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1.  Should We Test for CYP2C9 Before Initiating Anticoagulant Therapy in Patients with Atrial Fibrillation? 
Genetic variants of the warfarin sensitivity gene CYP2C9 have been associated with increased bleeding risk during warfarin initiation. Studies also suggest that such patients remain at risk throughout treatment.
Would testing patients with non-valvular atrial fibrillation (AF) for CYP2C9 before initiating warfarin improve outcomes?
Markov state transition decision model.
Ambulatory or inpatient settings necessitating new initiation of anticoagulation.
The base case was a 69-year-old man with newly diagnosed non-valvular AF. Interventions included: (1) warfarin, (2) aspirin, or (3) no antithrombotic therapy without genetic testing; and genetic testing followed by (4) aspirin or (5) no antithrombotic therapy in those with culprit CYP2C9 alleles.
Quality-adjusted life years (QALYs).
In the base case, testing and treating patients with CYP2C9*2 and/or CYP2C9*3 with aspirin rather than warfarin was best (8.97 QALYs). However, warfarin without genetic testing was a close second (8.96 QALYs), a difference of roughly 5 days. Sensitivity analyses demonstrated that genetic testing followed by aspirin was best for patients at lower risk of embolic events. Warfarin without testing was preferred if the rate of embolic events was greater than 5% per year, or the risk of major bleeding while receiving warfarin was lower.
For patients at average risk for ischemic stroke due to AF and at average risk for major hemorrhage, treatment based on genetic testing offers no benefit compared to warfarin initiation without testing. The gain from testing may be larger in patients at lower risk of embolic events or at greater risk of bleeding.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-009-0927-7) contains supplementary material, which is available to authorized users.
PMCID: PMC2669861  PMID: 19255811
anticoagulant therapy; warfarin; genetic testing; pharmacogenetics; decision analysis; atrial fibrillation; stroke
2.  Use of warfarin in long-term care: a systematic review 
BMC Geriatrics  2012;12:14.
The use of warfarin in older patients requires special consideration because of concerns with comorbidities, interacting medications, and the risk of bleeding. Several studies have suggested that warfarin may be underused or inconsistently prescribed in long-term care (LTC); no published systematic review has evaluated warfarin use for stroke prevention in this setting. This review was conducted to summarize the body of published original research regarding the use of warfarin in the LTC population.
A systematic literature search of the PubMed, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library was conducted from January 1985 to August 2010 to identify studies that reported warfarin use in LTC. Studies were grouped by (1) rates of warfarin use and prescribing patterns, (2) association of resident and institutional characteristics with warfarin prescribing, (3) prescriber attitudes and concerns about warfarin use, (4) warfarin management and monitoring, and (5) warfarin-related adverse events. Summaries of study findings and quality assessments of each study were developed.
Twenty-two studies met the inclusion criteria for this review. Atrial fibrillation (AF) was the most common indication for warfarin use in LTC and use of warfarin for stroke survivors was common. Rates of warfarin use in AF were low in 5 studies, ranging from 17% to 57%. These usage rates were low even among residents with high stroke risk and low bleeding risk. Scored bleeding risk had no apparent association with warfarin use in AF. In physician surveys, factors associated with not prescribing warfarin included risk of falls, dementia, short life expectancy, and history of bleeding. International normalized ratio was in the target range approximately half of the time. The combined overall rate of warfarin-related adverse events and potential events was 25.5 per 100 resident months on warfarin therapy.
Among residents with AF, use of warfarin and maintenance of INR levels to prevent stroke appear to be suboptimal. Among prescribers, perceived challenges associated with warfarin therapy often outweigh its benefits. Further research is needed to explicitly consider the appropriate balancing of risks and benefits in this frail patient population.
PMCID: PMC3364846  PMID: 22480376
3.  The risk of hemorrhagic complications in hospital in-patients who fall while receiving antithrombotic therapy 
Thrombosis Journal  2005;3:1.
The use of antithrombotic agents and falls are independently associated with an increased risk of hemorrhagic injury. However, few studies have delineated the risk of fall-related hemorrhagic complications in persons who are taking antithrombotic therapy. The objective of this study was to compare the rates of fall-related hemorrhagic injury in hospital in-patients who are taking and not taking antithrombotic therapy.
A 4-year retrospective chart review of consecutive patients who fell during admission to a 500-bed tertiary-care teaching hospital was conducted. Major hemorrhagic injuries including subdural hematomas and major bleeding/cuts, patients' use of antithrombotic medication (warfarin, aspirin, clopidogrel and heparin) and their anticoagulation status at the time of their fall were recorded.
A total of 2635 falls in 1861 patients were reviewed. Approximately 10% of falls caused major hemorrhagic injury. One fall resulted in a subdural hematoma. Persons taking warfarin were less likely to suffer a fall-related major hemorrhagic injury compared with persons not taking antithrombotic therapy (warfarin, 6%; no therapy, 11%; p = 0.01). Logistic regression showed that fall-related major hemorrhagic injury was associated with female gender (odds ratio 1.6; 95% CI 1.3, 2.1), use of aspirin (odds ratio 1.4; 95% CI 1.1, 1.8) and use of clopidogrel (odds ratio 2.2; 95% CI 1.1, 4.8), but not with the use of warfarin or heparin, or the intensity of anticoagulation.
In this study, compared with persons taking no antithrombotic therapy, those taking warfarin had lower rates of fall-related hemorrhagic injuries. The absolute rate of the development of fall-related intracranial hemorrhagic injury such as subdural hematomas was low, even in persons taking warfarin. These counter-intuitive results may be due to selection bias, and suggest that physicians are very conservative in selecting patients for warfarin therapy, choosing only those who are sufficiently healthy to be at much lower than average risk of suffering fall-related hemorrhagic injuries. This phenomenon may lead to physicians overestimating the potential for fall-related major hemorrhagic injury in persons taking antithrombotic therapy, with the possible denial of warfarin therapy to many of those who would benefit. This perception may contribute to the care gap between the number of patients who would theoretically derive overall benefit from warfarin therapy and those who are actually receiving it.
PMCID: PMC545051  PMID: 15638939
4.  Canadian atrial fibrillation anticoagulation study: were the patients subsequently treated with warfarin? Canadian Atrial Fibrillation Anticoagulation Study Group. 
OBJECTIVE: To determine the effect of the results of clinical trials on the behaviour of patients and physicians, the authors ascertained the proportion of patients participating in the Canadian Atrial Fibrillation Anticoagulation (CAFA) study who started or continued warfarin therapy at the end of the study and identified factors affecting the decision to use or not use warfarin. The CAFA study was a double-blind, randomized, placebo-controlled, multicentre study to evaluate the efficacy of warfarin in preventing stroke among patients with nonrheumatic atrial fibrillation. Recruitment and follow-up were stopped early because two other similar studies had shown a decrease in the rate of stroke among patients treated with warfarin. DESIGN: Mail survey 21 months after the end of the study. PARTICIPANTS: The personal physicians of 336 patients who had participated in the CAFA study. OUTCOME MEASURES: Type of antithrombotic therapy the patients had received since the CAFA study ended for patients who were not receiving warfarin, the reasons they were not. RESULTS: Questionnaires concerning 254 (76%) of the patients who had participated in the study were returned. Since the end of the CAFA study, 153 (60%) of these patients had been treated continually with warfarin, 14 (6%) had been treated with warfarin but had subsequently stopped taking it, 59 (23%) had taken acetylsalicylic acid (ASA) continually, 5 (2%) had been taking ASA but had subsequently stopped taking it, and 23 (9%) had not taken either drug. The responding physicians stated that 58 (67%) of the patients who were not treated with warfarin did not wish to take the drug. The patients who had received warfarin during the CAFA trial were more likely to be treated with warfarin after the trial (75%) than were those who had received a placebo (56%) (p = 0.001). The probability of the patients' being treated with warfarin also depended on which study centre they had been treated in (p = 0.001). CONCLUSIONS: Of the patients in the CAFA study for whom questionnaires were received, only 167 (66%) had been treated with warfarin after the end of the study. The patients were more likely to have been treated with warfarin after the study if they had received warfarin during the study. The positive results of clinical trials, on their own, are not enough to fully change the behaviour of patients and physicians.
PMCID: PMC1487895  PMID: 8646654
5.  The safety and adequacy of antithrombotic therapy for atrial fibrillation: a regional cohort study 
Atrial fibrillation is a common problem in older people. The evidence base for the safety of warfarin and aspirin in atrial fibrillation is largely derived from selective research studies and secondary care. Further assessment of the safety of warfarin in older people with atrial fibrillation in routine primary care is needed.
To measure the complication rates and adequacy of warfarin control in a cohort of patients with atrial fibrillation managed in primary care and compare them with published data from controlled trials and community patients with atrial fibrillation not receiving warfarin.
Design of study
Retrospective review of regional cohort.
Twenty-seven general practices in southwest Scotland.
Case note review of 601 patients previously identified as having atrial fibrillation by GPs.
The average age of our cohort was 77 years at recruitment. Two hundred and sixty-four (44%) patients died within 5 years of follow up. Three hundred and nine of the 601 (51%) patients with atrial fibrillation took warfarin at some stage during this study. INR (international normalised ratio) was maintained between 2 and 3 for 68% of the time. Bleeding risk was higher in patients taking warfarin than in those on aspirin or no antithrombotic therapy (warfarin 9.0% per year versus aspirin 4.7% per year versus no therapy 4.6% per year). The annual risk of any bleeding complication on warfarin (9%) was similar to that recorded in randomised trials (9.2%) whereas the annual risk of severe bleeding was approximately double (2.6 versus 1.3%).
Adequacy of anticoagulant control was broadly comparable to that reported in clinical trials, whereas the risk of severe bleeding was higher, possibly reflecting the older age and the comorbidities of our unselected cohort.
PMCID: PMC1876637  PMID: 16954003
anticoagulation; antithrombotic therapy; atrial fibrillation; cohort study
6.  Antithrombotic or Anti-Platelet Agents in Patients Undergoing Permanent Pacemaker Implantation 
Korean Circulation Journal  2012;42(8):538-542.
Background and Objectives
The growing implantations of electrophysiological devices in the context of increasing rates of chronic antithrombotic therapy in cardiovascular disease patients underscore the importance of an effective periprocedural prophylactic strategy for prevention of bleeding complications. We assessed the risk of significant bleeding complications in patients receiving anti-platelet agents or anticoagulants at the time of permanent pacemaker (PPM) implantation.
Subjects and Methods
We reviewed bleeding complications in patients undergoing PPM implantation. The use of aspirin or clopidogrel was defined as having taking drugs within 5 days of the procedure and warfarin was changed to heparin before the procedure. A significant bleeding complication was defined as a bleeding incident requiring pocket exploration or blood transfusion.
Permanent pacemaker implantations were performed in 164 men and 96 women. The mean patient age was 73±11 years old. Among the 260 patients, 14 patients took warfarin (in all of them, warfarin was changed to heparin at least 3 days before procedure), 54 patients took aspirin, 4 patients took clopidogrel, and 25 patients took both. Significant bleeding complications occurred in 8 patients (3.1%), all of them were patients with heparin bridging (p<0.0001). Heparin bridging markedly increased the length of required hospital stay when compare with other groups and the 4 patients (1.5%) that underwent the pocket revision for treatment of hematoma.
This study suggests that hematoma formation after PPM implantation was rare, even among those who had taken the anti-platelet agents. The significant bleeding complications frequently occurred in patients with heparin bridging therapy. Therefore, heparin bridging therapy was deemed as high risk for significant bleeding complication in PPM implantation.
PMCID: PMC3438263  PMID: 22977449
Aspirin; Clopidogrel; Warfarin; Hematoma
7.  The management of non-valvular atrial fibrillation (NVAF) in Australian general practice: bridging the evidence-practice gap. A national, representative postal survey 
BMC Family Practice  2008;9:62.
General practitioners (GPs) are ideally placed to bridge the widely noted evidence-practice gap between current management of NVAF and the need to increase anticoagulant use to reduce the risk of fatal and disabling stroke in NVAF. We aimed to identify gaps in current care, and asked GPs to identify potentially useful strategies to overcome barriers to best practice.
We obtained contact details for a random sample of 1000 GPs from a national commercial data-base. Randomly selected GPs were mailed a questionnaire after an advance letter. Standardised reminders were administered to enhance response rates. As part of a larger survey assessing GP management of NVAF, we included questions to explore GPs' risk assessment, estimates of stroke risk and GPs' perceptions of the risks and benefits of anticoagulation with warfarin. In addition, we explored GPs' perceived barriers to the wider uptake of anticoagulation, quality control of anticoagulation and their assessment of strategies to assist in managing NVAF.
596 out of 924 eligible GPs responded (64.4% response rate). The majority of GPs recognised that the benefits of warfarin outweighed the risks for three case scenarios in which warfarin is recommended according to Australian guidelines. In response to a hypothetical case scenario describing a patient with a supratherapeutic INR level of 5, 41.4% of the 596 GPs (n = 247) and 22.0% (n = 131) would be "highly likely" or "likely", respectively, to cease warfarin therapy and resume at a lower dose when INR levels are within therapeutic range. Only 27.9% (n = 166/596) would reassess the patient's INR levels within one day of recording the supratherapeutic INR. Patient contraindications to warfarin was reported to "usually" or "always" apply to the patients of 40.6% (n = 242/596) of GPs when considering whether or not to prescribe warfarin. Patient refusal to take warfarin "usually" or "always" applied to the patients of 22.3% (n = 133/596) of GPs. When asked to indicate the usefulness of strategies to assist in managing NVAF, the majority of GPs (89.1%, n = 531/596) reported that they would find patient educational resources outlining the benefits and risks of available treatments "quite useful" or "very useful". Just under two-thirds (65.2%; n = 389/596) reported that they would find point of care INR testing "quite" or "very" useful. An outreach specialist service and training to enable GPs to practice stroke medicine as a special interest were also considered to be "quite" or "very useful" by 61.9% (n = 369/596) GPs.
This survey identified gaps, based on GP self-report, in the current care of NVAF. GPs themselves have provided guidance on the selection of implementation strategies to bridge these gaps. These results may inform future initiatives designed to reduce the risk of fatal and disabling stroke in NVAF.
PMCID: PMC2611987  PMID: 19014560
8.  A net clinical benefit analysis of warfarin and aspirin on stroke in patients with atrial fibrillation: a nested case–control study 
As the management of patients treated with anticoagulants and antiplatelet drugs entails balancing coagulation levels, we evaluated the net clinical benefit of warfarin and aspirin on stroke in a large cohort of patients with atrial fibrillation (AF).
A population-based cohort study of all patients at least 18 years of age with a first-ever diagnosis of chronic AF during the period 1993–2008 was conducted within the United Kingdom General Practice Research Database. A nested case–control analysis was conducted to estimate the risk of ischemic stroke and intracranial hemorrhage associated with the use of warfarin and aspirin. Cases were matched up to 10 controls on age, sex, and date of cohort entry. The adjusted net clinical benefit of warfarin and aspirin (expressed as the number of strokes prevented per 100 persons per year) was calculated by subtracting the ischemic stroke rate (prevented by therapy) from the intracranial hemorrhage (ICH) rate (increased by therapy).
The cohort included 70,766 patients newly-diagnosed with chronic AF, of whom 5519 experienced an ischemic stroke and 689 an ICH during follow-up. The adjusted net clinical benefit of warfarin was 0.59 (95% CI: 0.45, 0.73). However, the benefit was not seen for patients below (0.08, 95%: -0.38, 0.54) and above (−0.49, 95% CI: -1.13, 0.15) therapeutic range. The net clinical benefit of warfarin, apparent after 3 months of continuous use, increased as a function of CHADS2 score. The net clinical benefit was not significant with aspirin (−0.07, 95% CI: -0.22, 0.08), though it was seen in certain subgroups.
Warfarin provides a net clinical benefit in patients with atrial fibrillation, which is maintained with longer duration of use, particularly when used within therapeutic range. A similar net effect is not as clear with aspirin.
PMCID: PMC3444325  PMID: 22734842
Atrial fibrillation; stroke; intracranial hemorrhage; warfarin; aspirin; net clinical benefit
9.  Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism 
Warfarin therapy reduces morbidity and mortality related to thromboembolism. Yet adherence to long-term warfarin therapy remains challenging due to the risks of anticoagulant-associated complications and the burden of monitoring. The aim of this paper is to review determinants of adherence and persistence on long-term anticoagulant therapy for atrial fibrillation and venous thromboembolism. We evaluate what the current literature reveals about the impact of warfarin on quality of life, examine warfarin trial data for patterns of adherence, and summarize known risk factors for warfarin discontinuation. Studies suggest only modest adverse effects of warfarin on quality of life, but highlight the variability of individual lifestyle experiences of patients on warfarin. Interestingly, clinical trials comparing anticoagulant adherence to alternatives (such as aspirin) show that discontinuation rates on warfarin are not consistently higher than in control arms. Observational studies link a number of risk factors to warfarin non-adherence including younger age, male sex, lower stroke risk, poor cognitive function, poverty, and higher educational attainment. In addition to differentiating the relative impact of warfarin-associated complications (such as bleeding) versus the lifestyle burdens of warfarin monitoring on adherence, future investigation should focus on optimizing patient education and enhancing models of physician–patient shared-decision making around anticoagulation.
PMCID: PMC2846139  PMID: 20361065
anticoagulation; warfarin; adherence; persistence; thromboembolism
10.  Evidence-based study on antithrombotic therapy in patients at risk of a stroke with paroxysmal atrial fibrillation 
The aim of the present study was to determine the optimal intensity of anticoagulation therapy in elderly patients with paroxysmal atrial fibrillation (PAF), using aspirin and varied concentrations of warfarin. Elderly patients with PAF (n=1,162) who met the inclusion criteria of the study and were at middle or high-risk of a stroke were investigated. Patients were divided into six groups (four high-risk groups and two middle-risk groups). Patients were treated with aspirin or varied concentrations of warfarin. The primary endpoint events, secondary endpoint events, major bleeding events and minor bleeding events were observed and compared. In high-risk elderly patients, warfarin significantly reduced primary and secondary endpoint events, total primary events and total events compared with aspirin. In middle-risk elderly patients, for all the events warfarin demonstrated no significant difference compared with aspirin. In high-risk patients with PAF, when the concentration of warfarin was adjusted to target international normalized ratio (INR) range 1.7–2.5, the primary and secondary endpoint events, total primary events and total events were significantly lower (P<0.05), compared with aspirin and warfarin at INR 1.2–1.6. When the intensity of warfarin was adjusted to the target INR 2.6–3.0, the primary and secondary endpoint events were significantly lower (P<0.05) compared with aspirin and warfarin INR at 1.2–1.6. This study determined that in high-risk elderly patients with PAF, warfarin is recommended for anticoagulation with an optimal INR range of 1.7–2.5. In patients at a middle-risk of a stroke, aspirin is the recommended treatment as an antithrombotic as results have indicated that there is limited benefit in the use of warfarin.
PMCID: PMC3787006  PMID: 24137200
paroxysmal atrial fibrillation; aspirin; warfarin; middle risk; high risk
11.  Comparative evaluation of warfarin utilisation in two primary healthcare clinics in the Cape Town area 
Although warfarin remains the anticoagulant drug of choice in a wide range of patients, its narrow therapeutic window makes patients susceptible to a high risk of bleeding complications or failure to prevent clotting. This has necessitated therapeutic monitoring in warfarinised patients. Factors that could be responsible for the fluctuating responses to warfarin vary from pharmacogenetic to concomitant morbidity, diet and medication. In order to assess the quality of management of warfarin treatment in a local primary-care setting, the current study evaluated warfarin utilisation and monitoring records in two hospitals with different patient groups.
A retrospective study was undertaken in the specialised warfarin clinics at Wesfleur and Gugulethu hospitals (Western Cape, South Africa) covering all warfarin-related therapy records over a 12-month period. Data extracted from the patients’ folders included age, gender, race, weight, address, concurrent chronic illnesses, treatment and medication, indication for warfarin and INR history.
A total of 119 patients’ folders were analysed. Attendance at the clinics reflects the demographics and racial distribution of the host location of the hospitals. While all the patients were maintained above the minimum international normalised ratio (INR) value of 2, about 50% had at least one record of INR above the cut-off value of 3.5. However, over a third of the patients (32.2%) had at least one record of INR greater than 3.5 in Gugulethu Hospital, compared to over half (58.3%) in Wesfleur Hospital.
In total, atrial fibrillation was the most common indication for warfarinisation while hypertension was the most common concurrent chronic condition in warfarinised patients. All patients who received quinolone antibiotics had INR values above the cut-off point of 3.5 within the same month of the initiation of antibiotic therapy, suggesting drug-induced warfarin potentiation. Other co-medications, including beta-lactam antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anti-ulcer drugs appeare to alter warfarin responses as measured by recorded INR values.
The study found inter-individual variability in the response to warfarin therapy, which cut across racial classifications. It also confirms the possible influence of concomitant morbidity on patient response to anticoagulant therapy.
PMCID: PMC3736381  PMID: 23750346
warfarin; drug monitoring; international normalised ratio; anticoagulant; warfarinisation
12.  A Review of the Role of Anticoagulation in the Treatment of Peripheral Arterial Disease 
Peripheral arterial disease (PAD) is a major medical/surgical problem associated with high risk for coronary heart disease (CHD). Anticoagulation plays a significant role in the management of the PAD patient. However, evidence-based medicine supports only select anticoagulants, mainly antiplatelet agents. The available anticoagulant classes, their individual medications, and the mechanisms of action are described. Dextran 40, platelet glycoprotein (GP) IIb/IIIa receptor antagonists, direct thrombin (factor IIa, FIIa) inhibitors, and factor Xa (FXa) inhibitors do not, at this juncture, appear to have a significant role to play in the PAD patient. Aspirin has been used in PAD patients for a few decades, as has warfarin, but the role of warfarin is very limited. An attempt has been made to place each medication and its function in context all the way to the present with oral direct thrombin (FIIa) and FXa inhibitors described. These inhibitors may ultimately play an, as yet, undefined role in PAD. Specific use of anticoagulants in PAD patients is described and aspirin still stands out as a fundamental therapy. The thienopyridines, especially clopidogrel, have their established place and there is some evidence for benefit from the use of clopidogrel in dual therapy with aspirin. Dipyridamole, especially with aspirin as dual therapy, and cilostazol also have their evidence-based niches. The main role played by warfarin is for the patient with a vein graft in the arterial circulation. Heparin retains significant procedural importance. For now, Class I, Level of Evidence A center around aspirin for the PAD patient with clopidogrel, an alternative agent.
PMCID: PMC3578611  PMID: 24293975
anticoagulation; aspirin; cardiovascular disease; coronary artery; peripheral arterial disease; risk factors; thienopyridines
13.  Recovery Time of Platelet Function After Aspirin Withdrawal 
Inappropriate antiplatelet therapy discontinuation increases the risk of thrombotic complications and bleeding after dental procedures. To determine the platelet reactivity recovery time after aspirin withdrawal in vivo, our study was conducted in patients with low-risk cardiovascular disease who can stop aspirin administration following the guidelines stipulated by the American College of Chest Physicians. The time it takes for platelet activity to normalize and the diagnostic accuracy of testing methods were assessed for a residual antiplatelet activity with multiple electrode aggregometry. Our study included patients with clinically indicated hypertension preparing for a dental extraction procedure.
Materials and methods
A total of 212 patients not taking aspirin (control group) and 248 patients with hypertension receiving long-time aspirin treatment at a 100-mg daily dose were prospectively included in the study, which involved stopping aspirin intake before dental extraction. The residual platelet activity and dental bleeding in patients who stopped aspirin intake were analyzed and compared with those of the control group. In addition, platelet reactivity recovery time and bleeding risk in patients who stopped taking aspirin every 24 hours for 0 to 5 days (0–143 hours) before dental extraction was also assessed.
Platelet reactivity normalized 96 hours after aspirin withdrawal. The cut-off value of 49 arbitrary units in the arachidonic acid platelet aggregation test excluded the effect of aspirin with 91% sensitivity and 66% specificity. AUC showed 0.86 (P < 0.001) diagnostic accuracy. The immediate bleeding complications in all treatment groups were similar to those seen in the control group and were successfully managed with local hemostatic measures.
The antiplatelet effects of aspirin disappeared 96 hours after aspirin withdrawal in our study, and dental extractions may be safely performed in this period when appropriate local hemostatic measures are taken. Based on these results, a shorter aspirin intake cessation period may be allowable in complex dental procedures and surgery for which a longer aspirin intake cessation period (7–10 days) is recommended based on the American College of Chest Physicians guidelines.
PMCID: PMC4008770  PMID: 25031665
antiplatelet reactivity; dental extraction; diagnostic accuracy; multiple electrode aggregometry
14.  'Aspirin resistance' or treatment non-compliance: Which is to blame for cardiovascular complications? 
Aspirin is one of the 'cornerstone' drugs in our current management of cardiovascular disorders. However, despite the prescription of aspirin recurrent vascular events still occur in 10–20% of patients. These, data together with the observations of diminished antiaggregatory response to aspirin in some subjects have provided the basis of the current debate on the existence of so-called "aspirin resistance". Unfortunately, many of the tests employed to define 'aspirin resistance' lack sufficient sensitivity, specificity, and reproducibility. The prevalence of 'aspirin resistance' as defined by each test varies widely, and furthermore, the value of a single point estimate measure of aspirin resistance is questionable. The rate of 'aspirin resistance' is law if patients observed to ingest aspirin, with large proportion of patients to be pseudo-'aspirin resistant', due to non-compliance. What are the implications for clinical practice? Possible non-adherence to aspirin prescription should also be carefully considered before changing to higher aspirin doses, other antiplatelet drugs (e.g. clopidogrel) or even combination antiplatelet drug therapy. Given the multifactorial nature of atherothrombotic disease, it is not surprising that only about 25% of all cardiovascular complications can usually be prevented by any single medication. We would advocate against routine testing of platelet sensitivity to aspirin (as an attempt to look for 'aspirin resistance') but rather, to highlight the importance of clinicians and public attention to the problem of treatment non-compliance.
PMCID: PMC2535592  PMID: 18759979
15.  Should Aspirin be Continued in Patients Started on Warfarin? 
Clinicians frequently face the decision of whether to continue aspirin when starting patients on warfarin. We performed a meta-analysis to characterize the tradeoffs involved in this common clinical dilemma.
Multiple computerized databases (1966 to 2003), reference lists of relevant articles, conference proceedings, and queries of primary authors.
Randomized trials comparing warfarin plus aspirin versus warfarin alone. Studies with target international normalized ratios (INRs) <2 were excluded.
Two reviewers independently extracted baseline data and major outcomes: rates of thromboembolism, hemorrhage, and all-cause mortality.
Nine studies met the inclusion criteria. Of the five that enrolled patients with mechanical heart valves, four used the same target INR in both groups, while one used a reduced target INR for the warfarin plus aspirin group. Pooling the results of the first four studies demonstrated that combination of warfarin plus aspirin significantly decreased thromboembolic events (relative risk [RR], 0.33; 95% confidence interval [CI], 0.19 to 0.58), increased major bleeding (RR, 1.58; 95% CI, 1.02 to 2.44), and decreased all-cause mortality (RR, 0.43; 95% CI, 0.23 to 0.81) compared to warfarin alone. The one valve trial using a reduced INR in the warfarin plus aspirin group reported no difference in thromboembolic outcomes but found decreased major bleeding and a significant mortality benefit with combination therapy. Of the remaining trials, three evaluated a warfarin indication not routinely used in the United States (post-myocardial infarction), and the only trial that considered atrial fibrillation was terminated early due to inadequate enrollment.
For mechanical heart valve patients, the benefits of continuing aspirin when starting warfarin therapy are clear. For other routine warfarin indications, there are not adequate data to guide this common clinical decision.
PMCID: PMC1492499  PMID: 15242475
aspirin; warfarin; thromboembolism; hemorrhage; mortality
16.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: Unique identifier: NCT00041938.
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin
17.  Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. 
A prospective study was carried out to see whether a small fixed dose of warfarin (1 mg daily) given before operation (mean 20 days) would prevent deep vein thrombosis in patients having major gynaecological surgery. One hundred and four patients were randomised into three groups: fixed minidose warfarin; full dose oral anticoagulation; and no treatment (controls). There was a significantly lower incidence of deep vein thrombosis in the minidose warfarin and full dose anticoagulant treatment groups (9% (3/32) and 3% (1/35) respectively) than in the controls (30%; 11/37) but no significant difference between the two anticoagulant treatment groups. Prothrombin time and the activated partial thromboplastin time were normal on the day of surgery in the warfarin treatment group, whereas times were prolonged in the group given full dose anticoagulation. Mean haemoglobin concentrations fell in all three groups after operation but the fall was significantly less in the minidose warfarin treatment group than after full dose anticoagulation. The benefit from full dose oral anticoagulant prophylaxis, based on a preoperative international normalised ratio of 1.5-2.5 with rabbit brain Manchester reagent, was similar to the protection achieved in an oral anticoagulant treatment group controlled with human brain Manchester comparative reagent at a similar level of anticoagulation. The lack of disturbance of normal haemostasis at the time of operation together with a significant reduction in deep vein thrombosis may encourage surgeons to introduce minidose prophylaxis with warfarin.
PMCID: PMC1248380  PMID: 3120989
18.  A test of financial incentives to improve warfarin adherence 
Sub-optimal adherence to warfarin places millions of patients at risk for stroke and bleeding complications each year. Novel methods are needed to improve adherence for warfarin. We conducted two pilot studies to determine whether a lottery-based daily financial incentive is feasible and improves warfarin adherence and anticoagulation control.
Volunteers from the University of Pennsylvania Anticoagulation Management Center who had taken warfarin for at least 3 months participated in either a pilot study with a lottery with a daily expected value of $5 (N = 10) or a daily expected value of $3 (N = 10). All subjects received use of an Informedix Med-eMonitor™ System with a daily reminder feature. If subjects opened up their pill compartments appropriately, they were entered into a daily lottery with a 1 in 5 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 1) or a 1 in 10 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 2). The primary study outcome was proportion of incorrect warfarin doses. The secondary outcome was proportion of INR measurements not within therapeutic range. Within-subject pre-post comparisons were done of INR measurements with comparisons with either historic means or within-subject comparisons of incorrect warfarin doses.
In the first pilot, the percent of out-of-range INRs decreased from 35.0% to 12.2% during the intervention, before increasing to 42% post-intervention. The mean proportion of incorrect pills taken during the intervention was 2.3% incorrect pills, compared with a historic mean of 22% incorrect pill taking in this clinic population. Among the five subjects who also had MEMS cap adherence data from warfarin use in our prior study, mean incorrect pill taking decreased from 26% pre-pilot to 2.8% in the pilot. In the second pilot, the time out of INR range decreased from 65.0% to 40.4%, with the proportion of mean incorrect pill taking dropping to 1.6%.
A daily lottery-based financial incentive demonstrated the potential for significant improvements in missed doses of warfarin and time out of INR range. Further testing should be done of this approach to determine its effectiveness and potential application to both warfarin and other chronic medications.
PMCID: PMC2635367  PMID: 19102784
19.  Summary of evidence-based guideline: Periprocedural management of antithrombotic medications in patients with ischemic cerebrovascular disease 
Neurology  2013;80(22):2065-2069.
To assess evidence regarding periprocedural management of antithrombotic drugs in patients with ischemic cerebrovascular disease. The complete guideline on which this summary is based is available as an online data supplement to this article.
Systematic literature review with practice recommendations.
Results and recommendations:
Clinicians managing antithrombotic medications periprocedurally must weigh bleeding risks from drug continuation against thromboembolic risks from discontinuation. Stroke patients undergoing dental procedures should routinely continue aspirin (Level A). Stroke patients undergoing invasive ocular anesthesia, cataract surgery, dermatologic procedures, transrectal ultrasound–guided prostate biopsy, spinal/epidural procedures, and carpal tunnel surgery should probably continue aspirin (Level B). Some stroke patients undergoing vitreoretinal surgery, EMG, transbronchial lung biopsy, colonoscopic polypectomy, upper endoscopy and biopsy/sphincterotomy, and abdominal ultrasound–guided biopsies should possibly continue aspirin (Level C). Stroke patients requiring warfarin should routinely continue it when undergoing dental procedures (Level A) and probably continue it for dermatologic procedures (Level B). Some patients undergoing EMG, prostate procedures, inguinal herniorrhaphy, and endothermal ablation of the great saphenous vein should possibly continue warfarin (Level C). Whereas neurologists should counsel that warfarin probably does not increase clinically important bleeding with ocular anesthesia (Level B), other ophthalmologic studies lack the statistical precision to make recommendations (Level U). Neurologists should counsel that warfarin might increase bleeding with colonoscopic polypectomy (Level C). There is insufficient evidence to support or refute periprocedural heparin bridging therapy to reduce thromboembolic events in chronically anticoagulated patients (Level U). Neurologists should counsel that bridging therapy is probably associated with increased bleeding risks as compared with warfarin cessation (Level B). The risk difference as compared with continuing warfarin is unknown (Level U).
PMCID: PMC3716407  PMID: 23713086
20.  Is Warfarin Really Underused in Patients with Atrial Fibrillation? 
There is agreement that warfarin decreases stroke risk in patients with atrial fibrillation (AF), but prior studies suggest that warfarin is markedly underused, for unclear reasons.
To determine if warfarin is underused in the treatment of patients with atrial fibrillation.
Tertiary care VA hospital.
All patients with a hospital or outpatient diagnosis of AF between 10/1/95 and 5/31/98.
One or more physician investigators reviewed pertinent records for each patient. When any of the 3 investigators thought warfarin might be indicated, the patient's primary care provider completed a survey regarding why warfarin was not used.
Of 1,289 AF patients, 844 (65%) had filled at least 1 warfarin prescription. Of the 445 remaining, 19 had died, 5 had inadequate medical records, and 54 received warfarin elsewhere, leaving 367 patients. Of these, 160 had no documented AF, 53 had only a history of AF, and 49 had only transient AF. Of the remaining 105 patients, 17 refused warfarin therapy and 72 had documented contraindications to warfarin use including bleeding risk or history, fall risk, alcohol abuse, or other compliance problems. The reasons for not using warfarin among the 16 patients remaining included provider oversight (n = 4) and various reasons suggesting provider knowledge deficits.
In contrast to prior studies that suggested that warfarin is markedly underused, we found that few patients with AF and no contraindication to anticoagulation were not receiving warfarin. We believe that differing study methodologies, including the use of physician review and provider survey, may explain our markedly different rate of warfarin underutilization, although local institutional factors cannot be excluded. The findings suggest that primary providers may be far more compliant with the standard of care for patients with atrial fibrillation than previously believed.
PMCID: PMC1495287  PMID: 11722687
warfarin; atrial fibrillation; quality of care; physician practice
21.  Low-dose aspirin before spinal surgery: results of a survey among neurosurgeons in Germany 
European Spine Journal  2006;16(3):365-372.
The main problem faced by the increasing numbers of patients presenting for spinal surgery are receiving concurrent medication with low-dose aspirin, leading to dysfunctional circulating platelets. The contribution of low-dose aspirin to increased peri-operative risk of bleeding and blood loss is a contentious issue with conflicting published results from different surgical groups. Data from neurosurgical spine patients is sparse, but aspirin has been identified as an important risk factor in the development of post-operative hematoma following intracranial surgery. We surveyed the opinions and working practices of the neurosurgical facilities performing spinal operations in Germany regarding patients who present for elective spinal surgery. Identical questionnaires were sent to 210 neurosurgical facilities and proffered five main questions: (1) the adherence of any policy of stopping aspirin pre-operatively, (2) the personal risk assessment for patients with spinal surgery under low-dose aspirin medication, (3) the preferred method of treatment for excessive bleeding in this context, (4) personal knowledge of hemorrhagic complications in this group of patients, and (5) the characteristics of the neurosurgical units concerned. There were 145 (69.1%) responses of which 142 (67.6%) were valid. Of the respondents, 114 (80.3%) had a (written) departmental policy for the discontinuation of pre-operative aspirin treatment, 28 (19.7%) were unaware of such a policy. The mean time suggested for discontinuation of aspirin pre-operatively was 6.9 days (range: 0–21 days), with seven respondents who perform the operations despite the ongoing aspirin medication. Ninety-four respondents (66.2%) considered that patients taking low-dose aspirin were at increased risk for excessive peri-operative hemorrhage or were indetermined (8.6%), and 73 (51.4%) reported having personal experience of such problems. Ninety-two respondents (65.5%) would use special medical therapy, preferably Desmopressin alone or in combination with other blood products or prohemostatic agents (46.1%), if hemorrhagic complications developed intra- or post-operatively. The average number of spinal operations per year in each service was 607.9 (range: 40–1,500). Despite the existence of distinct departmental policies concerning the discontinuation of low-dose aspirin pre-operatively in the majority of neurosurgical facilities performing spinal operations, there is a wide range of the moment of this interruption with an average of 7 days. Two-thirds of the respondents felt that aspirin was a risk factor for hemorrhagic complications associated with spinal procedures, and more than half of the interviewees reported having personal experience of such problems. Finally, various medicamentous methods of counteracting aspirin-induced platelet dysfunction and excessive bleeding in this context are elicited, discussed and evaluated.
PMCID: PMC2200713  PMID: 16953446
Aspirin; Spine surgery; Hemorrhage; Survey; Desmopressin
22.  Nurses’ self-reported time estimation of anticoagulation therapy: a survey of warfarin management in long-term care 
BMC Nursing  2015;14:8.
A nursing shortage in the United States has resulted in increased workloads, potentially affecting the quality of care. This situation is particularly concerning in long-term care (LTC) facilities, where residents are older, frailer, and may be receiving multiple medications for comorbidities, thus requiring a greater commitment of nurse time. We conducted a survey of LTC nurses to determine how much of their time each week is spent managing newly started and stable warfarin-treated residents.
Forty LTC nurses validated the questionnaire to determine what protocols/procedures are involved in warfarin management. Twenty LTC nurses completed the survey, quantifying the time they spend on procedures related to warfarin management, and how often they performed each procedure for each resident each week.
The nurses reported that 26% of their residents were receiving warfarin; the majority (approximately 75%) of these residents began warfarin after admission to the facility. On average, the nurses spent 4.6 hours per week for treatment procedures and monitoring patients initiating warfarin therapy and 2.35 hours per week for each resident who was stable on warfarin therapy on admission. Overall, to care for an average number of newly initiated and stable warfarin patients in a medium-size LTC facility, staff nurses are estimated to spend 68 hours per week.
Study limitations include the potential for bias because of the small sample size, representativeness of the sample, and the possibility of inaccuracies in respondents’ self-reported time estimation of warfarin-related procedures.
In the context of a well-documented and expanding nursing shortage in the United States, the substantial use of time and resources necessary to initiate, monitor, and manage warfarin treatment in elderly LTC patients is of concern. Until the problem of understaffing is resolved, implementation of therapies that are simpler and require less nursing time—e.g. the use of new oral anticoagulants in the place of warfarin—may be a way to free up nursing time for other essential care tasks.
Electronic supplementary material
The online version of this article (doi:10.1186/s12912-015-0058-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4336714
Anticoagulants; Long-term care; Nursing shortage; Quality of care; Warfarin management; Monitoring
23.  Analysis of Antithrombotic Therapy After Cardioembolic Stroke Due to Atrial Fibrillation or Flutter 
Hospital Pharmacy  2013;48(2):127-133.
Guidelines recommend that all patients with atrial fibrillation and a history of ischemic stroke should receive an anticoagulant. Prior analyses show that warfarin is underutilized in most populations.
To examine the use of antithrombotic and anticoagulant therapy in patients with atrial fibrillation or flutter during the index hospitalization for acute, ischemic stroke.
Retrospective electronic medical record review of 200 patients treated at a tertiary care hospital with a primary ICD-9 code for ischemic stroke and a secondary ICD-9 code for atrial fibrillation or flutter. Exclusion criteria were active bleeding, pregnancy, age less than 18, pre-existing warfarin allergy, or dabigatran use.
Fifty-two percent of patients received at least one dose of warfarin during the index hospitalization. There was no relationship between CHADS2 score and likelihood of receiving warfarin (P > .05). There was no significant difference in adverse event rate in patients receiving warfarin compared to those receiving aspirin (3.8% vs 9.1%; P = .14), but the rate of hemorrhagic transformation was lower in patients receiving warfarin (1% vs 7%; P = .03). The composite of hemorrhagic stroke or hemorrhagic transformation was significantly lower in patients receiving bridging therapy (0% vs 11%; P = .03). Sixteen patients were readmitted for stroke within 3 months of discharge. Ten were readmitted for ischemic stroke, 3 for hemorrhagic stroke or hemorrhagic transformation, and 3 for systemic bleeding. Ten patients (62.5%) were receiving warfarin at readmission, but only one of these patients had a therapeutic INR.
Warfarin was underutilized as secondary stroke prophylaxis in these high-risk patients. Bridging therapy appeared to be safe and was not associated with an increase in adverse events.
PMCID: PMC3839477  PMID: 24421450
anticoagulant; atrial fibrillation; atrial flutter; stroke; warfarin
24.  Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial 
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
PMCID: PMC4256381  PMID: 23921215
Aspirin; Cardiac embolism; Heart failure; Stroke prevention
25.  Real-time ultrasound guidance reduces total and major vascular complications in patients undergoing pulmonary vein antral isolation on therapeutic warfarin 
Vascular complications are a known risk of catheter-based pulmonary vein antral isolation (PVAI). Procedure-related thromboembolic events necessitate full-dose anticoagulation, which worsens outcomes in the event of vascular access injury.
Real-time ultrasound allows direct visualization of vascular structures. We hypothesized that ultrasound use with venipuncture reduces vascular complications associated with PVAI.
Retrospective analysis of all adverse events occurring with PVAI was performed during two periods: 2005– 2006 when ultrasound was not used and 2008–2010 when ultrasound was routinely employed. All patients received full-dose IV heparin during PVAI. In the no ultrasound cohort, only 14 % underwent PVAI without stopping warfarin, while 91 % of patients in the ultrasound cohort were on continued warfarin. Only patients deemed at high risk for thromboembolism with a periprocedural international normalized ratio (INR) less than 2 were bridged with subcutaneous low-molecular-weight heparin.
Ultrasound reduced total vascular complications (1.7 vs. 0.5 %, p<0.01) and decreased the incidence of major vascular complications by sevenfold. Warfarin with INR≥1.2 on the day of PVAI was associated with more vascular complications (4.3 vs. 1.2 %, p<0.01). Ultrasound guidance overcame the risk associated with warfarin therapy. Vascular complications in anticoagulated patients with INR≥1.2 using ultrasound guidance were two- and ninefold lower than those in patients not using ultrasound with an INR<1.2 (0.5 vs. 1.2 %, p<0.05) and INR≥1.2 (0.5 vs. 4.3 %, p<0.01), respectively.
Ultrasound-guided venipuncture improves the safety profile of PVAI, reducing vascular complications in patients on warfarin to levels below those with no ultra-sound and off warfarin.
PMCID: PMC4081545  PMID: 23585239
Vascular complications; Ultrasound guidance; Pulmonary vein antral isolation; Periprocedural anticoagulation; Procedure-related thromboembolic events

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