Anticoagulant Use, the Prevalence of Bridging, and Relation to Length of Stay among Hospitalized Patients with Non-Valvular Atrial Fibrillation

Objective: The objectives of this study were to describe inpatient anticoagulation and bridging in patients with non-valvular atrial fibrillation (NVAF) and to identify whether differences exist in length of stay (LOS) among bridged versus non-bridged NVAF patients. Design: Administrative claims data were used to select patients ≥18 years with a primary or secondary discharge diagnosis of NVAF and inpatient warfarin use from 1 July 2004 to 30 September 2009. Patients with valvular or transient causes of NVAF or pregnancy were excluded. Inpatient bridging was defined as receipt of an anticoagulant in addition to warfarin during the hospitalization. LOS was reported for non-bridged patients (warfarin only) and compared with three bridging regimens: low molecular weight heparin/pentasaccharide (LMWH/PS); unfractionated heparin (UFH); and two-agent bridging (LMWH/PS and UFH). Multivariate analyses were performed to evaluate the association between bridging and LOS, adjusting for demographic and clinical variables. Results: Of 6340 NVAF patients, 48% received inpatient warfarin (mean LOS 5.5 days); among them, 64% received bridging therapy (mean LOS 6.3 days) [LMWH/PS 45% (mean LOS 5.6 days), UFH 36% (mean LOS 6.0 days), two-agent bridging 18% (mean LOS 8.4 days)]. Following multivariate analysis, relative to patients who received inpatient warfarin only, LOS was significantly higher for patients with UFH (19.3%) and patients with two-agent bridging (45.1%). Patients with pre-period warfarin, cancer, or diabetes mellitus who received bridging agents had significantly longer LOS than patients with those conditions who were not bridged. Conclusion: LOS was longer for bridged than non-bridged patients. Further studies are needed to identify predictors of bridging and to explain why bridged NVAF patients had longer LOS.     

Risks for stroke and bleeding with warfarin or aspirin treatment in patients with atrial fibrillation at different CHA2DS2VASc scores: experience from the Stockholm region

Purpose

This study evaluated the benefits of and possible contraindications to warfarin treatment in patients with atrial fibrillation (AF) prior to the introduction of new oral anticoagulants using health registry data from inpatient care, specialist ambulatory care, and primary care.

Methods

This is a cohort study including all patients in the region of Stockholm, Sweden (2.1 million inhabitants) with a diagnosis of non-valvular AF (n?=?41 810) recorded during 2005–2009. The risks of suffering ischemic stroke, bleeding, or death with warfarin, aspirin, or no antithrombotic treatment during 2010 were related to CHA₂DS₂VASc scores, age, and complicating co-morbidities.

Results

One-year risks for ischemic stroke were 1.0–1.2 % with aspirin, 0–0.3 % with warfarin, and 0.1–0.2 % without treatment at CHA₂DS₂VASc scores 0–1. Among the aspirin-treated patients with CHA₂DS₂VASc scores ≥2, half had possible contraindications and high risks for ischemic stroke (5.2 %), bleeding (5.0 %), and death (19.3 %). The other half of the patients with no identified contraindications had a high risk for ischemic stroke (4.0 %) but a low bleeding risk (1.8 %) and a moderate mortality rate (8.4 %).

Conclusions

The present observations confirm earlier findings of undertreatment with warfarin and half of the high-risk patients treated with aspirin were obvious candidates for anticoagulant treatment. However, the other half of the patients had complicating co-morbidities, high bleeding risk, and poor prognosis. This and possible overtreatment of low-risk patients should be taken into account when considering more aggressive use of anticoagulant treatment.     

Anticoagulation Therapy for Patients with Non-Valvular Atrial Fibrillation

Background: Anticoagulation in patients with atrial fibrillation (AF) is challenging because stroke-risk reduction must be balanced against increased bleeding risk. Objective: We developed a decision model integrating both stroke and bleeding risk schemes to guide optimal use of anticoagulation in AF, and compared model recommendations with warfarin use in a real-world database. Methods: A Markov model based on demographics, CHADS₂ (Congestive Heart Failure, Hypertension, Age of 75 years and greater, Diabetes Mellitus and History of Stroke) stroke and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleed risk scores, and anticoagulation treatment effects from clinical trials simulated health state transitions for recently diagnosed AF patients. The model recommended the treatment with greater quality-adjusted life expectancy. Model recommendations were contrasted with actual warfarin use recorded in the Thomson Reuters MarketScan database (N=64 946). Results: 74.8% (n = 48 548) of the Marketscan AF cohort had CHADS₂ ≥1, of whom 14.3% had moderate/high (≥4) ATRIA bleeding risk. While the model recommended warfarin for almost all patients with CHADS₂ ≥1 who are at low bleeding risk, it recommended warfarin for fewer patients as bleeding risk increased. Of the 44 611 patients recommended warfarin, 63.4% of patients were considered warfarin exposed (concordant with model recommendation), and of the 20 335 patients recommended aspirin (ace-tylsalicylic acid), 59.7% received warfarin (discordant with model recommendations). Actual warfarin use decreased modestly with higher stroke risk (p< 0.0001) and with higher bleeding risk (p< 0.0001). Conclusion: High discordance between actual warfarin use and model recommendations suggests that anticoagulation decisions are not based on systematic evaluation of stroke and bleeding risks. Model-based clinical decision aids may improve oral anticoagulation decisions by more systematically weighing bleed and stroke risk.     

Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial

Purpose

We investigated whether acetaminophen, given at 2?g/day and 3?g/day might potentiate the anticoagulant effect of warfarin.

Methods

Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2?g/day or 3?g/day) or placebo.

Results

The mean maximal INR increase was 0.70?±?0.49 and 0.67?±?0.62 in patients receiving acetaminophen at 2?g/day and 3?g/day, respectively (P?=?0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R ²?=?0.36, P?R ²?=?0.46, P?R ²?=?0.563, P?Conclusion Acetaminophen, at 2?g/day or 3?g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.     

Pharmacy students provide care comparable to pharmacists in an outpatient anticoagulation setting

Objective

To evaluate whether student participation in ambulatory clinics influenced the percentage of therapeutic international normalized ratio (INR) results among patients on chronic warfarin therapy.

Methods

Medical records in outpatient anticoagulation clinics managed by pharmacists under physician protocol were reviewed retrospectively in 2 university-affiliated clinics in Amarillo and Lubbock, TX. Pharmacy student activities included patient interviews, vital sign measurements, fingersticks, counseling, and documentation. Patient visits were conducted by a precepted pharmacy student or a pharmacist without a student, and the INR was measured at the subsequent patient visit.

Results

Records of 1,958 anticoagulation patient visits were reviewed; 865 patients were treated by pharmacists, and 1093 were treated by precepted students. The follow-up INR was therapeutic for 48.5% of third-year (P3) students'' patients, 45.6% of fourth-year (P4) students'' patients, 51.2% of residents'' patients, and 44.7% of pharmacists''s patients (p = 0.23). Eight variables were associated with the follow-up INR (baseline INR, warfarin noncompliance, held warfarin doses, a warfarin dosage adjustment, diet change, alcohol use, tobacco use, and any medication changes).

Conclusion

Student participation in the patient-care process did not compromise patient care and no significant difference in patient outcomes was found between patients in an anticoagulation clinic cared for by precepted students and those cared for by pharmacists.     

Outcomes After Cardioversion in Atrial Fibrillation Patients Treated with Non-Vitamin K Antagonist Oral Anticoagulants (NOACs): Insights from a Meta-Analysis

Background

There are limited data on outcomes following cardioversion in atrial fibrillation (AF) patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). A meta-analysis was performed to evaluate the efficacy and safety of NOACs in patients with AF undergoing cardioversion.

Methods

PubMed, Cochrane Library, EMBASE, Web of Science and CINAHL databases were searched from January 1, 2001 through to October 30, 2014. Randomized controlled trials (RCTs) comparing NOACs (apixaban, rivaroxaban and dabigatran) with warfarin in AF patients undergoing cardioversion were selected. The primary efficacy outcome was stroke and systemic embolism, and the primary safety outcome was major or clinically relevant non-major (CRNM) bleeding. We used random-effects models.

Results

Four RCTs were included, involving a total of 3635 randomized participants who underwent a total of 4257 cardioversions. A total of 12 events of stroke and systemic embolism were found in the NOAC group and ten events in the warfarin group [odds ratio (OR) 0.73, 95 % confidence interval (CI) 0.31–1.72]. Risk of major or CRNM bleeding was not different with NOACs, when compared with warfarin (OR 1.41, 95 % CI 0.87–2.28).

Conclusions

Data from patients enrolled in RCTs, showed that NOACs are effective and safe for AF patients undergoing cardioversion.

     

Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics and pharmacodynamics of warfarin

Purpose

Vorapaxar is an orally active protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet aggregation. This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose vorapaxar in 12 healthy men.

Methods

Subjects received two treatments separated by ≥7-day washout: Treatment A warfarin 25?mg (Day 1); Treatment B vorapaxar 2.5?mg/day on Days 1–6 and vorapaxar 40?mg coadministered with warfarin 25?mg (Day 7). R-warfarin, S-warfarin, and prothrombin time (PT) were assayed predose and up to 120?h postdose.

Results

The geometric mean ratio (GMR) as a percentage (warfarin + vorapaxar/warfarin) was calculated. The GMR (90?% CIs) estimates of C_max were 105 (99, 111) and 105 (99, 112) for R- and S-warfarin, respectively. The GMR (90?% CIs) estimates of AUC_0-∞ were 108 (101, 116) and 105 (96, 115) for R- and S-warfarin, respectively. The GMR (95?% CIs) estimates of AUC_0–120?h for PT and INR were 97 (95, 98) and 96 (94, 98), respectively.

Conclusion

Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin, suggesting that the coadministration of these two drugs or vorapaxar coadministered with other CYP2C9/CYP2C19 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction.     

Development of a Bayesian Forecasting Method for Warfarin Dose Individualisation

Purpose

The aim of this study was to develop a Bayesian dose individualisation tool for warfarin. This was incorporated into the freely available software TCIWorks (www.tciworks.info) for use in the clinic.

Methods

All pharmacokinetic and pharmacodynamic (PKPD) models for warfarin in the medical literature were identified and evaluated against two warfarin datasets. The model with the best external validity was used to develop an optimal design for Bayesian parameter control. The performance of this design was evaluated using simulation-estimation techniques. Finally, the model was implemented in TCIWorks.

Results

A recently published warfarin KPD model was found to provide the best fit for the two external datasets. Optimal sampling days within the first 14?days of therapy were found to be days 3, 4, 5, 11, 12, 13 and 14. Simulations and parameter estimations suggested that the design will provide stable estimates of warfarin clearance and EC50. A single patient example showed the potential clinical utility of the method in TCIWorks.

Conclusions

A Bayesian dose individualisation tool for warfarin was developed. Future research to assess the predictive performance of the tool in warfarin patients is required.     

Impact of clinical pharmacist intervention in anticoagulation clinic in Sudan

Background Many trials have compared anticoagulation management provided by a pharmacist led anticoagulation clinic versus usual physician care showing the role for clinical pharmacist in the management of anticoagulant therapy, and demonstrating excellent outcomes. In Sudan, there is no published research evaluating the role of pharmacist in providing pharmaceutical care for patients taking warfarin. Objective The objective of the study is to assess the role of clinical pharmacist intervention in warfarin patients compared to usual medical care. Setting This study was conducted in Ahmed Gasim cardiac surgery and renal transplant center warfarin clinic. Methods One hundred thirty-five patients were randomly selected from adult patients on warfarin therapy The history of INR records, and adverse effects for the past year, were recorded. Then patients’ warfarin dose adjustments according to INR, was done by the clinical pharmacist for one year. Patients received continuous verbal education and written information about warfarin. Main outcome measure The primary outcome for this study was the INR control, while the secondary outcomes were the bleeding events and hospitalization due to warfarin. Results After the clinical pharmacist intervention there was significant (P < 0.01) improvement in INR control and a significant (P < 0.05) reduction in incidence of bleeding after clinical pharmacist intervention. Hospitalization due to warfarin related complications (bleeding, high INR, low INR) was also significantly (P < 0.001) reduced. Conclusion Clinical pharmacists intervention in warfarin therapy improve INR control, reduce bleeding and hospitalization due to warfarin complications.     

Dronedarone and the Incidence of Stroke in Patients with Paroxysmal or Persistent Atrial Fibrillation

Background

Stroke is the most feared complication of atrial fibrillation (AF). Dronedarone is an antiarrhythmic drug with multichannel-blocking properties. Recently, a post hoc analysis of a large randomized trial has suggested a reduction of stroke risk in patients with paroxysmal or persistent AF receiving dronedarone.

Objective

We performed a systematic review and meta-analysis on the effect of dronedarone on the occurrence of stroke or transient ischemic attack (TIA) in patients with paroxysmal or persistent AF.

Methods

We searched PubMed, EMBASE, and ISI Web of Knowledge as well as abstracts of major conferences for randomized trials comparing dronedarone with placebo in patients with paroxysmal or persistent AF. The endpoint was the occurrence of stroke or TIA during follow-up. Fixed effect risk differences (RDs) were calculated with the Mantel-Haenszel method. We also performed random effects analysis with the DerSimonian Laird method.

Results

Four trials were included in the analysis; a total of 5967 patients were analyzed, 3183 receiving dronedarone 400 mg twice daily and 2784 receiving placebo. 160 strokes or TIAs were reported in the four trials: 67 in the dronedarone group (2.1%) and 93 in the placebo group (3.3%). In the fixed effect model, patients in the dronedarone group had a significantly lower risk for the occurrence of stroke or TIA during follow-up compared with patients in the placebo group. The RD of the incidence of stroke or TIA in all trials between patients randomized to dronedarone and those randomized to placebo was ?0.0094 (95% confidence interval [CI] ?0.0178, ?0.0011; p = 0.027). The ATHENA trial had by far the highest statistical weight (79.5%). There was no evidence of heterogeneity (χ² = 2.41, p = 0.300). In the random effects model, the statistical weight of the ATHENA trial was much lower (45.1%) and the RD for stroke or TIA between the dronedarone and the placebo groups did not reach statistical significance (RD ?0.0064, 95% CI ?0.0144, 0.0016; p = 0.120).

Limitations

First, stroke was not a prespecified outcome measure in the included trials. Second, we did not analyze trials studying patients with permanent AF; very recent data show an adverse outcome in patients with permanent AF receiving dronedarone.

Conclusions

The meta-analysis indicates a reduced risk of stroke or TIA in patients with paroxysmal or persistent AF receiving dronedarone. These findings are largely due to the results of the ATHENA trial. Further research on this topic is necessary.     

A probable clinically significant interaction between warfarin and cloxacillin: three case reports

Cases

Three patients were admitted to the Imam Hospital, Tehran, Iran with a diagnosis of bacterial endocarditis. The patients had indications for valve replacement surgery and anticoagulant therapy. The administration of cloxacillin reduced the effect of warfarin, and subsequent increases in warfarin doses were unable to overcome this effect.

Conclusion

A decrease in warfarin anticoagulation effects was detected in our three patients following cloxacillin therapy for infective endocarditis. Penicillinase-resistant penicillins remain essential antibiotics in the treatment of severe infections caused by Staphylococcus aureus due to their bactericidal activity, safety, and cost. Thus, in situations where anticoagulants are indicated in patients with infective endocarditis, it would be better to replace warfarin with low-molecular-weight or unfractionated heparin.     

Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients

Objective

African populations, including the Sudanese, are underrepresented in warfarin pharmacogenetic studies. We designed a study to determine the associations between the polymorphisms and haplotype structures of CYP2C9 and VKORC1 and warfarin dose response in Sudanese patients, one of the most genetically diverse populations in Africa.

Material and methods

The effect of the CYP2C9 polymorphisms (*2, *3, *5, *6, *8, *9, and *11), 20 VKORC1 tag SNPs and haplotypes, and clinical covariates were comprehensively assessed in 203 Sudanese warfarin-treated patients.

Results

Patients with the CYP2C9*2,*5,*6, or *11 variant required a daily warfarin dose that was 21% lower than those with CYP2C9*1/*1 (4.7 vs 5.8?mg/day, P?VKORC1 and POL3S genes were divided into two haplotype blocks in Sudanese populations. According to multiple linear regression results, rs8050984, rs7294, and rs7199949 in the VKORC1 and POL3S genes (P?<0.001, <0.001, <0.001, respectively), CYP2C9 genotype (*2, *5, *6, *11; P?P?=?0.04), target INR (P?=?0.007), and concurrent medications (P?=?0.029) could explain about 36.7% of the total warfarin dose variation.

Conclusion

Our data revealed that VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese patients. Our data suggest that combinations of the SNPs may improve predictions of warfarin dose requirements.     

Potential use of NOACs in developing countries: pros and cons

Purpose

Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries’ health care systems.

Methods

A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were “atrial fibrillation”, “oral anticoagulants”, “warfarin”, “NOACs”, “dabigatran”, “rivaroxaban”, “apixaban”, “edoxaban”, “time in therapeutic range”, “International Normalized Ratio” “cost-effectiveness”, “stroke”, “adverse-drug reactions” and “drug–drug interactions”, together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles.

Results

Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised.

Conclusion

The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice.     

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies

Aim

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.

Methods

We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.

Results

The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l⁻¹).

Conclusions

The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.     

Primary prevention aspirin use in high-risk patients: A pharmacist intervention and comparison of risk stratification tools

Objectives

The objectives of this project are 1) to describe aspirin use for primary prevention in an underserved, minority population; 2) to determine the impact of a pharmacist-led intervention on the prevalence of aspirin use for primary prevention; and 3) to compare aspirin indications based on Framingham Risk Score (FRS) and atherosclerotic cardiovascular disease (ASCVD) risk score.