9; p = 0.009) were significant predictors of hematoma expansion. The ICU length of stay (8 ± 8 vs. 4 ± 6, p = 0.004), intubation rate (82% vs. 32%, p = 0.034), and hospital mortality (68% vs. 20%, p = < 0.001) were significantly higher among patients with hematoma expansion. Conclusion: Patient with prior Warfarin use and IVHs are at risk of hematoma expansion. Aggressive measures to prevent hematoma growth are important in these patients.

Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: Results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial

Patients with atrial fibrillation who are vitamin K antagonist (VKA)-naive may have a higher risk of thrombosis and/or bleeding than VKA-experienced patients. Using data from ARISTOTLE, we assessed baseline characteristics and the treatment effect of apixaban versus warfarin in the VKA-naive and VKA-experienced cohorts. We compared rates of study drug discontinuation and time-in-therapeutic range. Overall, 7,800 (43%) were VKA naive, and 10,401 were VKA experienced. At baseline, both groups were similar with respect to age and congestive heart failure, hypertension, age, diabetes, stroke score (CHADS2). Fewer VKA-naive patients had a history of prior stroke (18% vs 21%) or prior bleeding (10% vs 22%) and were more often female (39% vs 33%). The effect of apixaban on the primary efficacy and safety outcomes was similar in VKA-naive (stroke/systemic embolism: hazard ratio [HR] 0.86, 95% CI 0.67-1.11 and major bleeding: HR 0.73, 95% CI 0.59-0.91) and VKA-experienced populations (stroke/systemic embolism: HR 0.73, 95% CI 0.57-0.95, P value for interaction = 0.39 and major bleeding: HR 0.66, 95% CI 0.55-0.80, P value for interaction = 0.50). Permanent study drug discontinuation was numerically less likely in patients receiving apixaban whether they were VKA naive (HR for discontinuation: 0.87, 95% CI 0.79-0.95) or VKA experienced (HR for discontinuation: 0.93, 95% CI 0.85-1.02). Among patients receiving warfarin, the mean/median times in therapeutic range were lower in the VKA-naive group (VKA-naive: 57.5/61.4, VKA-experienced: 66.0/69.1, P < .001). The treatment effects of apixaban (vs warfarin) were not modified by VKA naivety. The rates of stroke/systemic embolism and major bleeding were numerically lower among the patients assigned to apixaban, irrespective of prior VKA use.

Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03)

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

Abstract 234: Prior Warfarin Treatment and Intracranial Hemorrhage among Patients With Acute Ischemic Stroke Treated With Intravenous Tissue Plasminogen Activator: A Meta-analysis

Background and Purpose: The risk for bleeding complications after intravenous thrombolysis for ischemic stroke in patients on warfarin with international normalized ratio [INR] ≤1.7) remains unclear. The aim of the current study is to perform a meta-analysis to determine whether there is an association between warfarin and risk of symptomatic intracranial hemorrhage (sICH). Methods: We searched MEDLINE, Web of Science and EBSCO databases for articles published through Jul 2012. A random-effects model was used to compute the pooled risk estimate. Results: Overall, 11 observational studies were identified that met our study inclusion criteria. This included 29,283 stroke participants treated with tPA; of which 2129 (7.3%) patients were on home warfarin prior treatment. Warfarin pretreatment was associated with an increased crude OR for symptomatic intracranial hemorrhage (sICH) (combined OR=1.77; 95% CI, 1.07~2.93;P=0.03).Of these studies, 7 studies had conducted a multivariate adjusted analyses, which demonstrated no association between warfarin use and increased risk of sICH following tPA use (combined adjusted OR=1.73; 95% CI, 0.91-3.28; p=0.10). Conclusions: These data suggested that the risk of sICH after thrombolytic therapy is not increased in patients using warfarin with sub therapeutic INR levels.

Warfarin treatment and thrombolysis

The study by Xian et al.,1 published in JAMA (June 27, 2012), adds to the growing literature on the safety of IV thrombolysis among stroke patients undergoing anticoagulation treatment. This study, which uses data from the American Heart Association Get With The Guidelines (GWTG)–Stroke Registry, concluded that there was no association between IV thrombolysis and symptomatic intracranial hemorrhage (SICH).1 These findings are in agreement with some2–4 but contrast with other studies (including 2 meta-analyses).5–8 The study by Xian et al. is the largest study to date drawing from hospitals throughout the United States, including 23,437 patients who received IV thrombolysis.1 Nearly 8% of these patients had prior warfarin use and 48.6% of the warfarin-treated patients who met the eligibility criteria did not receive IV thrombolysis.1

Risk of Intracranial Hemorrhage among Patients with Acute Ischemic Stroke Receiving Warfarin and Treated with Intravenous Tissue Plasminogen Activator: Xian Y, Liang L, Smith EE, et al. JAMA 2012;307:2600–8.

The authors of this retrospective observational study analyzed national data from the American Heart Association “Get with the Guidelines–Stroke Registry” to determine the safety of tissue plasminogen activator (tPA) administration for acute ischemic stroke in patients on prior warfarin therapy with an international normalized ratio (INR) of 1.7 or lower. The main outcome measure studied was symptomatic intracranial hemorrhage (sICH), with secondary outcome measures of systemic hemorrhage, any tPA complication, or in-hospital mortality. Of 23,437 total patients receiving tPA in the Registry, a total of 1802 (7.7%) patients were on warfarin before admission. Compared to their non-warfarin peers, these patients tended to have more comorbidities, and after adjustment for these characteristics the authors found no difference in primary or secondary outcomes between the two groups. Furthermore, the authors found no correlation between INR level (at or below 1.7) and sICH risk among patients on warfarin receiving tPA. The authors concluded that there is sufficient evidence to back American Heart Association guidelines that allow for the use of tPA for acute ischemic stroke in warfarin-treated patients with an INR≤1.7.

Pre‐ICH warfarin use, not antiplatelets, increased case fatality in spontaneous ICH patients

Anticoagulant and antiplatelets for prevention of ischaemic stroke and cardiovascular diseases may increase the risk of intracerebral hemorrhage (ICH). This study aimed to investigate the influence of pre-ICH use of anticoagulant and antiplatelets on ICH patients. Consecutive patients with acute spontaneous ICH registered in a single-center stroke registry during 2001 to 2010 were analyzed and categorized according to their pre-ICH use of warfarin (Group I), antiplatelets (Group II), or neither (Group III). Survival analysis and the Cox proportional hazard model were used to compare between the three groups and the predictors. Of 2021 ICH patients (male, 63.3%; mean age, 62.6 ± 14.4 years) included, there were 94 (4.7%) in Group I, 232 (11.4%) in Group II, and 1695 (83.9%) in Group III. Warfarin users had larger hematoma volume, more intraventricular extension, higher frequencies of lobar ICH, and higher case fatality than non-warfarin users (Groups II and III). The Cox proportional hazard model showed increased 6-month case fatality in pre-ICH warfarin users (adjusted hazard ratio 2.75, 95% confidence interval 2.04-3.72, P < 0.001), but not in pre-ICH antiplatelet users (adjusted hazard ratio 0.95, 95% confidence interval 0.72-1.26). Intracerebral hemorrhage patients with prior warfarin use, but not antiplatelet use, had significantly higher case fatality at 6 months.

Abstract 171: Warfarin Use And Stroke Risk Among Patients With Nonvalvular Atrial Fibrillation In A Large Managed Care Population

Introduction Warfarin discontinuation among real world nonvalvular atrial fibrillation (NVAF) patients is common. Hypothesis We hypothesized that in a managed care population, warfarin discontinuation is associated with increased stroke risk. Methods Patients who initiated warfarin therapy between Jan 2005 and Jun 2009 and had a healthcare claim related to AF within 30 days prior to the first warfarin claim, but no evidence of valvular disease, were included. Warfarin discontinuation was defined as a supply gap of &gt;60 days without evidence of International Normalized Ratio (INR) measurements. Follow-up was divided into periods of warfarin treatment and discontinuation. Stroke events were identified based on claims for inpatient stays with a primary diagnosis for stroke or transient ischemic attack (TIA). Cox proportional hazards models were constructed to assess the relationship between warfarin discontinuation and incident stroke while adjusting for baseline demographics, stroke and bleeding risk, and comorbidities, as well as time-dependent antiplatelet use, stroke, and bleeding events in the prior warfarin treatment period. Results The mean (SD) age of the study sample (N=16,253) was 67±12 years; 64.8% was male. Mean CHADS2 score was 1.84±1.30; mean HAS-BLED score was 2.00±1.18. Half (51.4%) of patients discontinued warfarin therapy at least once and the overall sample had a mean of 1.87 warfarin treatment periods during a mean of 668 days follow-up. Approximately 1186 patients (7%) had a stroke or TIA at any site of service during follow-up. Risk of stroke significantly increased during warfarin discontinuation periods compared with therapy periods (HR 1.60; 95%CI 1.35-1.90; P&lt;.0001). Stroke risk was significantly increased for patients with baseline CHADS2 score ≥2 (HR 2.69; 95%CI 1.44-5.03; P=.002), HAS-BLED score ≥3 (HR 1.46; 95%CI 1.05-2.05; P=.027), or who had a bleeding (HR 1.29; 95%CI 1.06-1.57; P=.013) or stroke event (HR 3.04; 95%CI 2.47-3.75; P&lt;.0001) in the prior treatment period. Conclusions In the real world, over half of patients on anticoagulation therapy had treatment gaps or permanently discontinued therapy. These usage patterns, as well as prior bleeding, were associated with increased stroke risk.

Thrombolytic therapy for ischaemic stroke in patients using warfarin: a systematic review and meta-analysis

BackgroundIt is uncertain whether thrombolytic therapy is safe in patients with acute ischaemic stroke who are treated with warfarin and have a subtherapeutic international normalised ratio (INR) at stroke onset.MethodsThe...

Abstract 187: Electrocardiographic Heart Rate-corrected Qt Interval And Risk Of Stroke In The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Background: Prolongation of heart rate-corrected QT interval (QTc) is a well established predictor of cardiovascular morbidity and mortality. Little is known, however, about the relationship between this simple electrocardiographic (ECG) marker and risk of stroke. Methods: A total of 27,411 participants aged &gt; 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during an up to 7 years of follow-up (median 2.7 years). Cox proportional hazards analysis was used to estimate the hazard ratios for incident stroke associated with prolonged QTcFram interval (vs. normal) and per 1 standard deviation (SD) increase, separately, in a series of incremental models. Results: The risk of incident stroke in the study participants with baseline prolonged QTcFram was almost 3 times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p&lt;0.0001]. After adjustment for age, race, sex, antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease, QRS duration, warfarin use, and QT-prolonging drugs (full model), the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0060)], and was consistent across several subgroups of REGARDS participants. When the risk of stroke was estimated per 1 SD increase in QTcFram, a 24% increased risk was observed [HR (95% CI): 1.24 (1.16, 1.33), p&lt;0.0001)]. This risk remained significant in the fully adjusted model [HR (95% CI): 1.12 (1.03, 1.21), p=0.0055]. Similar results were obtained when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used. Conclusions: QTc prolongation is associated with a significantly increased risk of incident stroke independently from known stroke risk factors. In light of our results, examining the risk of stroke associated with QT-prolonging drugs may be warranted.

Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy.

By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R(2) was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R(2)= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

The Association Between Prior Use of Aspirin and/or Warfarin and the In-hospital Management and Outcomes in Patients Presenting With Acute Coronary Syndromes: Insights From the Global Registry of Acute Coronary Events (GRACE)

Background The role of acetylsalicylic acid (ASA [aspirin]) and warfarin in secondary prevention after acute coronary syndromes (ACS) is well established. However, there are sparse data comparing the presentation and outcomes of patients who present with ACS while on ASA and/or warfarin therapy and those on neither. Methods Using data from the Canadian Global Registry of Acute Coronary Events (GRACE), we stratified 14,090 ACS patients into 4 groups according to prior use of antithrombotic therapies and compared in-hospital management and outcomes. Results Among 14,090 ACS patients, 7411 (52.6%) were not on prior ASA or warfarin therapy, 5724 (40.6%) were on ASA only, 593 (4.2%) were on warfarin only, and 362 (2.6%) were on both ASA and warfarin. ACS patients taking ASA and/or warfarin were older with more comorbidities than the patients on neither drug. Patients receiving prior warfarin only or ASA and warfarin were less likely to receive guideline-recommended therapies. Patients who were taking prior warfarin only had higher unadjusted rates of death, death and/or reinfarction (re-MI), congestive heart failure (CHF), and major bleeding as compared with patients on no prior therapy. Furthermore, patients who were taking ASA and warfarin had higher unadjusted rates of death and/or re-MI and CHF than patients on prior ASA only. Conclusions ACS patients on prior warfarin are a high-risk population, yet they receive less guideline-recommended therapies and have higher unadjusted adverse event rates during their index hospitalization. With the increasing use of oral anticoagulants, clinical trials are needed to guide the optimal management of these ACS patients.

Effectiveness and Safety of Warfarin Initiation in Older Hemodialysis Patients with Incident Atrial Fibrillation

Although generally recommended in atrial fibrillation (AF) patients, the effectiveness and safety of oral anticoagulation in dialysis patients with AF is unknown. We assembled a cohort of older hemodialysis patients who initiated dialysis without prior record of AF and who had prescription drug benefits through three state-administered programs. The index event was a first hospitalization with diagnosed AF; patients with any recorded prior warfarin use were excluded. Eligible patients survived ≥30 days from discharge, and new warfarin use was recorded from prescription records during that 30-day window. Propensity-matched warfarin users and nonusers were compared using Cox regression. Outcomes included ischemic stroke, hemorrhagic stroke, and mortality. Among 2313 patients with new AF who survived 30 days from discharge, 249 (10.8%) filled a prescription for warfarin. Comparing 237 warfarin users and 948 propensity-matched nonusers over 2287 person-years of follow-up, the occurrence of ischemic stroke was similar (HR = 0.92; 95% CI, 0.61 to 1.37), whereas warfarin users experienced twice the risk of hemorrhagic stroke (HR = 2.38; 95% CI, 1.15 to 4.96). The risks of stroke, gastrointestinal hemorrhage, and mortality did not differ between groups. As-treated analyses yielded similar findings, as did analyses restricted to patients with CHADS(2) scores ≥2. Although we confirmed association between warfarin use and hemorrhagic stroke in dialysis patients with AF, we found no association between warfarin use and ischemic stroke. Adequately powered randomized trials are required to conclusively determine the risks and benefits of the studied warfarin indication in hemodialysis patients.

316 Patient satisfaction with anticoagulation clinics across Alberta

316 Patient satisfaction with anticoagulation clinics across Alberta