Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic

doi:10.1016/j.clinthera.2004.09.002

Clinical Therapeutics

Volume 26, Issue 9, September 2004, Pages 1470-1478

https://doi.org/10.1016/j.clinthera.2004.09.002 Get rights and content

Abstract

Objective:

The goal of this study was to investigate the complications and control of warfarin treatment in patients with nonvalvular atrial fibrillation (NVAF) newly referred to an outpatient anticoagulation clinic.

Methods:

This study included new patients with NVAF who were referred to an anticoagulation clinic for warfarin therapy over a recruitment period of 21 months. To reflect real-world clinical practice, patient selection for anticoagulation and patient management were left to the referring physicians, who were blinded to their patients' participation in the study. Patients were interviewed in person at the first clinic visit and then by telephone every 4 to 6 weeks. They were questioned about any bleeding or thromboembolic events.

Results:

A total of 402 patients were included (100% of all new referrals over 21 months). The mean (SD) age was 72.3 (10.3) years, and 224 (56%) patients were men. The mean (SD) international normalized ratio (INR) was 2.4 (0.31). Patients were followed up for a mean (SD) of 19 (8.1) months (range, 1.0–31.0 months). They spent a mean (SD) 66% (18.3) of time in the target range of INR (ie, 2.0–3.0). Annual event rates were 1.7% (95% CI, 0.4%–3.0%) for major bleeding, 16.6% (95% CI, 13.0%–20.2%) for minor bleeding, 1.2% (95% CI, 0.1%–2.3%) for ischemic stroke, and 0.3% (95% CI, 0.2%–0.8%) for transient ischemic attacks. There were no cases of hemorrhagic stroke or fatal bleeding. Variability of INR and number of medications were identified as risk factors for bleeding (P = 0.03 and P = 0.001, respectively). There was no significant association between age and bleeding.

Conclusions:

Based on this analysis, the risks of long-term oral anticoagulation therapy in an outpatient anticoagulation clinic appear to reflect the results of clinical trials. Rates of ischemic stroke, major bleeding, and anticoagulation control were comparable. There was no age-related risk of complications.

References (24)

LandefeldC.S. et al.
Major bleeding in outpatients treated with warfarin: Incidence and prediction by factors known at the start of outpatient therapy
Am J Med
(1989)
Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized clinical trials
Arch Intern Med
(1994)
EzekowitzM.D. et al.
Preventing stroke in patients with atrial fibrillation
JAMA
(1999)
AntaniM.R. et al.
Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation
J Gen Intern Med
(1996)
WheeldonN.M. et al.
Screening for atrial fibrillation in primary care
Heart
(1998)
Stroke prevention in atrial fibrillation study Final results
Circulation
(1991)
RosendaalF.R. et al.
A method to determine the optimal intensity of oral anticoagulant therapy
Thromb Haemost
(1993)
LancasterT.R. et al.
The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial
Arch Intern Med
(1991)
FihnS.D. et al.
The risk for and severity of bleeding complications in elderly patients treated with warfarin
Ann Intern Med
(1996)
O'ReillyR.A. et al.
Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans
Clin Pharmacol Ther
(1987)

CohenN. et al.

Warfarin for stroke prevention still underused in atrial fibrillation: Patterns of omission

Stroke

(2000)

KalraL. et al.

Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness

BMJ

(2000)

Cited by (50)

Neurological complications of cardiovascular drugs
2021, Handbook of Clinical Neurology
Citation Excerpt :
Within the clinical practice setting of the Kaiser Permanente health care system, ICHs occurred in 0.46% of patients receiving warfarin for atrial fibrillation and 0.23% in patients who not receiving warfarin (Go et al., 2003). No hemorrhagic stroke occurred in a cohort of 408 patients on warfarin for atrial fibrillation followed over 19 months in an anticoagulation clinic (Abdelhafiz and Wheeldon, 2004). The risk of ICH is influenced by the intensity of anticoagulation and patient factors such as older age, arterial hypertension, and Asian race (Shen et al., 2007; Schulman et al., 2008).
Cardiovascular drugs are used to treat arterial hypertension, hyperlipidemia, arrhythmias, heart failure, and coronary artery disease. They also include antiplatelet and anticoagulant drugs that are essential for prevention of cardiogenic embolism. Most neurologic complications of the cardiovascular drugs are minor or transient and are far outweighed by the anticipated benefits of treatment. Other neurologic complications are more serious and require early recognition and management. Overtreatment of arterial hypertension may cause lightheadedness or fatigue but often responds readily to dose adjustment or an alternative drug. Other drug complications may be more troublesome as in myalgia associated with statins or headache associated with vasodilators. The recognized bleeding risk of the antithrombotics requires careful calculation of risk/benefit ratios for individual patients. Many neurologic complications of cardiovascular drugs are well documented in clinical trials with known frequency and severity, but others are rare and recognized only in isolated case reports or small case series. This chapter draws on both sources to report the adverse effects on muscle, nerve, and brain associated with commonly used cardiovascular drugs.
New strategies for effective treatment of vitamin K antagonist-associated bleeding
2015, Journal of Thrombosis and Haemostasis
Vitamin K antagonists have been used as oral anticoagulants in the treatment and prevention of thromboembolic events for over half a century. Although vitamin K antagonists are effective in the management of thromboembolic events, the need for routine monitoring and the associated risk of bleeding has resulted in the development and licensing of direct oral anticoagulants for specific clinical indications. Despite these developments, vitamin K antagonists remain the oral anticoagulants of choice in many clinical conditions. Severe bleeding associated with oral anticoagulation requires urgent reversal. Several options for the reversal of vitamin K antagonist exist, including vitamin K, prothrombin complex concentrates and plasma. In this manuscript, we review current evidence and provide physicians with treatment strategies for more effective management of vitamin K antagonist‐associated bleeding.
Physical activity and risk of bleeding in elderly patients taking anticoagulants
2015, Journal of Thrombosis and Haemostasis
Although the possibility of bleeding during anticoagulant treatment may limit patients from taking part in physical activity, the association between physical activity and anticoagulation‐related bleeding is uncertain.
To determine whether physical activity is associated with bleeding in elderly patients taking anticoagulants.
In a prospective multicenter cohort study of 988 patients aged ≥ 65 years receiving anticoagulants for venous thromboembolism, we assessed patients' self‐reported physical activity level. The primary outcome was the time to a first major bleeding, defined as fatal bleeding, symptomatic bleeding in a critical site, or bleeding causing a fall in hemoglobin or leading to transfusions. The secondary outcome was the time to a first clinically relevant non‐major bleeding. We examined the association between physical activity level and time to a first bleeding by using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time‐varying covariate.
During a mean follow‐up of 22 months, patients with a low, moderate, and high physical activity level had an incidence of major bleeding of 11.6, 6.3, and 3.1 events per 100 patient‐years and an incidence of clinically relevant non‐major bleeding of 14.0, 10.3, and 7.7 events per 100 patient‐years, respectively. A high physical activity level was significantly associated with a lower risk of major bleeding (adjusted sub‐hazard ratio 0.40, 95% confidence interval 0.22–0.72). There was no association between physical activity and non‐major bleeding.
A high level of physical activity is associated with a decreased risk of major bleeding in elderly patients receiving anticoagulant therapy.
Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: A single centre, double-blind, randomised, non-inferiority trial
2015, The Lancet Haematology
Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well.
The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2–3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239.
Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1–1·9). During days 1–720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25–1·13; p_{non-inferiority}<0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45–1·61; p_{non-inferiority}=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring.
Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR.
Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.
Bleeding risk in randomized controlled trials comparing warfarin and aspirin: A systematic review and meta-analysis
2012, Journal of Thrombosis and Haemostasis
Background:Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives:To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods:Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results:Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions:This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.
Evaluation of telephone assessment in stroke and TIA recurrence
2012, Neurologia
La recurrencia de ictus o AIT es un aspecto clave en la mayoría de los registros de ictus, pero la revisión presencial de todos los pacientes no siempre es viable. Con frecuencia, la revisión telefónica es utilizada para evaluar las recurrencias, la situación funcional y los tratamientos a largo plazo. El objetivo es evaluar la revisión telefónica en un registro de ictus.
Se registraron prospectivamente 380 pacientes con ictus o AIT valorando las características basales y tipo de evento. Posteriormente, fueron evaluados a los 6 meses tras el evento inicial. Doscientos cuarenta y ocho pacientes fueron revisados telefónicamente mediante una entrevista estructurada y 132 fueron revisados físicamente en consulta. Se compararon ambos grupos analizando las diferencias detectadas en las escalas funcionales, tratamientos y recurrencias (AIT o ictus).
No hubo diferencias en las características basales de ambos grupos, ni en el tipo de evento o gravedad al inicio. A los 6 meses, los tratamientos realizados fueron similares en ambos grupos, presentando un 10,5% (40 pacientes) recurrencia de ictus o AIT. No hubo diferencias significativas en la tasa de nuevos ictus isquémicos (6,1% revisión física vs 4,4% telefónica, p = 0,49), pero se detectó un mayor número de AIT en la revisión física frente a la telefónica (9,1% vs 4,0%, p = 0,04).
La revisión telefónica de los pacientes con ictus es viable y facilita la realización de registros de ictus, permitiendo una adecuada identificación de los tratamientos y recurrencias de ictus. Sin embargo, es probable que los nuevos eventos transitorios o AIT estén infraestimados.
Stroke recurrence is an important issue in stroke registries, but direct patient contact months after stroke is not always feasible. Telephone assessment is often used to evaluate long term stroke outcome, treatments and recurrences. Our aim is to evaluate telephone interview in a stroke registry.
Three hundred and eighty patients with a stroke or TIA were prospectively registered, evaluating baseline characteristics and type of event. At 6 months, 248 patients were reviewed by structured telephone interview and 132 were reviewed by direct contact. We analysed stroke outcome and disability, treatments and stroke or TIA recurrences.
There were no differences in baseline characteristics and type or severity of the index event. At 6 months, treatments were similar between both groups and 10.5% (40 patients) had a recurrent event. There were no differences in recurrent ischaemic strokes (6.1% in direct contact vs 4.4% telephone, P = .49), but we detected a higher number of TIA in direct examination compared to phone interview (9.1% vs 4.0%, P = .04).
Telephone assessment of stroke patients is reliable and facilitates stroke registries in detecting long-term treatments and stroke recurrences. However, it is probable that new transient events or TIA are under-estimated.

View all citing articles on Scopus

View full text

Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic

Abstract

Objective:

Methods:

Results:

Conclusions:

Am J Med

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized clinical trials

Arch Intern Med

Preventing stroke in patients with atrial fibrillation

JAMA

Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation

J Gen Intern Med

Screening for atrial fibrillation in primary care

Heart

Stroke prevention in atrial fibrillation study Final results

Circulation

A method to determine the optimal intensity of oral anticoagulant therapy

Thromb Haemost

The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial

Arch Intern Med

The risk for and severity of bleeding complications in elderly patients treated with warfarin

Ann Intern Med

Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans

Clin Pharmacol Ther

Warfarin for stroke prevention still underused in atrial fibrillation: Patterns of omission

Stroke

Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness

BMJ