Risk Of Overanticoagulation Research Articles

The impact of acute diarrhea on the coagulation status of patients with vitamin K antagonists

Acute diarrhea is associated with a reduced absorption of both vitamin K antagonists (VKA) and vitamin K itself. To date, the net effect on the coagulation status of subjects with VKA remains elusive. We performed a systematic retrospective single-center analysis using an electronic data extraction approach to identify subjects with plasmatic anticoagulation (either VKA or direct oral anticoagulant (DOAC)) and diarrhea in a German University Hospital over a period of eight years. Acute diarrhea and complete documentation of coagulation status on admission were defined as inclusion criteria, anticoagulation other than VKA/DOAC and obvious inadherence as exclusion criteria. Subjects with VKA/DOAC admitted for hypertension served as control group. Data extraction yielded 356 subjects with gastrointestinal diagnoses and 198 hypertensive subjects, 55 and 83 of whom fulfilled all in- and exclusion criteria. INR values of subjects with VKA were significantly higher in subjects with diarrhea than in hypertensive controls (4.3 ± 3.7 vs. 2.3 ± 0.7, p < 0.001). The distribution of subjects having INR values lower, higher or within the target range differed significantly among groups with a substantially higher prevalence of overanticoagulation in the diarrhea group (46.4% vs. 14.3%, p < 0.001). In a multinomial logistic regression model, acute diarrhea was significantly associated with overanticoagulation (odds ratio 7.2, 95% confidence interval 2.163–23.921; p < 0.001), whereas age, sex, creatinine, and indication of anticoagulation were not (p > 0.05 each). Acute diarrhea is associated with a highly increased risk for overanticoagulation in patients with VKA. Thus, gastroenteritis necessitates a close monitoring of INR in order to identify subjects needing a temporary pause of VKA therapy.

Risk of overanticoagulation during acute kidney injury in patients treated with vitamin K antagonists.

BackgroundVitamin K antagonists (VKAs) are still in use for oral anticoagulation, but not all indications allow their replacement by direct oral anticoagulants. Although formal dose reduction is not required in patients with impaired kidney function, case reports indicate that acute kidney injury (AKI) might be associated with derailment of VKA therapy.MethodsThe study retrospectively collected patients from a tertiary nephrology care centre who experienced AKI while being treated with VKA. In these individuals, the international normalized ratio (INR) as a measure of anticoagulant effect during renal failure was compared with a reference time point with stable kidney function.ResultsA total of 100 patients with AKI and ongoing VKA therapy met the inclusion criteria. The majority (76%) of patients had AKI with CKD. Volume depletion (n = 43), septic renal failure (n = 22), decompensated heart failure (n = 18) and toxic renal damage (n = 11) were the most important causes of AKI. The average INR values at the time of AKI were higher than at the reference time point [median 3.17 (range 1.10–13.0) versus 2.24 (1.07–5.17); P < 0.0001]. Fifty-four patients had INR values above the recommended therapeutic range for their indication at the time point of AKI. Bleeding complications occurred in 24 patients during AKI and the VKA dose had to be reduced in 55. Women, patients with low body mass index and patients with diabetes were predisposed to overanticoagulation during AKI.ConclusionsThe effect of AKI on anticoagulation by VKA has not been systematically described. This risk should be considered in patients at high risk for AKI.

Influence of CYP2C9 and VKORC1 on Warfarin Dose and Complications in Kazakhstani Patients with Left Ventricular Assist Device

Purpose The use of anti-platelet and anti-thrombotic therapy is a main stay in left ventricular assist devises (LVAD) to mitigate complicationssuch as pump thrombosis or systemic thromboembolism. Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance is limited. The purpose of this study is to evaluate the influence of CYP2C9 and VKORC1 polymorphisms on warfarin response and dosing algorithms in LVAD patients. Methods 100 patients implanted the HW, HM2, HM3 LVAD, irrespective of intended goal of therapy (either bridge to transplantation or destination therapy) after December 2011 at a single clinic - National Research Center for Cardiac Surgery, Astana, Kazakhstan with genotype data available for CYP2C9 (*1, *2, and *3 [rs1799853 and rs1057910]) and VKORC1 (-1639 G>A [rs9923231]) variants were included into study after institutional ethics committee approved the protocol. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). Results 32.0% of patients with implanted LVADs had at least one polymorphism: VKORC1 (14.0%), CYP2C9*2 (15.0%), CYP2C9*2 and VKORC1 (3.0%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.2±1.5 vs. 5.5±3.7 mg, p = 0.015) and achieved a similar mean INR (2.20±0.67 vs. 2.19±0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first days of therapy. Conclusion This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in LVAD patients and demonstrates an impact of genetic factors on clinical outcomes and proof of concept that genotype data could be incorporated into Warfarin dosing algorithm in LVAD patients.

Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60≤PTTR<70%), or excellent (PTTR≥70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (≥60 vs. <60) and major hemorrhages, respectively. Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60≤PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60≤PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.

Effect of Left Ventricular Systolic Dysfunction on Response to Warfarin

Candidates for chronic warfarin therapy often have co-morbid conditions, such as heart failure, with reduced left ventricular ejection fraction. Previous reports have demonstrated an increased risk of over-anticoagulation due to reduced warfarin dose requirement in patients with decompensated heart failure. However, the influence of left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction <40%, on warfarin response has not been evaluated. Here, we assess the influence of LVSD on warfarin dose, anticoagulation control (percent time in target range), and risk of over-anticoagulation (international normalized ratio >4) and major hemorrhage. Of the 1,354 patients included in this prospective cohort study, 214 patients (16%) had LVSD. Patients with LVSD required 11% lower warfarin dose compared with those without LVSD (p <0.001) using multivariate linear regression analyses. Using multivariate Cox proportional hazards model, patients with LVSD experienced similar levels of anticoagulation control (percent time in target range: 51% vs 53% p= 0.15), risk of over-anticoagulation (international normalized ratio >4; hazard ratio 1.01, 95% confidence interval 0.82 to 1.25; p= 0.91), and risk of major hemorrhage (hazard ratio 1.11; 95% confidence interval 0.70 to 1.74; p= 0.66). Addition of LVSD variable in the model increased the variability explained from 35% to 36% for warfarin dose prediction. In conclusion, our results demonstrate that patients with LVSD require lower doses of warfarin. Whether warfarin dosing algorithms incorporating LVSD in determining initial doses improves outcomes needs to be evaluated.

Influence of the CYP4F2 polymorphism on the risk of hemorrhagic complications in coumarin-treated patients.

Objectives:To evaluate the impact of the CYP4F2 polymorphism on bleeding complications and over-anticoagulation due to coumarin.Methods:A comprehensive literature search was performed to look for eligible studies published prior to February 2015 in EMBASE and PubMed. References were strictly identified by inclusion and exclusion criteria, and authors of primary studies were consulted for additional information and data. Revman 5.3 software was used to analyze the impact of the CYP4F2 polymorphism on hemorrhagic complications and over-anticoagulation events (international normalized ratio >4).Results:Eight studies involving 3,101 samples met the specified inclusion criteria. Compared with wild-type homozygotes (CYP4F2*1*1), carriers of the CYP4F2*3 variant had no significant effects on total bleeding events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.71-1.05; p=0.15), major hemorrhage complications in coumarin users (OR: 0.80; 95% CI: 0.64-1.01; p=0.06). Patients carried CYP4F2*3 also had nonsignificant associations with the risk of over-anticoagulation (relative risk [RR]: 079; 95% CI: 0.59-1.06; p=0.12). We found a lower risk in patients with homozygotes for CYP4F2*3, but there was no statistical significance (RR: 0.66; 95% CI: 0.43-1.01; p=0.05).Conclusion:This meta-analysis indicated the impact of the CYP4F2 polymorphism on bleeding complications and over-anticoagulation in coumarin-treated patients failed to reach the level of statistical significance. However, large-scale and well designed studies are necessary to determine conclusively the association between the CYP4F2 polymorphism and hemorrhage risk.

Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users.

The p.V433M in cytochrome P450 4F2 (rs2108622, CYP4F2*3) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP4F2*3 on warfarin dose, time to target international normalized ratio (INR), and stable dose, proportion of time spent in target range (PTTR), as well as the risk of overanticoagulation and hemorrhage among European and African Americans. CYP4F2*3 was genotyped in 1238 patients initiated on warfarin in a prospective inception cohort. Multivariable linear regression was used to assess warfarin dose and PTTR; proportional hazards analysis was performed to evaluate time to target INR and stable dose, overanticoagulation, and hemorrhage. Two outpatient anticoagulation clinics. A total of 1238 anticoagulated patients. Warfarin dose (mg/day), time to target INR and stable dose, PTTR, overanticoagulation (INR more than 4), and major hemorrhage. Minor allele frequency for the CYP4F2*3 variant was 30.3% among European Americans and 8.4% among African Americans. CYP4F2*3 was associated with higher dose among European Americans but not African Americans. Compared to CYP4F2*1/*1, *1/*3 was associated with a statistically nonsignificant increase in dose (4.5%, p=0.22) and *3/*3 was associated with a statistically significant increase in dose (13.2%, p=0.02). CYP4F2 genotype did not influence time to target INR, time to stable dose, or PTTR in either race group. CYP4F2*3/*3 was associated with a 31% lower risk of over anticoagulation (p=0.06). Incidence of hemorrhage was lower among participants with CYP4F2 *3/*3 compared with *1/*3 or *1/*1 (incidence rate ratio = 0.45, 95% confidence interval 0.14-1.11, p=0.09). After controlling for covariates, CYP4F2 *3/*3 was associated with a 52% lower risk of hemorrhage, although this was not statistically significant (p=0.24). Possession of CYP4F2*3 variant influences warfarin dose among European Americans but not African Americans. The CYP4F2-dose, CYP4F2-overanticoagulation, and CYP4F2-hemorrhage association follows a recessive pattern with possession of CYP4F2*3/*3 genotype likely demonstrating a protective effect. These findings need further confirmation.

Abstract 16445: Anticoagulation Control, Risk of Overanticoagulation and Major Hemorrhage Among Warfarin Users is Influenced by Race

Objective: Racial differences in warfarin response have been of significant interest. Differences in dose requirements have been extensively studied. Herein, we assess whether anticoagulation control [percent time in target range (PTTR; INR range 2-3)], risk of overanticoagulation (INR&gt;4) and major hemorrhage differ by race among warfarin users. Methods: The analysis included 1357 participants [595 African Americans (AA); 762 European Americans (EA)]. The Rosendaal interpolation method was used to compute the PTTR, percent time above range (PTAR) and percent time below range (PTBR). Major hemorrhages included serious, life threatening and fatal bleeding events. The influence of race (AA vs. EA) on PTTR, PTBR, and PBAR was evaluated using linear regression; overanticoagulation and hemorrhage by Cox proportional hazards analysis adjusting for clinical and genetic factors. Results: Over 1912 person-years (pyrs) accrued (average per patient 1.4 (± 0.9) years), after adjusting for covariates, compared to EAs, AAs had lower PTTR (56.3% vs. 50.8% p&lt;0.001), higher PTBR (26.5% vs. 31.2%; p=0.001) and were also more likely to experience overanticoagulation (HR: 1.31, 95% CI 1.10-1.56, p=0.003). A total of 156 major hemorrhagic events were encountered (incidence 8.2/100 pyrs, 95% CI: 7.0 – 9.5/100 pyrs). AAs had higher incidence of hemorrhage compared to EAs (IRR: 1.38, 95% CI 1.00-1.89, p=0.046). After adjusting for clinical and genetic factors, AAs remained at a higher risk for hemorrhage (HR: 1.60, 95% CI: 1.10-2.34, p=0.016). Older age, antiplatelet therapy, renal impairment, and possession of CYP2C9 variants increased the risk of hemorrhage. Higher PTTR was associated with a lower risk of hemorrhage in both race groups. Compared to patients with PTTR&lt;50%; those with PTTR 50-60% had a 37% lower risk (HR=0.63; 95%CI0.4-0.97; p=0.04), those with PTTR 60-70% had a 43% lower risk (HR=0.57; 95%CI 0.35-0.92; p=0.02), and those with PTTR &gt;70 had a 75% lower risk (HR=0.25; 95%CI0.14-0.43; p&lt;0.0001). Conclusion and Relevance: Among warfarin users, African Americans spent less time in target INR range, and had a higher risk of overanticoagulation and hemorrhage. Strategies to improve anticoagulation control among African Americans can lower risk of hemorrhage.

Abstract 16324: Genetic Predisposition Influences Anticoagulation Control and Major Hemorrhage Among Warfarin Users

Objective: Genetic variants in Cytochrome P450 2C9 ( CYP2C9 ) and Vitamin K epoxide reductase complex 1 ( VKORC1 ) are recognized predictors of warfarin dose. However, their influence on percent time in target range (PTTR; INR range 2-3), overanticoagulation (INR&gt;4) and risk of major hemorrhage have not been extensively evaluated. Herein, categorizing warfarin users possessing CYP2C9 (*2,*3,*5,*6,*11) and/or VKORC1 (-1639 C&gt;T) variants as sensitive responders, we evaluated whether sensitive responders (vs. normal) were more likely to have lower PTTR and a higher risk of overanticoagulation and major hemorrhage. Methods: The analysis included 1262 participants [310 sensitive responders (SR); 952 normal responders (NR)] in a warfarin pharmacogenetics inception cohort. The Rosendaal interpolation method was used to compute the PTTR, percent time above range (PTAR) and percent time below range (PTBR). Major hemorrhages included serious, life threatening and fatal bleeding events. The influence of responder status (SR vs. NR) on PTTR, PTBR, and PBAR was evaluated using linear regression, and overanticoagulation and hemorrhage by Cox proportional hazards analysis adjusting for clinical factors. Results: Participants were followed for an average of 1.4 (± 0.9) years; with 1799 person-years (pyr) accrued. There was no difference in PTTR between SRs (54.4% vs. 53.8%, p=0.66) compared to NRs. However SRs had higher PTAR (20.3% vs. 16.7%, p=0.005) and lower PTBR (25.2% vs. 29.5%, p=0.01) and were more likely to experience over-anticoagulation (HR: 1.38, 95% CI: 1.23-1.56, p&lt;0.001). SRs had higher incidence of hemorrhage compared to NRs ((IRR: 1.48, 95% CI: 1.04-2.08, p=0.03). After adjusting for clinical factors, SRs remained at a higher risk for hemorrhage (HR: 1.81, 95% CI: 1.23-2.68, p=0.003). Conclusion: Warfarin users possessing CYP2C9 and/or VKORC1 variants are sensitive responders, spending higher percent of time above target INR range. These patients are more likely to experience overanticoagulation and major hemorrhagic events. Future research evaluating alterative treatment strategy including candidacy for the non-vitamin K antagonist oral anticoagulants is needed.

Potential statin-drug interactions: prevalence and clinical significance.

BackgroundStatins are cholesterol-lowering drugs widely used for cardiovascular prevention. Although safe when used alone, in combination with other drugs the likelihood of adverse drug reactions increases significantly. The exposure of the Bulgarian population to coprescriptions leading to potential statin-drug interactions is currently unknown.ObjectiveThe aim of this study was to investigate the incidence of coprescriptions involving statins and to compare the exposure of outpatients and inpatients to potential statin-drug interactions.SettingA cardiology clinic of the teaching University hospital in Varna, Bulgaria.MethodThis observational retrospective study examined the medical records of hospitalized patients prescribed a statin in combination with potentially interacting drugs. Patients who entered the hospital with a statin coprescription (considered outpatients) were compared with those coprescribed a statin at discharge from hospital (considered inpatients). Potentially interacting drugs included inhibitors and inducers of cytochrome P450 (CYP) enzymes and drugs of narrow safety margin (coumarin anticoagulants, digitalis).Main outcome measureThe proportion of patients exposed to statin coprescriptions with potentially interacting drugs at hospital admission and discharge. Secondary outcome measures: laboratory evidence supporting possible statin-drug interactions.ResultsOut of 1641 hospitalized patients examined, 572 were prescribed a statin, either at hospital admission or discharge. Simvastatin was most commonly prescribed and simvastatin-drug coprescription predominated, especially at discharge. The exposure to all potential statin-drug interactions was similar at hospital admission (26.1%) and discharge (24.4%), as was the exposure to statin combinations with CYP inhibitors, 6.4% and 4%, correspondingly. Overall, more coprescriptions were generated, than were eliminated by hospital physicians. Amiodarone was the CYP inhibitor most frequently coprescribed. Of all interacting drugs acenocoumarol was the most commonly found, the proportions of statin-acenocoumarol coprescriptions being roughly the same at hospital entry (11.5%) and discharge (12.4%). In 7 patients out of 69 exposed to the combination, INR was found to be higher than 3, indicating a risk of over-anticoagulation.ConclusionsPotential statin-drug interactions are common. Although they do not differ between outpatient and inpatient settings, new hazardous coprescriptions are more frequently generated in hospital. Caution is required when acenocoumarol is coprescribed with statins, especially simvastatin.

Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population

BackgroundTwo variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.FindingsWe conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.ConclusionsOur data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.

Pharmacogenetics of warfarin safety and effectiveness in children

ObjectivesTo assess the contribution of CYP2C9/VKORC1 genotypes and variation in other genes involved in warfarin biotransformation and coagulation pathways to warfarin‐related outcomes in children. Furthermore, to validate the performance of a previously published pediatric pharmacogenetics‐dosing model when predicting the required dose in an independent cohort of children.MethodsClinical and genetic data was collected from 93 patients ≤18 years of age who received warfarin therapy. Genotyping was performed using a custom 96 SNP genotyping assay.ResultsTogether, VKORC1–1639G/A and CYP2C9 *2/*3 accounted for 21.1% of dose variability. There was a strong correlation (R2=0.64; P&lt;0.001) between actual and predicted warfarin dose using a pediatric pharmacogenetics‐dosing model. VKORC1 genotype also had a significant impact on time to therapeutic INR (P=0.047), time to INR&gt;;4 (P=0.028), and risk of over‐anticoagulation (INR&gt;;4) during the initiation of therapy (odds ratio, 3.3; P=0.014). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose in a multivariate model.ConclusionsThis study confirms the importance of VKORC1/CYP2C9 genotype for warfarin outcomes in children and validates a pediatric‐specific genotype‐based dosing algorithm. Research funding provided by CIHR‐DSEN and CFI.

Pharmacogenetic tests could be helpful in predicting of VKA maintenance dose in elderly patients at treatment initiation

Several studies have linked mutations in the genes encoding cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) to a reduced VKA dose requirement and an increased risk of bleeding. Nevertheless, implementation of genotyping as a routine practice is still controversial. Our study was conducted in order to investigate the impact of genetic factors, presence of VKORC1-c.1639A, CYP2C*2 and CYP2C*3 among outpatients referred to Anticoagulation Service due to extremely unstable anticoagulant therapy. From 2008 to 2011, 68 patients, mean age 65.9, were included in the study. They were referred from primary care physicians due to inability to sustain the therapeutic range in the period of initiation of anticoagulant therapy. Genotyping results showed that 17 (25%) of them were carriers of both CYP2C9 and VKORC1 variant alleles, 38 (55.9%) were carriers of VKORC1 c.1639AA, 6 (8.8%) were carriers of CYP2C9 variant alleles, while 7 (10.3%) of them were carriers of wild type alleles. INR control upon admission showed that 34 (50%) of them were over-anticoagulated, while 12 (17.6%) of them had subsequent bleeding complications. Among over-anticoagulated patients, 32 were carriers of mutated alleles in both CYP2C9 and VKORC1 gene or VKORC1 alone, while 2 of patients carried wild type alleles. In addition to presence of CYP2C9 or VKORC 1 alleles, older age was an important factor related to a lower dose and risk for over-anticoagulation. Genotype (CYP2C9/VKORC1) and age are the most important factors that could predispose an extreme response and subsequent bleeding complications during the initiation of VKA.

Selective serotonin re‐uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment

The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment. All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated. The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine. Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects.

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.

Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs.

Genotypes Associated With Reduced Activity of VKORC1 and CYP2C9 and Their Modification of Acenocoumarol Anticoagulation During the Initial Treatment Period

The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

CYP2C9 genotypes and the quality of anticoagulation control with warfarin therapy among Brazilian patients

To evaluate the impact of the two most common CYP2C9 variant alleles (*2 and *3) on the maintenance dose of warfarin and on the quality of anticoagulation control in Brazilians. Patients (n = 103) initiated warfarin therapy with 5 mg/day (or 2.5 mg/day when over 80 years old). The international normalized ratio (INR) was targeted between 2 and 3, monitored every week until four consecutive adequate measures had been obtained, and then monthly. Serious hemorrhagic events were defined by the need for inpatient hospitalization. CYP2C9 genotyping was obtained by PCR-RFLP. The frequencies of CYP2C9*2 and CYP2C9*3 were 0.097 and 0.073, respectively, with genotypic distribution fitting Hardy-Weinberg equilibrium. CYP2C9 genotype was the only clinical feature associated with the risk of severe bleeding (one-sided P = 0.019, Fisher exact method), with an odds ratio of 4.8 (95% confidence interval of 1.4-16.6) for any variant genotype as compared to CYP2C9*1*1. Patients with either CYP2C9*2 or CYP2C9*3 were equally difficult to maintain in the INR target range, showing significantly (one-sided P = 0.038, Mann-Whitney U-test) reduced ratio of adequate INR measures (0.54 +/- 0.2), when compared to CYP2C9*1*1 patients (0.63 +/- 0.2). Patients with CYP2C9*3, but not CYP2C9*2, required significantly (one-sided P = 0.001, Mann-Whitney U-test) lower warfarin maintenance doses (3.1 +/- 1.8 mg) than CYP2C9*1*1 patients (5.3 +/- 2.1 mg). Patients with either CYP2C9*2 or CYP2C9*3 show higher risk of over-anticoagulation compared to CYP2C9*1*1 subjects and could benefit from a reduction in the initial warfarin standard dose (e.g., to 2.5 mg/day).

Antivitamines K et pharmacogénétique: vers une meilleure compréhension de la variabilité individuelle de l'effet dose–réponse

Vitamin K antagonists (VKA) are difficult to use because of a narrow therapeutic index and of a marked inter- and intra individual variability among patients in the required dosage. Beside well known demographic or environmental factors (advanced age, co-morbid conditions, acute illnesses, concomitant drugs, vitamin K intake), genetic single nucleotide polymorphisms (SNPs) have been identified as strongly affecting the maintenance dosage and its variability. First, SNPs of vitamin K epoxide reductase complex subunit-1 (VKORC1) gene have been identified, affecting the enzyme shown as one of the target of VKA. Secondly, SNPs of cytochrome P450 2C9 (CYP2C9) gene have been shown to decrease the catabolism of coumarin derivatives (acenocoumarol, warfarin). Several recent studies have shown that being carrier of at least one mutated allele of either VKORC1 or CYP2C9 (CYP2C9*2, CYP2C9*3) allele is associated with a hypersensitivity to VKA therapy, i.e. a lower maintenance dose. Moreover, it has been associated with an increased risk of over-anticoagulation, a longer time to achieve the maintenance dose and an increased risk of bleeding. Finally, the combined analysis of VKORC1 and CYP2C9 SNPs with age may account for more than 50% of the individual variability of the warfarin maintenance dosage. Predicting models of warfarin maintenance dosage taking into account these individual parameters are currently developed.

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction.

ObjectiveThe objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics.MethodsA follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected.ResultsThe study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01–0.51] and 0.09 (95% CI: 0.01–0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics.ConclusionPDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs.