International Normalized Ratio Range Research Articles

Frequency of adverse events in patients with poor anticoagulation: a meta-analysis

Patients taking anticoagulants orally over the long term have international normalized ratios (INRs) outside the individual therapeutic range more than one-third of the time. Improved anticoagulation control will reduce hemorrhagic and thromboembolic event rates. To gauge the potential effect of improved anticoagulation control, we undertook to determine the proportion of anticoagulant-associated events that occur when INRs are outside the therapeutic range. We conducted a meta-analysis of all studies that assigned hemorrhagic and thromboembolic events in patients taking anticoagulants to discrete INR ranges. We identified studies using the MEDLINE (1966-2006) and EMBASE (1980-2006) databases. We included studies reported in English if the majority of patients taking oral anticoagulants had an INR range with a lower limit between 1.8 and 2 and an upper limit between 3 and 3.5, and their INR at the time of the hemorrhagic or thromboembolic event was recorded. The final analysis included results from 45 studies (23 that reported both hemorrhages and thromboemboli; 14 that reported hemorrhages only; and 8, thromboemboli only) involving a median of 208 patients (limits of interquartile range [25th-75th percentile] 131-523 subjects; total n = 71 065). Of these studies, 64% were conducted at community practices; the remainder, at anticoagulation clinics. About 69% of the studies were classed as having moderate or high quality. Overall, 44% (95% confidence interval [CI] 39%-49%) of hemorrhages occurred when INRs were above the therapeutic range, and 48% (95% CI 41%-55%) of thromboemboli took place when below it. The mean proportion of events that occurred while the patient's INR was outside the therapeutic range was greater for studies with a short mean follow-up (< 1 yr). Between-study heterogeneity was significant (p < 0.001). Improved anticoagulation control could decrease the likelihood of almost half of all anticoagulant-associated adverse events.

Incidence and predictors of severe bleeding during warfarin treatment

Optimal warfarin prescription requires correct, individualized assessment of the warfarin-related bleeding risk, which randomised controlled trials may underestimate . Observational studies have reported a range of bleeding risks that differ 40-fold. This variation may be caused by time trends, variation in bleeding definition and study subject selection. We investigated the incidence of, and risk factors for severe bleeding in un-selected warfarin-treated patients from Sweden. Between 2001 and 2005, 40 centres recruited warfarin-naïve patients commencing warfarin therapy and followed them prospectively with continuous registration of clinical data. The primary outcome was severe bleeding, according to the WHO universal definition of severe adverse drug reactions. The influence of potential risk factors was investigated by means of a Cox proportional-hazards model. A total of 1523 patients contributed 1276 warfarin-exposed patient-years. The incidence of first-time severe bleeding was 2.3 per 100 patient-years (95% confidence interval 1.4 to 3.1). Male sex and use of drugs potentially interacting with warfarin were the only independent risk factors of severe bleeding, with hazard ratios of 2.8 and 2.3, respectively. Age, target International Normalized Ratio (INR), time spent outside target INR range, and warfarin dose requirement were not significantly associated with bleeding risk. The risk of severe bleeding in a large naturalistic, prospective cohort of first-time warfarin users was lower than reported in some previous reports. Male gender was an independent predictor of severe bleeding as was the receipt of warfarin-interacting medications at the onset of anticoagulation therapy. Further studies are required to evaluate the effect these findings may have on the quality of current risk-benefit analysis involved in warfarin prescription.

Catheter ablation for atrial fibrillation: Should it be first-line therapy?

Although much has changed in the management of atrial fibrillation (AF) over the past 20 years, pharmacologic therapy still remains the principal means of treatment. h-Adrenergic blockers, calcium-channel blockers, and digoxin are used to slow the ventricular rate during AF. Warfarin and aspirin are used to decrease the stroke risk associated with AF. Class I (eg, propafenone, flecainide, disopyramide) and class III (eg, sotalol, dofetilide, amiodarone) antiarrhythmic drugs are used to decrease the frequency of recurrences of AF. Although these pharmacologic approaches are all relatively effective, there are significant limitations and risks of side effects. Rate control drugs frequently have associated nuisance side effects, such as fatigue, decreased exercise capacity, and sexual dysfunction, and may exacerbate bradyarrhythmias, heart failure, and obstructive lung disease. Pharmacologic approaches for rate control may also be ineffective for controlling rate during AF in up to 25% of patients. Warfarin is substantially more effective than either aspirin alone or the combination of aspirin and clopidogrel for prevention of strokes in patients with AF. Nonetheless, pooled data from prospective trials with warfarin demonstrate only a 65% reduction in stroke risk by intention-to-treat analysis. This lower than expected risk reduction is primarily related to the frequent discontinuation of warfarin because of concerns about bleeding risks and the difficulties maintaining patients in the relatively narrow therapeutic international normalized ratio range of 2 to 3. Based on pooled data from clinical trials, warfarin is associated with a 1% per patient-year risk of major bleeding and a 0.3% per patientyear risk of intracerebral hemorrhage. Accumulated over time; this represents a substantial risk to patients. The risks of anticoagulation therapy are even worse under more typical clinical circumstances (ie, outside of controlled clinical studies), where the risk of major bleeding may be as high as 12%. Perhaps most controversial is the use of class I or III antiarrhythmic drugs for suppression of AF recurrences.

Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin

AbstractPatients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 µg oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (−0.24 ± 0.14 vs −0.11 ± 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% ± 20% vs 15% ± 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.

Management of dental patients taking common hemostasis-altering medications

Millions of patients worldwide are taking medications that alter hemostasis and decrease the risk for thromboembolic events. This systematic review is intended to provide recommendations regarding optimal management of such patients undergoing invasive dental procedures. The primary focus of this report is on warfarin therapy, although issues related to heparin and aspirin are briefly discussed because of the frequency with which they are encountered in dental practice. The review of literature and development of recommendations was based on the Reference Manual for Management Recommendations for the World Workshop in Oral Medicine IV (WWOM IV). A total of 64 publications were identified for initial review. From these publications, the following types of articles were critically analyzed using WWOM standard forms: randomized controlled trials (RCT), non-RCT studies that assess effects of interventions, and studies that assess modifiable risk factors. Development of recommendations was based on the findings of these reviews as well as expert opinion. The following evidence-based recommendations were developed: (1) For patients within the therapeutic range of International Normalized Ratio (INR) below or equal to 3.5, warfarin therapy need not be modified or discontinued for simple dental extractions. Nevertheless, the clinician's judgment, experience, training, and accessibility to appropriate bleeding management strategies are all important components in any treatment decision. Patients with INR greater than 3.5 should be referred to their physician for consideration for possible dose adjustment for significantly invasive procedures. (2) A 2-day regimen of postoperative 4.8% tranexamic acid mouthwash is beneficial after oral surgical procedures in patients on warfarin. (3) It is not necessary to interrupt low-dose aspirin therapy (100 mg/day or less) for simple dental extractions. For most patients undergoing simple single dental extractions, the morbidity of potential thromboembolic events if anticoagulant therapy is discontinued clearly outweighs the risk of prolonged bleeding if anticoagulant therapy is continued.

Warfarin metabolism and anticoagulant effect: A prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions

Background: Cytocbrome P450 (CYP) 2C9 polymorphism affects the warfarin dosage requirement in stable outpatients. However, it is not known whether the CYP2C9 genotype contributes to the variability in warfarin dosage in the presence of drug-disease and drug-drug interactions. Objective: The aim of this study was to examine the effects of CYP2C9 genetic polymorphism on warfarm dosage requirements in patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin. Methods: This prospective, observational study was conducted at Hadassah University Hospital, Jerusalem, Israel. Data from consecutive patients treated with warfarin for at least 3 months and admitted to the internal medicine ward were eligible for inclusion. Clinical data, international normalized ratio (INR), and warfarin dosage were recorded from medical records. The CYP2C9 genotype was determined using polymerase chain reaction restriction fragment length polymorphism, and plasma concentrations of (S)- and ( R)-warfarin were determined by high-performance liquid chromatography using chiral methods. Results: One hundred nineteen subjects (52% women) were studied. Mean age was 65.8 years (95% CI, 63.1–68.4), and weight was 74.9 kg (95% CI, 72.1–77.7). The mean warfarin dosage was 33% lower in patients with the CYP2C9-*1/*3 genotype (mean [SEM], 0.045 [0.006] mg/kg · d −1) compared with the CYP2C9-*1/*1 genotype (0.067 [0.004] mg/kg · d −1) ( P = 0.008); an intermediate value was found for the CYP2C9-*1/*2 genotype (0.062 [0.008] mg/kg · d −1). However, despite the lower dosage, INR was significantly higher in patients with the *1/*3 genotype (mean [95% CI], 3.29 [2.44-4.14]) (n = 18) compared with the *1/*1 genotype (2.52 [2.34-2.71]) (n = 64) ( P = 0.029). In addition to genotype, older age, congestive heart failure (CHF), and treatment with antibiotics were associated with lower warfarin dosages, whereas treatment with drug-metabolism inducers was associated with higher warfarin dosages. In addition, the ratios of ( S)- to ( R)-warfarin concentrations were significantly higher in patients with *1/*3 compared with those in patients with the *1/*1 genotype. Conclusions: In this study population of patients with severe comorbid conditions and those treated with medications that potentially interact with warfarm, CYP2C9 *1/*3 genotype, older age, CHF, and the use of antibiotics were associated with lower warfarm dosage requirements. The CYP2C9*1/*3 genotype, compared with CYP2C9 *1/*1, was associated with 33% lower mean warfarin dosage requirements and higher INR values, which were higher than the upper therapeutic range of INR (ie, 3). Genetic CYP2C9 polymorphism contributed to the variability in warfarm dosage requirements in the presence of drug-disease and drug-drug interactions.

Probable Elevation in International Normalized Ratio from Cranberry Juice

Objective: To report a case in which cranberry juice interacted with warfarin, resulting in an elevated international normalized ratio (INR). Case Summary: A 77-year-old male had maintained stable INR values for 6 months while on a warfarin maintenance dose of 24 mg/wk. On a routine follow-up examination, the INR was 5.9; one month prior to presentation, the INR had been 2.4. The patient reported several recent nosebleeds and a red mark on his left eye. He stated he had been adherent to therapy and denied any changes in medications or recent illnesses such as fever, flu, or diarrhea. His physical activity level and diet had been consistent, with no alcohol intake. The only change identified was the addition of daily cranberry juice (1–3 cups/day) for the last month. Cranberry juice was stopped, and the dose of warfarin was decreased to 22 mg/wk. Subsequently, the INR stabilized at the low end of the therapeutic range. Discussion: Whether cranberry juice interacts with warfarin is unclear. Three previously published case reports suggested a possible interaction. In at least 2 of these cases, confounding factors and incomplete information make assessing the influence of cranberry juice difficult. The interaction in our patient was scored as probable by the Naranjo probability scale, based on the temporal relationship, return to the therapeutic INR range after discontinuing cranberry juice, and elimination of alternative causes for the INR elevation. Conclusions: This case suggests that cranberry juice may interact with warfarin, leading to an elevated INR.

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.

Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM)

Expert oral anticoagulation management is the key to good outcomes and is performed variably in different health care systems throughout the world. We set out to assess the quality of anticoagulation management in five countries in patients receiving vitamin K antagonists (VKAs) for stroke prophylaxis in chronic non-valvular atrial fibrillation (NVAF), and to compare the anticoagulation management practices in these countries. This was a retrospective, multi-centre cohort study in the United States, Canada, France, Italy, and Spain. About 1,511 patients were randomly recruited from representative practices (routine medical care (RMC) in the US, Canada, and France; anticoagulation clinics in Italy and Spain) and data pertaining to their oral anticoagulation care were abstracted from their medical records. The predominant anticoagulant in use was warfarin in the US, Canada, and Italy; acenocoumarol in Spain; and fluindione in France. Documentation of care was poor in the US, Canada, and France, countries where RMC was studied. Percent INRs or time-in-therapeutic range was greater in the two anticoagulation clinic samples compared with the RMC samples. Oral anticoagulation care varies considerably from country to country. Findings suggest that anticoagulation clinic care (ACC) may provide better outcomes as assessed by international normalized ratio (INR) time-in-range. Physicians tend to under treat more than over treat. Finally, documentation of care is often inadequate. Condensed Abstract Oral anticoagulation management (routine medical care or anticoagulation clinic care) was retrospectively assessed in 5 countries using a uniform, structured assessment tool. Major management differences were detected, especially between anticoagulation clinic care and routine care. Documentation was often a problem in the latter setting. Less time in therapeutic INR range was noted in routine medical care. Findings suggest that anticoagulation clinic care may provide better outcomes as assessed by international normalized ratio (INR) time-in-range. Physicians tend to under treat more than over treat. Finally, documentation of care is often inadequate.

The quality of oral anticoagulant therapy and recurrent venous thrombotic events in the Leiden Thrombophilia Study.

The International Normalized Ratio (INR) target range is a relatively narrow range in which the efficacy of oral anticoagulant treatment, i.e. prevention of extension and recurrence of thrombosis, is balanced with the risk of hemorrhagic complications. Over the years, different INR target ranges have been implemented for individual indications, depending on their thrombotic potential. In most of the studies defining these INR targets, the treatment of the patients was aimed at a certain INR range, but in the analysis no account was taken of the time that the patients spent within this range in reality. The Leiden Thrombophilia Study (LETS) is a population-based case-control study on risk factors for venous thrombosis, in which many genetic and acquired factors have been investigated. Our aim was to investigate the effect of the quality of the oral anticoagulant therapy for the initial venous thrombosis and its relationship with recurrence of thrombosis. Quality of anticoagulation was defined as the time spent at various INR levels during treatment, and we focused on the effect of sustained intensities above a certain INR in preventing recurrences later on. Two hundred and sixty-six patients with a total follow-up of 2495 patient-years were studied. The mean duration of the initial anticoagulant therapy was 194.5 days (range 48-4671). During follow-up, 58 recurrences were diagnosed (cumulative recurrence rate of 21.8% over 9 years). The mean INR during initial therapy was 2.90, with 90.3% [95% confidence interval (CI) 88.4-92.3%] of the time being spent above an INR of 2.0, and 39.1% (95% CI 35.5-42.7%) above an INR of 3.0. Patients who spent more time below the target range, or who had a shorter duration of anticoagulation, did not experience a higher risk of recurrence after the initial period of anticoagulation had passed. Provided that oral anticoagulant treatment is adequately managed, according to international guidelines, recurrent thrombosis cannot be ascribed to variation in the primary treatment. Further attempts to reduce the risk of recurrence should therefore be aimed at identifying other explanatory factors, and subsequently fine-tuning the target ranges.

Paper-based dosing algorithms for maintenance of warfarin anticoagulation

We examined the quality of anticoagulation produced by two paper-based warfarin dosing algorithms in a randomized clinical trial of warfarin therapy. Fifty-eight patients were randomized to receive warfarin at a target international normalized ratio (INR) range of 2.1-3.0 and were followed for an average of 2.7 years. As a proportion of total patient-time, the percentage of time spent above, within, and below the therapeutic range was 11%, 71%, and 19% respectively. Fifty-six patients were randomized to receive warfarin at a higher target INR range (3.1-4.0) and had INRs within the therapeutic range for 40% of total patient time. We conclude that the performance, minimal cost, and ease-of-use of these algorithms make them well-suited for patient management within primary-care and research settings.

PT and INR Interference by the Antibiotic Daptomycin in Commercial Thromboplastin Reagents: Dependence on Phospholipid Composition.

The antibiotic, daptomycin (brand name Cubicin, Cubist Pharmaceuticals) is approved in the US for treatment of complicated skin and skin structure infections caused by gram-positive pathogens (e.g., MRSA, methicillin-resistant Staphylococcus aureus). Recently, this antibiotic has been shown to interfere with prothrombin time (PT) assays, resulting in a prolongation of clotting times and artificial increases in the INR (International Normalized Ratio). The level of interference varies with Daptomycin concentration in the plasma, the brand of prothrombin time reagent as well as the type (normal or abnormal) of patient sample being analyzed. The bactericidal action of the antibiotic is known and is through a depolarization of bacterial membranes in the presence of physiologic calcium (Silverman, et al, Antimicrobial Agents and Chemotherapy, Aug 2003); therefore, daptomycin interference with the PT clotting assay is likely mediated through the phospholipid component of the thromboplastin formulations. To examine the dependence of daptomycin interference for a number of commercial PT formulations, testing was performed with daptomycin spiked samples of normal pooled plasma as well as abnormal samples from oral anticoagulant therapy (OAT) patients. For spiked normal samples, a small degree of prolongation in clotting times was observed with most PT reagents, with one reagent showing a significant prolongation. In OAT samples spiked with Daptomycin, the PT prolongation was greater for all formulations, with the one reagent again showing greater prolongation as for the normals. Ultimately, this variation in response was attributed to differences in phospholipid composition among the reagents, supported by previous studies of daptomycin with neutral and acidic phospholipids in the presence of calcium (D. Jung, et al., Chemistry and Biology, Jul 2004). A four-dimensional experimental design matrix was constructed using a mixture of four synthetic phospholipids (DOPC, DOPS, DOPE and DOPG), and the relationship of daptomycin-PT interference to percent composition of the phospholipids was examined. In both normal and OAT plasmas spiked with daptomycin, the major contributor to PT prolongation was the concentration of DOPG (phosphatidylglycerol) in the lipid mixture, with additional contributions correlated with DOPC (phosphatidylcholine). Because of the ubiquitous use of these phospholipids in commercial PT formulations, this work suggests that daptomycin interference should be assessed for each combination of PT reagent and INR range used.

Comparison of Outcomes Using 2 Delivery Models of Anticoagulation Care

Studies demonstrate the effectiveness of anticoagulation management service (AMS) in providing antithrombotic therapy for eligible patients. We sought to extend this concept by determining whether an interim telephone model (IT) is comparable to our current AMS model at achieving optimal therapeutic outcomes. The 36-month trial (24-month study plus 12-month extension) enrolled 192 eligible patients receiving long-term warfarin therapy at a Veterans Affairs hospital. Consenting participants were randomly assigned to either our current face-to-face clinic model (AMS), or our IT model. The primary outcome was the percentage of time individuals' international normalized ratios (INRs) were maintained within their target INR range (2.0-3.0 or 2.5-3.5). Secondary outcomes included the number of adverse events (eg, thromboembolism or hemorrhage) experienced during the study. We found no statistically significant difference between the 2 groups in the percentage of time maintained within INR target range overall (55.1% for AMS; 57.8% for IT; P = .28) nor over the course of the study. There were no statistically significant differences in the rate of thromboembolic or serious bleeding events between IT and AMS participants. Nevertheless, we did note differences related to intensity of anticoagulation. The IT group receiving treatment at a higher intensity (INR, 2.5-3.5) experienced greater anticoagulation control (P = .04) and fewer complications than the AMS group. The IT participants, however, reported a significantly higher rate of minor bleeding events, experienced mainly by those at an INR range of 2.0 to 3.0. Our IT model is a viable modification of our AMS model for the management of patients undergoing chronic anticoagulant therapy.

Low-Dose Vitamin K to Augment Anticoagulation Control

To determine the effect of daily low-dose oral vitamin K supplementation on reducing variations in the international normalized ratios (INRs) in patients taking warfarin. Retrospective analysis. Anticoagulation clinic in a large, private-practice hematology group. Eight motivated patients (three men, five women), aged 45-79 years, receiving anticoagulant therapy with warfarin, whose INRs had been fluctuating for reasons not associated with identifiable changes in diet, warfarin dosage, activity level, illness, or changes in drug therapy. Daily supplementation with oral vitamin K, starting with 100 microg/day Anticoagulation providers monitored INR responses; all documented INR values were included in the analysis, even those intentionally allowed outside the therapeutic range when dosages were adjusted for procedures. After dietary vitamin K supplementation, INR fluctuations diminished in nearly all patients. Overall, a significant decrease was noted in the INR standard deviation (p<0.05), and more INRs were in the therapeutic range after the start of supplementation. Allowing for small fluctuations on either side of the target range, the number of INRs within 0.2 units of the target range increased from 32% to 57% (relative increase 76%). Time in range also increased by a similar degree. Supplementation with daily low-dose oral vitamin K significantly increased the number of INRs in range as well as the time in range, and decreased INR fluctuation in this small series of selected patients.

Atrial fibrillation and stroke: Four treatment controversies

Atrial fibrillation is an important cause of disabling ischemic stroke, and adjusted-dose warfarin is highly effective for prevention and remains the therapy of choice for high-risk patients. Ximelagatran, a novel oral anticoagulant, is clinically equivalent to warfarin for preventing stroke in patients with atrial fibrillation, but concerns about potential hepatic toxicity have precluded US Food and Drug Administration approval. Many patients with low-risk atrial fibrillation do not benefit substantially from anticoagulation, and these patients can be reliably identified using the CHADS2 stroke risk stratification scheme. A target International Normalized Ratio (INR) range of 2 to 3 is usually recommended for anticoagulation of patients with atrial fibrillation, but a lower INR target (2, range 1.6-2.5) may be a reasonable benefit/risk trade-off for primary prevention in those aged older than 75 years. Adding aspirin to adjusted-dose anticoagulation increases bleeding (including central nervous system bleeding), is of uncertain value, and should only be done after careful consideration and with vigorous efforts to control blood pressure.

Guidelines on oral anticoagulation (warfarin): third edition – 2005 update

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.

Outcomes for Ximelagatran Compared with Warfarin According to INR Control: Results from SPORTIF III and V Atrial Fibrillation Trials.

Background: Warfarin effectively reduces the risk of stroke in patients with atrial fibrillation, but requires regular monitoring to maintain the target international normalized ratio (INR). Ximelagatran, a novel direct thrombin inhibitor, does not require coagulation monitoring and can be administered at a fixed oral dose.Methods: Outcomes in warfarin patients (n = 3587) from the SPORTIF III and V trials according to time spent in the therapeutic target INR range of 2–3 (≥ 76% of the time = good INR control [n = 1190]; 60–75% of the time = moderate INR control [n = 1207]; and < 60% of the time = poor INR control [n = 1190]) were compared with ximelagatran patients (n = 3664). The primary endpoint was stroke/systemic embolic event (SEE).Results: Mean follow-up was 16.6 (± 6.3) months. Outcomes in warfarin patients according to INR control are shown in the table. Ximelagatran patients had numerically lower stroke/SEE rates than the warfarin patients with poor INR control (1.43%/yr vs 2.10%/yr; P = 0.08), as well as lower mortality (2.36%/yr vs 4.20%/yr; P < 0.01) and major bleeding (1.89%/yr vs 3.85%/yr; P < 0.01). The incidence of stroke/SEE and major bleeding did not differ statistically among the moderate INR control, good INR control, and ximelagatran groups. However, major + minor bleeding was more common in the moderate INR control group than the ximelagatran group (41.8% vs 32.5%; P < 0.01).Conclusions: In warfarin-treated atrial fibrillation patients, the risks of stroke/SEE, mortality, and major bleeding are related to INR control, with a significant reduction in these events with good vs poor INR control. Compared with the one-third of patients who experienced poor INR control, patients randomized to ximelagatran administered at a fixed oral dose without the need for coagulation monitoring had a lower mortality rate and less major bleeding.OutcomePoor INR ControlModerate INR ControlGood INR ControlPoor vs ModeratePoor vs GoodGood vs ModerateStroke/SEE, %/yr2.101.341.07P = 0.09P = 0.02P < 0.01Total mortality, %/yr4.201.841.69P < 0.01P < 0.01P < 0.01Major bleeding, %/yr3.851.961.58P < 0.01P < 0.01P < 0.01

Pulmonary embolism: Current treatment options

The initial treatment of patients with acute pulmonary embolism has traditionally involved unfractionated heparin. Given the more predictable pharmacodynamic and pharmacokinetic properties of low molecular weight heparins, their simpler (fixed) dosing regimens, and few or no laboratory monitoring requirements, low molecular weight heparins are gradually replacing heparin for the initial treatment of most patients diagnosed with acute pulmonary embolism, except in very obese patients or patients with renal failure. Only selected patients with massive, life-threatening pulmonary embolism should be managed with intravenously administered thrombolytic drugs, surgical embolectomy, or catheter-based embolectomy. Likewise, inferior vena caval filter should be considered only in patients with an absolute contraindication to, or a documented failure of, anticoagulant therapy. New anticoagulants, such as ximelagatran, an oral direct thrombin inhibitor, or fondaparinux and idraparinux, selective factor X(a) inhibitors with an almost complete bioavailability after subcutaneous injection are promising alternatives, but these drugs have yet to find a place in the initial treatment of pulmonary embolism in standard day-to-day clinical practice. Long-term anticoagulation treatment is still provided by antivitamin K antagonists (eg, warfarin), which unfortunately have a narrow therapeutic window. Consequently, time-consuming monitoring is required to ensure the therapeutic anticoagulant effect. A target International Normalized Ratio (INR) of 2.5 (INR range: 2.0 to 3.0) is recommended for warfarin therapy. This treatment should be continued for at least 3 months for patients with a first episode of pulmonary embolism secondary to a transient (reversible) risk factor, or up to 6 to 12 months for patients with a first episode of idiopathic pulmonary embolism.

Poster 52: Pharmacy Versus Physician Warfarin Dosing

Objective: To compare the efficacy a new method of intervention for the monitoring of international normalized ratios (INRs) for patients taking warfarin (Coumadin) in an inpatient rehabilitation hospital. Design: Retrospective study including all data from all patients taking Coumadin in an inpatient rehabilitation study over the past year. During that year, the pharmacy ordered Coumadin based on normograms and INRs. Data were compared with those using a previous method of Coumadin ordering. Setting: Freestanding rehabilitation hospital laboratory and pharmacy. Participants: All inpatients taking Coumadin over the past year. Interventions: Not applicable. Main Outcome Measures: The number of blood draws in which the INR was within therapeutic range. Results: The percentage of blood draws that were in the target INR range was 67% over the 12 months of this trial. Compared with data from the same institution when physicians looked at INRs, it was 36.7%. Conclusions: This retrospective study demonstrates that the use of a normagram by pharmacists should be involved in INRs being maintained with the target therapeutic range at a better rate than physicians dosing without computer assistance or a normagram.

The Lowest Effective Intensity of Prophylactic Anticoagulation for Patients with Atrial Fibrillation

Background: Stroke prevention trials in patients with atrial fibrillation (AF) mainly studied the use of warfarin in Caucasians, and the international normalized ratio (INR) was targeted in the range of 2–4. The result may not necessarily be applicable to other ethnic groups. This study aimed to determine the optimal intensity of anticoagulation for stroke prevention in Chinese patients. Methods: We performed a retrospective study on all Chinese patients with AF taking warfarin for stroke prevention in our hospital from January 1, 2000, to June 30, 2002. Patients with a mechanical heart valve were excluded. We systematically studied their indication of using warfarin, duration of therapy and all INR results. Only those patients whose indications of using warfarin were consistent with the ACC/AHA/ESC Executive Summary were included. Thrombo-embolic episodes, sudden death, major bleeding, intracranial haemorrhage and the INR at the time of the event were recorded. The INR range was divided into six categories: <1.5, 1.5–1.9, 2.0–2.5, 2.6–3.0, 3.1–3.5, >3.5. The number of events was recorded for each category, and this formed the numerator. The denominator was the summation of time each patient stayed in each category of INR. The event rate was then calculated for each INR category. Results: 555 patients were included in the analysis, they constituted 893 patient-years. The INR was kept below 2.6 in 84.9% of the time and between 1.5 and 1.9 in 35% of the time. The overall event rate in our patients was 6.0%, of which 3.9% were due to thrombo-embolic events and 2.1% were due to serious bleeding. The overall event rate was lowest in the INR range from 1.5 to 1.9. which is not significantly different from that of INR 2.0–2.5 and 2.6–3.0. The overall event rate was 3.6% in INR 1.5–3.0 which was significantly lower than 15.1% in INR <1.5 and 20.5% in INR >3.0 (p < 0.01). Conclusions: Our retrospective cohort showed that a lower INR range of 1.5–3.0 was safe and effective for stroke prevention in Chinese patients treated in a single hospital.