Anticoagulation endpoints with clinical implementation of warfarin pharmacogenetic dosing in a real-world setting: A proposal for a new pharmacogenetic dosing approach.

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8 ± 5.8, 7.2 ± 4.7, and 5.4 ± 4.6 days, P = 0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P = 0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population.

Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: their influence on pharmacogenetic dosing algorithms.

Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9*1/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.

Incidence of hospital readmission in patients diagnosed with DVT and PE: clinical burden of recurrent events.

BACKGROUND: Venous thromboembolism (VTE), which comprises deep-vein thrombosis (DVT) and pulmonary embolism (PE), is associated with significant morbidity and mortality and represents a considerable economic burden to the US healthcare system. Although it is well established that patients with an initial VTE are at increased risk for recurrent VTE, limited data exist on the clinical burden of a secondary DVT or PE event. The objective of this retrospective observational study was to conduct an epidemiologic evaluation, from a hospital perspective, of patients with an initial DVT or PE who experienced a recurrent event postdischarge requiring hospital readmission. METHODS: Hospital claims containing DVT or PE as a primary diagnosis for hospitalisation during the period October 2009 to April 2013 were identified by retrospective analysis using the MarketScan database. The time to hospital readmission for DVT or PE was assessed using the MarketScan Treatment Pathways tool. RESULTS: Of 214,901 patient admissions identified with a diagnosis of DVT or PE at hospital admission, approximately 4% were subsequently readmitted to the hospital with a diagnosis of PE (8217) or DVT (9138). Of all readmitted patients with a diagnosis of DVT on initial admission, 66% were rehospitalised with a diagnosis of DVT, and 34% were rehospitalised with a diagnosis of PE. Of all readmitted patients with a diagnosis of PE on initial admission, 63% were rehospitalised with a diagnosis of PE and 37% with a diagnosis of DVT. Of all hospital readmissions with a diagnosis of PE or DVT, 62% and 58% occurred within the first 30 days following an initial PE or DVT event, respectively. CONCLUSIONS: The burden of DVT or PE is large, not only because of the initial hospitalisation event but also because of the high number of hospital readmissions, more than half of which occur within 30 days.

Warfarin pharmacogenetics: to genotype or not to genotype, that is the question.

Genotype is well recognized to influence the dose of warfarin necessary for therapeutic anticoagulation. Recent randomized controlled trials evaluating the clinical utility of genotype-guided warfarin dosing have produced varying results. We review the design and results of the recent clinical trials, assess the impact of their findings on warfarin dosing, and examine unanswered questions related to clinical implementation of warfarin pharmacogenetics.

Risk factors associated with myocardial infarction in venous thromboembolism patients.

BACKGROUND: Although risk factors for MI have been described in the general population, there is a lack of data on the assessment of risk factors associated with MI in venous thromboembolism (VTE) patients. OBJECTIVE: The purpose of this study was to identify risk factors associated with MI in VTE patients. PATIENTS AND METHODS: Health insurance claims between January 2004 and September 2008 from the Ingenix IMPACT database were analyzed. Patients aged ≥18 years were identified as of the date of their first VTE diagnosis with ≥1 year of continuous insurance coverage before the index VTE. The risk of MI for VTE patients with 1, 2, and ≥3 major risk factors as identified by published guidelines was calculated. Multivariate Cox proportional hazard models were conducted to identify the most predictive risk factors associated with MI. RESULTS: A total of 177,885 VTE patients were identified; 4412 (2.5%) developed an MI during a mean follow-up period of 1.3 years. Previous MI, age (≥65 years), and coronary artery disease were the most predictive risk factors of MI with adjusted hazard ratios (HRs; 95% CI) of 5.47 (5.01-5.97), 1.78 (1.66-1.91), and 1.60 (1.48-1.74), respectively. Adjusted HRs (95% CI) for VTE patients with 1, 2, and ≥3 major risk factors relative to no major risk factor were 2.34 (1.94-2.81), 3.21 (2.67-3.85), and 6.93 (5.85-8.22), respectively. LIMITATIONS: These included possible inaccuracies or omissions in diagnoses, classification bias such as the identification of false-positive MI events, and the likely undercoding of some risk factors such as social issues. CONCLUSIONS: Traditional major cardiovascular risk factors are also predictive of MI in VTE patients. Having multiple major risk factors significantly increases the probability of developing MI events in VTE patients.

Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism.

The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We conducted a pharmacokinetic study to examine whether the CYP2C9*8 allele impacts warfarin clearance in African-American patients. We also conducted an in vitro kinetic study of S-warfarin 7-hydroxylation using complementary DNA (cDNA)-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and a 25% lower R- to S-warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein. These data show that the R150H variant protein expressed by the CYP2C9*8 allele is associated with lower S-warfarin clearance. This finding provides clinical and experimental evidence to explain the lower warfarin dose requirements in patients with the CYP2C9*8 allele.

In-hospital risk of venous thromboembolism and bleeding and associated costs for patients undergoing total hip or knee arthroplasty.

OBJECTIVE: Benefits of anti-coagulation for venous thromboembolism (VTE) prevention in total hip and knee arthroplasty (THA/TKA) may be offset by increased risk of bleeding. The aim was to assess in-hospital risk of VTE and bleeding after THA/TKA and quantify any increased costs. METHODS: Healthcare claims from the Premier Perspective(TM) Comparative Hospital Database (January 2000-September 2008) were selected for subjects ≥ 18 years with ≥ 1 diagnosis code for THA/TKA. VTE was defined as ≥ 1 code for deep vein thrombosis or pulmonary embolism. Bleeding was classified as major/non-major. Incremental in-hospital costs associated with VTE and bleeding were calculated as cost differences between inpatients with VTE or bleeding matched 1:1 with inpatients without VTE or bleeding. RESULTS: A total of 820,197 inpatient stays were identified: 8042 had a VTE event and 7401 a bleeding event (2740 major bleeding). The risks of VTE, any bleeding, and major bleeding were 0.98, 0.90, and 0.33/100 inpatient stays, respectively. Mean incremental in-hospital costs per inpatient were $2663 for VTE, $2028 for bleeding, and $3198 for major bleeding. LIMITATIONS: These included possible inaccuracies or omissions in procedures, diagnoses, or costs of claims data; no information on the amount of blood transfused or decreases in the hemoglobin level to evaluate bleeding event severity; and potential biases due to the observational design of the study. CONCLUSIONS: In-hospital risk and incremental all-cause costs with THA/TKA were higher for VTE than for bleeding. Despite higher costs, major bleeding occurred less frequently than VTE, suggesting a favorable benefit/risk profile for VTE prophylaxis in THA/TKA.

Genetic and clinical predictors of warfarin dose requirements in African Americans.

The objective of this study was to determine whether, in African-American patients, additional vitamin K oxidoreductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), CYP4F2, or apolipoprotein E (APOE) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9*2 and *3 alleles and the VKORC1 -1639G>A genotype. In a cohort of 226 African-American patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). The combination of CYP2C9 alleles, VKORC1 -1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9*5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1, CYP4F2, or APOE polymorphism contributed to the variance. The inclusion of additional CYP2C9 variants may improve the predictive ability of warfarin dosing algorithms for African Americans.

Low-molecular-weight heparin in pregnancy: peripartum bleeding complications.

OBJECTIVE: To compare bleeding complications in pregnant patients treated with low-molecular-weight heparin (LMWH) to untreated controls. STUDY DESIGN: A case-control study of patients from 2001 to 2005 who received prophylactic or therapeutic doses of LMWH during pregnancy was carried out. Indications for LMWH included current or prior thromboembolism, thrombophilia, or heart valve replacement. Controls were chosen in a 2:1 ratio to cases, matched for delivery route, and selected as the next two consecutive deliveries. The primary outcome was postpartum hemorrhage (PPH). Odds ratios (ORs) were calculated with 95% confidence intervals (CIs). RESULTS: Forty-nine women treated with LMWH delivered 55 infants. Current or prior thromboembolic disease was the anticoagulation indication in 15/55 (27.3%) and 26/55 (47%) of pregnancies, respectively. There were more obese gravidas (OR 3.91, CI 1.70 to 9.09) and labor induction was more common in the LMWH group, 25/55 (45%) vs 29/110 (26%), P=0.01. There was no difference in estimated blood loss (295.7+/-145.7 vs 308.6+/-111.9 cm(3), P=0.62 vaginal; 687.5+/-251.8 vs 765.0+/-313.2 cm(3), P=0.34 cesarean), PPH (6/55, 11% vs 9/110, 8.2% OR 1.37, CI 0.16 to 11.5) or transfusion (3/55, 5.4% vs 4/110, 3.6% OR 1.50, CI 0.3 to 7.48) between the cases and controls. There were two cases of postpartum pulmonary emboli, one with a maternal mortality. CONCLUSION: Bleeding complications, including PPH and transfusion, in patients treated with LMWH during pregnancy were not increased when compared to normal controls matched for delivery route.

Dosing and monitoring of low-molecular-weight heparins in special populations.

As a result of numerous clinical trials and meta-analyses supporting the superior efficacy and relative safety of low-molecular-weight heparins (LMWHs) compared with unfractionated heparin (UFH), LMWHs are emerging as the antithrombotic agents of choice for the prevention and treatment of deep vein thrombosis and pulmonary embolism. In addition, data indicate that enoxaparin given with low-dosage aspirin is more effective than UFH in treating acute coronary syndromes. Anti-Xa activity can be used as a biologic marker of LMWH activity. Because of the more predictable anticoagulant response to subcutaneous administration of LMWHs compared with UFH, routine monitoring of anti-Xa activity in clinically stable adults with uncomplicated disease is not recommended. Because the optimal dosage of LMWHs has not been established for patients with renal insufficiency or extremes of body weight, during pregnancy, or for children, anti-Xa activity monitoring may be warranted in these subsets.

Warfarin-acetaminophen drug interaction revisited.

Physicians and pharmacists routinely advise patients receiving warfarin to take acetaminophen for pain or fever because of its relative safety; however, a recent study questioned the safety of such practice. A comprehensive search of MEDLINE and IPA for human studies and case reports from 1966-1999 revealed evidence that acetaminophen may potentiate the effect of warfarin by a mechanism that has yet to be elucidated. Due to lack of a safer alternative, acetaminophen still should be the analgesic and antipyretic of choice in patients taking warfarin, as long as excessive amounts and prolonged administration (> 1.3 g acetaminophen/day for > 2 wks) are avoided. With the high degree of interpatient variability and the unpredictability of various drug-drug interactions with warfarin, close and frequent monitoring of international normalized ratios is the key for safe oral anticoagulation therapy.