Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation

STUDY OBJECTIVE: To compare the efficacy of managing excessive anticoagulation in the absence of bleeding by either omitting warfarin therapy alone or administering oral phytonadione in addition to omitting warfarin therapy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical pharmacy anticoagulation service in a group model health maintenance organization. SUBJECTS: Thirty nonbleeding patients with international normalized ratios (INRs) ranging from 6.0-10.0. INTERVENTIONS: Patients were randomized to receive either a single oral dose of phytonadione 2.5 mg or placebo. Both groups omitted warfarin doses until the INR became less than or equal to 4.0. MEASUREMENTS AND RESULTS: The mean calculated time to reach an INR of 4.0 was significantly greater in the placebo than the phytonadione group (2.6 vs 1.4 days, p=0.006). Overcorrection of anticoagulation was significantly more common in patients receiving phytonadione. Overt warfarin resistance was not observed in either group after reinitiating warfarin therapy. No major bleeding or thromboembolic complications occurred, and minor bleeding episodes were similar in both groups. CONCLUSION: The addition of oral phytonadione 2.5 mg reduced the time to achieve an INR of 4.0 by approximately 1 day compared with omitting warfarin therapy alone. Adverse events did not differ between the two groups. Both strategies were effective in managing asymptomatic patients with INRs of 6.0-10.0. Oral phytonadione may be most appropriate for patients at high risk for bleeding in whom the benefit of prompt INR reduction would outweigh the thromboembolic risk associated with INR overcorrection.     

Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin

STUDY OBJECTIVE: To assess the effectiveness of using low-dose recombinant activated factor VII (rFVIIa) to reverse the effects of warfarin in critically ill patients with major bleeding events. DESIGN: Prospective observational study. SETTING: Intensive care unit of a 500-bed university-affiliated hospital. PATIENTS: Sixteen nonhemophiliac patients who had been receiving warfarin and had an acute major bleeding event. INTERVENTION: Patients received rFVIIa 1.2 mg for reversal of anticoagulation. MEASUREMENTS AND MAIN RESULTS: Patients were identified from clinical pharmacology consult service electronic tracking records, and their data were cross-checked with the pharmacy information system. Information collected for each patient included extent of bleeding and magnitude of elevation in international normalized ratio (INR). A mean +/- SD dose of rFVIIa 16.3 +/- 4.1 microg/kg (range 11-25 microg/kg) reduced the mean INR from 2.8 +/- 1.6 (range 1.44-6.34) to 1.07 +/- 0.27 (range 0.86-1.92, p<0.001). A rapid onset of response for achieving a desirable hemostatic effect was observed in 14 of the 16 patients. CONCLUSION: Low-dose rFVIIa appears to be an effective, rapid reversal modality for major bleeding events in the presence of warfarin and an elevated INR. The agent's response is quicker than that expected with fresh frozen plasma combined with vitamin K. In emergency situations, rFVIIa 1.2 mg can be used to reverse the anticoagulant effect of warfarin and other vitamin K antagonists without inducing a hypercoagulable state; the product, however, is expensive.     

Warfarin maintenance dosages in the very elderly.

PURPOSE: The effect of age on maintenance dosages among elderly patients with a stable International Normalized Ratio (INR) was studied. METHODS: The records of all patients monitored by an anticoagulation clinic between October 2000 and July 2002 were randomly selected for review. Data collection continued until at least 50 patients were enrolled in each of the following age groups: <75, 75-79, 80-84, and >/=85 years. To be included in the analysis, patients had to have been >50 years of age, had to have had a targeted INR of 2-3, and had to have had two consecutive INR values within the targeted range not more than 60 days apart. RESULTS: A total of 532 patient charts were reviewed, and 253 met the criteria for inclusion in the study. The mean +/- S.D. age of the patients was 80.6 +/- 7.8 years (range, 55-98 years). Atrial fibrillation or flutter was the most common indication for treatment. The mean daily warfarin dose was significantly lower with increasing age; the mean +/- S.D. daily dose for patients younger than 75 years was 4.9 +/- 2.6 mg/day, while that for patients 85 years or older was 3.5 +/- 2.6 mg/day. CONCLUSION: The warfarin dosage for maintenance therapy in elderly patients, especially those older than 75 years, appeared to be inversely related to age.     

Increased sensitivity to warfarin in elderly Hispanics

It has been suggested that aging enhances the pharmacologic effect of warfarin, but there is little information about the effects of warfarin in aging minority populations. The authors examine the response of an aging Hispanic population to warfarin. Charts in their anticoagulation clinic were retrospectively examined for the following information: age, sex, weight, duration of anticoagulant therapy, number of medical problems, number of medications, number of minor or major bleeding episodes, prothrombin time, warfarin dose, and international normalized ratio (INR). The dose-adjusted prothrombin time ratio (PTR) and dose-adjusted INR were calculated by dividing the PTR and INR by the mean warfarin dose. Four groups were compared by age: < 50, 50 to 59, 60 to 69, and > or = 70. A total of 243 charts were reviewed: 113 female, 130 male; 90% were Hispanic. The most common indication for anticoagulation was atrial fibrillation. Elderly patients had more medical problems (3.1 vs. 2.4) and took more medications (3.4 vs. 2.4) than younger patients. The dose-adjusted PTR and dose-adjusted INR increased with aging (0.59 vs. 0.38 and 0.85 vs. 0.59, p < .05 ANOVA). In a multiple linear regression analysis, only age remained significantly associated with the anticoagulant effect. These results are consistent with previous reports on the effect of warfarin in aging patients and extend these data to the Hispanic population.     

Evaluation of warfarin initiation regimens in elderly inpatients

STUDY OBJECTIVE: To compare initial warfarin doses of 5 mg or below and doses above 5 mg in hospitalized elderly. DESIGN: Retrospective review of charts identified from computerized pharmacy records. SETTING: County teaching hospital. PATIENTS: Inpatients aged 65 years or older receiving at least three warfarin doses. INTERVENTION: We measured the time to first international normalized ratio (INR) of 2.0 or greater, bleeding complications, number of warfarin doses held, and vitamin K use. MEASUREMENTS AND MAIN RESULTS: The average initial low dose (33 patients) was 4.8 +/- 0.8 mg and the average initial high dose (40 patients) was 9.0 +/-1.2 mg. The mean time to first INR of 2.0 or greater was similar, 3.4 and 3.0 days, respectively (p=0.38). The low-dose group had fewer bleeds (7 vs 13, p=0.28) and doses held (11 vs 18 patients, p=0.27, 30 vs 50 doses). Four patients in each group received vitamin K (p=0.8). Forty-four percent of patients with an INR of 4 or above and 48% of patients who had a dose held were on a long-term drug or had a new drug added that could cause a major drug interaction with warfarin. CONCLUSION: In this pilot study, hospitalized elderly who received a low versus high initial dose of warfarin achieved therapeutic INRs in a similar time and had lower but not significantly different safety outcomes.     

An observational study examining the impact of capecitabine on warfarin antithrombotic activity and bleeding complications

OBJECTIVE: The objectives of this study are to quantify the frequency of concomitant use of capecitabine and warfarin, and to quantify the rate of bleeding events and elevated international normalized ratio (INR) among concomitant users of warfarin and capecitabine. RESEARCH DESIGN AND METHODS: We conducted a retrospective population-based study within the Henry Ford Health System (Detroit, MI) and the Kaiser Permanente Medical Care Program of Northern California (Oakland, CA). The study population included patients prescribed concomitant capecitabine and warfarin from 1 April 1997 through 31 July 2002. Data from the medical records of concurrent users were extracted through 31 August 2002. MAIN OUTCOME MEASURES: Concomitant use of capecitabine and warfarin, bleeding events, and INR laboratory results, collected from computerized databases and medical record review. RESULTS: Overall, 11% of capecitabine users also received warfarin (99 / 883). Among 17 patients who received warfarin for venous access device prophylaxis, one bleeding event occurred during concomitant capecitabine/warfarin use (rate = 35.7 bleeding events per 100 person-years, 95% confidence interval [CI] 0.9-198.9), and no events occurred during use of warfarin alone (95% CI 0.0-136.2) (p = 0.50). Among patients prescribed warfarin for indications other than port prophylaxis, no bleeding events occurred during concomitant use of capecitabine and warfarin (95% CI 0.0-34.6), and one event occurred during warfarin use alone (rate = 9.2 bleeding events per 100 person-years, 95% CI 0.2-51.3) (p = 0.54). We found one INR elevation > 3.0 among concomitant capecitabine/warfarin users receiving warfarin for port prophylaxis (rate = 35.7 per 100 person-years) and no INR elevations > 3.0 during use of warfarin alone (p = 0.46). Among patients using warfarin for indications other than port prophylaxis, the rates of INR > 3.0 were 309.7 per 100 person-years (95% CI 213.2-434.9) during concomitant capecitabine/warfarin use and 193.5 events per 100 person-years (95% CI 119.8-295.8) during use of warfarin alone (p = 0.09). CONCLUSIONS: The results of our study show a low prevalence of capecitabine and warfarin concomitant use. We did not find large differences in the rates of bleeding events and elevated INR in patients receiving concomitant capecitabine and warfarin when compared with use of warfarin alone. While these results do not imply a lack of biologic interaction, our findings indicate that patients appear to be appropriately managed in clinical practice.     

Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study

STUDY OBJECTIVE: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. DESIGN: Retrospective, matched cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. MEASUREMENTS AND MAIN RESULTS: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). CONCLUSION: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.     

Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?

AIM: To examine the optimal range of International Normalized Ratio (INR) for Chinese patients receiving warfarin for moderate-intensity anticoagulation. METHODS: This was a retrospective cohort study conducted at the ambulatory setting of a 1400-bed public teaching hospital in Hong Kong. The INR measurements and occurrence of serious or life-threatening haemorrhagic and thromboembolic events among patients newly started on warfarin from 1 January 1999 to 30 June 2001 for indications with target INR 2-3 were analysed. The INR-specific incidence of bleeding and thromboembolism were calculated. RESULTS: A total of 491 patients were included, contributing to 453 patient-years of observation period. Forty-seven of the 491 patients experienced 25 haemorrhagic events (5.5 per 100 patient-years) and 27 thromboembolic events (6.0 per 100 patient-years). The percentage of patient-time spent within therapeutic INR range (2-3), INR <2 and INR >3 were 50, 44 and 6%, respectively. The incidence of either haemorrhagic or thromboembolic events was lowest (< or =4 events per 100 patient-years) at INR values between 1.8 and 2.4. CONCLUSIONS: An INR of 1.8-2.4 appeared to be associated with the lowest incidence rate of major bleeding or thromboembolic events in a cohort of Hong Kong Chinese patients receiving warfarin therapy for moderate-intensity anticoagulation.     

Management of Chinese patients on warfarin therapy in two models of anticoagulation service - a prospective randomized trial

AIM: To compare the treatment outcomes of a clinical pharmacist-managed anticoagulation service with physician-managed service in Chinese patients. METHODS: A prospective, randomized clinical trial was conducted at the anticoagulation clinic of a teaching hospital in Hong Kong. Patients aged > or = 18 years who would required warfarin therapy for at least 3 months were recruited. Patients were randomized to the pharmacist-managed or physician-managed group. Primary clinical outcome was assessed by the percentage of patient time spent within the target international normalized ratio (INR) range. The incidence of major thromboembolic events (TEs) and major bleeding was assessed as secondary clinical outcomes. The cost per patient per month (cPPPM) was calculated and patient satisfaction was assessed by patient satisfaction questionnaire (PSQ)-18. RESULTS: One hundred and forty-one patients were recruited at the anticoagulation clinic and 137 patients completed the study. Patients in the pharmacist-managed group (n = 68) were in the target INR 64% of patient time vs. 59% in the physician-managed group (n = 69) (P < 0.001). There was no significant difference in incidence of major TEs or bleeding. The cPPPM in the pharmacist-managed group (76 +/- 95 US dollar) (43 +/- 53 British pound) was lower than in the physician-managed group (98 +/- 158 US dollar) (55 +/- 89 British pound) (P < 0.001). The PSQ-18 score of the pharmacist-managed group (3.8 +/- 0.2) was higher than that of the physician-managed group (3.6 +/- 0.3) (P < 0.001). CONCLUSION: The pharmacist-managed anticoagulation service was more effective and less costly than the physician-managed service in achieving target anticoagulation control for Chinese patients on warfarin therapy.     

心脏机械瓣膜置换术后华法林抗凝治疗的研究

目的:探讨心脏机械瓣膜置换术后华法林临床抗凝治疗的影响因素、给药方法以及国际标准化比值(INR)监测。方法:对114例心脏瓣膜置换术后应用华法林抗凝治疗的患者的临床资料进行分析,记录年龄、性别、华法林剂量和INR值等,观察出血、栓塞等不良反应发生情况。结果:华法林维持剂量及达标时间个体差异较大,与年龄、性别、体重无关。华法林维持剂量范围1～6mg·d~(-1),71.1%的患者维持剂量为2.0～4.5mg·d~(-1),INR稳定达标时间为10～21d。结论:华法林抗凝治疗个体差异大,应在严密监测INR值条件下使用。     

心脏机械瓣膜置换术后华法林抗凝观察

目的:探讨心脏机械瓣膜置换术后华法林抗凝治疗的影响因素、给药方法和国际标准比值(INR)的关系。方法:对123例行心脏机械瓣膜置换术后患者进行随访研究。术后使用华法林抗凝,出院后定期复查随访。记录年龄、性别、华法林剂量和INR值等,观察出血、栓塞、死亡等不良事件发生情况。结果:术后无死亡病例,出院发生股静脉血栓1例,牙龈出血11例,泌尿系出血3例。出院随访因抗凝出现不良事件的发生率与国外文献报道相近。结论:心脏机械瓣膜置换术后5d根据INR给予个体化剂量,控制INR值在1.5～2.0之间可以达到一定的抗凝效果,且相对安全。     

慢性房颤华法令抗凝治疗的理想INR值探讨

目的:探讨慢性房颤华法令抗凝治疗的理想国际标准化比值(INR)。方法:对115例有血栓栓塞高危因素的慢性房颤患者给予华法令抗凝治疗,定期随访INR,同时观察治疗中发生的血栓栓塞和出血事件。结果:115例患者中有8例共10次发生血栓栓塞事件,7例7次发生与抗凝有关的出血事件,10次血栓栓塞事件中9次发生在INR<1.7,而所有的出血事件都发生在INR>3.5,INR 1.7～3.5时栓塞或出血发生率均较低。结论:INR 1.7～3.5是慢性房颤华法令抗凝治疗较理想的抗凝强度。     

非瓣膜病房颤患者不同强度抗凝的疗效分析

目的分析非瓣膜病房颤患者不同强度抗凝的治疗效果。方法把我院2005年1月到2011年10月有效随访的236例非瓣膜病房颤患者,分成四组,第一组61例,采用阿司匹林(100mg/d)抗凝治疗;第二组54例,采用华法林(INR1.5-2.0)抗凝治疗;第三组63例,采用华法林(INR2.01-2.5)抗凝治疗;第四组58例,采用华法林(INR2.51-3.0)抗凝治疗。最后对四组患者在随访期内的血栓事件及出血事件进行比较。结果第一组患者的栓塞事件发生率为13.1%,高于其他各组,差异有显著性(P<0.05),第四组栓塞事件发生率为1.7%,低于其他组,差异有显著性(P<0.05)。第四组严重血事件发生率10.3%,高于其他各组(P<0.05),而第一组无严重出血事件发生,低于其他组,差异有显著性(P<0.05),但在总出血发生率上四组比较差异无显著性(P>0.05)。结论在非瓣膜病房颤患者抗凝治疗中,华法林预防栓塞疗效优于阿司匹林,随INR强度上升栓塞事件发生降低,但严重出血风险升高,INR1.5-2.5时有效且安全,推荐国人采用。     

Predictors of Warfarin Use in Atrial Fibrillation Patients in the Inpatient Setting

Background

There is substantial published evidence that warfarin reduces the risk of stroke in patients with atrial fibrillation (AF). However, the current literature suggests that not all patients who could benefit from warfarin receive the drug.

Objective

To evaluate patient-related demographic and clinical factors that could influence warfarin use or other anticoagulant use in hospitalized patients with AF.

Study Design

Retrospective observational study using claims data from the Wolters Kluwer Pharma Solutions Hospital Patient Level Database, evaluating characteristics of patients hospitalized in the US between 1 November 2003 and 31 October 2004.

Setting

Hospital care.

Patients

The study included 44 193 patients aged ≥40 years who were hospitalized between 1 November 2003 and 31 October 2004 and had a diagnosis of AF during hospitalization (AF did not need to be the cause of hospitalization).

Interventions

Use of warfarin or other anticoagulants (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) was evaluated.

Main Outcome Measures

A logistic regression model was used to identify factors associated with warfarin use, international normalized ratio (INR) monitoring, or the use of anticoagulants (UFH or LMWH).

Results

In this analysis of hospitalized patients with AF in the real-world setting, about 56% of patients received anticoagulation therapy with warfarin. Elderly patients aged ≥75 years were less likely to be treated with warfarin than younger patients, but patients between the ages of 60 and 74 years were more likely to use warfarin than their younger counterparts. Except for patients with congestive heart failure or vascular malformation, patients with other bleeding risk factors (hepatic disease, renal disease, aspirin use, and fractures) were significantly less likely to receive warfarin than those without these risk factors. CHADS₂ scores for stroke risk of 2 and 3 were associated with a significantly higher likelihood of warfarin treatment than scores of 0 or 1. Patients admitted through a routine admission (an outpatient department) were significantly more likely to be prescribed warfarin than patients admitted through an emergency room. Patients aged ≥75 years and aspirin users were more likely to have their INR monitored during hospitalization. With respect to other anticoagulant use, females and older patients (≥65 years) were less likely to use UFH or LMWH, and patients with renal disease or vascular malformation and those receiving aspirin were more likely to use UFH or LMWH than patients without these conditions/not receiving aspirin. Patients admitted through the emergency room were more likely to receive an anticoagulant than patients admitted through an outpatient department, an inpatient transfer, or any other source.

Conclusions

Older age, female sex, and certain risk factors for bleeding, including hepatic disease, renal disease, aspirin use, and fractures, were associated with a lower likelihood of warfarin treatment, while a higher stroke risk (as indicated by CHADS₂ scores) was associated with a higher likelihood of warfarin treatment, in hospitalized patients with a diagnosis of AF. The likelihood of INR being monitored increased for patients aged ≥75 years and for aspirin users. Older patients and female patients were less likely to be prescribed other anticoagulants (UFH or LMWH) also.     

The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US

BACKGROUND: Anticoagulation therapy with warfarin is widely considered the standard of care for stoke prophylaxis in patients with atrial fibrillation who are at high risk of stroke. Community-based studies in the US have reported that the effectiveness of anticoagulation varies by management approach and that patients receiving warfarin have international normalised ratio (INR) values within the target therapeutic range less than half the time. OBJECTIVE: To estimate the lifetime societal costs and health benefits of warfarin therapy to prevent strokes, specifically in elderly patients (mean age 70 years) with atrial fibrillation who are at high risk of stroke, when anticoagulation is managed through usual care versus anticoagulation management services, where dedicated anticoagulation professionals (e.g. physician or pharmacist) monitor and oversee patients. METHODS: Semi-Markov decision model with a 30-day cycle length and 10-year time horizon (to reflect the mean life expectancy of the study population). Univariate sensitivity analyses and Bayesian second-order multivariate probabilistic sensitivity analysis using Monte Carlo simulation were performed. Outcomes measures were costs and QALYs. Most of the probability and outcome estimates included were derived from the recent SPORTIF (Stroke Prevention using ORal Thrombin Inhibitor in atrial Fibrillation) V trial. Utility values were derived from a large, nationally representative sample of individuals in the Medical Expenditure Panel Survey and were adjusted for age, sex, race, ethnicity, income, education and co-morbidity. Resource utilisation was based on experience at the University Medicine Group Practice Anticoagulation Clinic (University of Colorado, Denver, CO, USA) and costs ($US; 2004 values) included were for warfarin and aspirin (acetylsalicylic acid) use and those associated with major bleeding, treatment of primary events, routine INR and biochemistry monitoring, ECGs, and clinic visits. Costs and outcomes were discounted by 3% per annum. RESULTS: The anticoagulation management service improved effectiveness by 0.057 (95% credible interval 0, 0.36) QALYs and reduced costs by $US2100 (95% credible interval -$US19,800, $US300) [2004 values] compared with usual care. Results were sensitive to the extent of the increase in risk of primary events (all strokes and systemic embolic events attributable to usual care, but were robust to variation in other input variables). The anticoagulation management service was the dominant strategy in 91% of Monte Carlo simulations. CONCLUSION: The anticoagulation management service appears to cost less and provide greater effectiveness than usual care. To enhance stroke prophylaxis among high-risk patients with atrial fibrillation, physicians and Medicare plans may wish to consider augmenting 'usual care' by the addition of patient-monitoring technology strategies such as formally organised anticoagulation monitoring programmes.     

Secondary prevention of stroke in patients with nonvalvular atrial fibrillation: optimal intensity of anticoagulation

Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (> or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (> 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women > 75 years old, prior stroke, systolic blood pressure > 160mm Hg, recent heart failure, and fractional shortening < 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established.     

Guidelines for stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is most commonly associated with nonvalvular cardiovascular disease and is especially frequent among the elderly. The annual risk for stroke in patients with AF is approximately 5% with a wide range depending on the presence of additional risk factors. For patients who cannot successfully be converted and maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective method for preventing stroke. The 2 drugs which are indicated for stroke prophylaxis in patients with AF are warfarin and aspirin. For primary prevention, warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less effective, resulting in a 20 to 30% risk reduction. Combination therapy with aspirin and low intensity warfarin adjusted to an International Normalised Ratio (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history of stroke or transient ischaemic attack (TIA), the absolute risk reduction with warfarin is even greater because of the high risk of stroke in this population. In contrast, aspirin has not been shown to significantly reduce the risk of stroke in patients with AF when used for secondary prevention. When appropriately managed, warfarin is associated with a low risk of major bleeding. In controlled trials of highly selected patients, the annual rate of intracranial haemorrhage (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty anticoagulation clinics can achieve similar low rates of major bleeding. However, these results cannot be extrapolated to the general population. Factors which have been identified as predictors of bleeding include advanced age, number of medications and most importantly, the intensity of anticoagulation. INR values above 4.0 have been associated with an increased risk of major bleeding while values below 2.0 have been associated with thrombosis. Slow careful dosage titration, regular laboratory monitoring and patient education can substantially reduce the risk of complications. In patients with AF, antithrombotic therapy has been shown to be cost effective. For high risk patients, warfarin is the most cost-effective therapy, provided the risks for bleeding are minimised. In contrast, aspirin is the most cost-effective agent for low risk patients. Current practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5: range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75 years of age or younger patients with additional risk factors. Aspirin should be reserved for low risk patients or those unable to take warfarin. Although these recommendations are strongly supported by the clinical trial evidence, studies show that many patients are not receiving appropriate antithrombotic therapy. In particular, warfarin is underutilised in high risk elderly patients. Additional studies are needed to identify barriers that prevent implementation of the clinical trial findings into clinical practice.     

Adequacy of anticoagulation in patients with atrial fibrillation coming to a hospital

STUDY OBJECTIVE: To evaluate the adequacy of anticoagulation in patients with atrial fibrillation (AF) coming to a hospital. DESIGN: Retrospective medical record review. SETTING: Tertiary care hospital. PATIENTS: Consecutive patients with a history of AF who had been prescribed warfarin and who had the international normalized ratio (INR) measured when they arrived at the hospital. Those who developed AF as a complication during hospitalization were excluded. MEASUREMENTS AND MAIN RESULTS: Of 1085 patients, 375 (mean age 73 yrs, 56.3% men) were eligible for further evaluation. Most had nonvalvular AF; in 44.5% the INR was subtherapeutic, in 36.5% it was therapeutic, and in 18.9% it was supratherapeutic. Patients admitted for any thromboembolic event and for ischemic stroke were significantly more likely to have subtherapeutic INRs. CONCLUSION: It is well documented in the literature that warfarin is underprescribed, but our results suggest that even in treated patients, about half are inadequately protected from thromboembolism.