Alan K. Jacobson

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data

BACKGROUND Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

Summary.  Background: Patients who receive long‐term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low‐molecular‐weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long‐term OAC therapy. Patients/methods: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long‐term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). Results: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice‐daily treatment doses, represented approximately 80% of the study population. LMWH‐bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH‐bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24‐h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non‐significant trends towards an increased risk of major bleed. Conclusions: Treatment‐dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.

Delivery of Optimized Anticoagulant Therapy: Consensus Statement from the Anticoagulation Forum

Objective: To provide recommendations, policies, and procedures pertaining to the provision of optimized anticoagulation therapy designed to achieve desired clinical endpoints while minimizing the risk of anticoagulant-related adverse outcomes (principally bleeding and thrombosis). Study Selection and Data Extraction: Due to this documents scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors who constitute the Board of Directors of The Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The Board is composed of physicians, pharmacists, and nurses with demonstrated expertise and significant collective experience in the management of patients receiving anticoagulation therapy. Data Synthesis: Recommendations for delivering optimized anticoagulation therapy were developed collaboratively by the authors and are summarized in 9 key areas: (I) Qualifications of Personnel, (II) Supervision, (III) Care Management and Coordination, (IV) Documentation. (V) Patient Education, (VI) Patient Selection and Assessment, (VII) Laboratory Monitoring, (VIII) Initiation and Stabilization of Warfarin Therapy, and (IX) Maintenance of Therapy. Recommendations are intended to inform the development of care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized anticoagulation therapy are intended to apply to all clinicians involved in the care of outpatients receiving anticoagulation therapy, regardless of the structure and setting in which that care is delivered. Conclusions: Anticoagulation therapy, although potentially life-saving, has inherent risks. Whether a patient is managed in a solo practice or a specialized anticoagulation management service, a systematic approach to the key elements outlined herein will reduce the likelihood of adverse events. The need for continued research to validate optimal practices for managing anticoagulation therapy is acknowledged.

Perioperative Bridging Therapy With Unfractionated Heparin or Low-Molecular-Weight Heparin in Patients With Mechanical Prosthetic Heart Valves on Long-Term Oral Anticoagulants (from the REGIMEN Registry)

Patients with mechanical prosthetic heart valves require long-term oral anticoagulant therapy (OAT). During the temporary interruption of OAT, bridging anticoagulant therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is recommended. This prespecified subgroup analysis from REGIMEN-a large, prospective, multicenter registry-compared UFH (n = 73) and LMWH (n = 172) as bridging anticoagulation in patients with mechanical heart valves on long-term OAT. Patient demographics and co-morbidities were generally similar between groups. There were more bileaflet valves in the LMWH group (67.4% vs 43.8%, p = 0.0005), but no differences in valve positions between groups. The LMWH group was less likely to undergo major surgery (33.7% vs 58.9%, p = 0.0002) and cardiothoracic surgery (7.6% vs 19.2%, p = 0.008), and to receive intraprocedural anticoagulants or thrombolytics (4.1% vs 13.7%, p = 0.007). Major adverse event rates (5.5% vs 10.3%, p = 0.23) and major bleeds (4.2% vs 8.8%, p = 0.17) were similar in the LMWH and UFH groups, respectively; 1 arterial thromboembolic event occurred in each group. More LMWH-bridged patients were treated as outpatients or discharged from the hospital in <24 hours (68.6% vs 6.8%, p <0.0001). Multivariate logistic analysis found no significant differences in major bleeds and major composite adverse events when adjusting for cardiothoracic or major surgery between groups. In conclusion, for patients with mechanical prosthetic heart valves on long-term OAT, mostly outpatient-based LMWH bridging therapy appears to be feasible for selected procedures, is as safe as UFH, and is associated with a low arterial thromboembolic rate.

The impact of patient self-testing of prothrombin time for managing anticoagulation: rationale and design of VA Cooperative Study #481--the Home INR Study (THINRS).

Background: Anticoagulation (AC) with warfarin reduces the risk of thromboembolism (TE) in a variety of applications, yet despite compelling evidence of the value and importance of high quality AC, warfarin remains underused, and dosing is often suboptimal. Approaches to improve AC quality include (1) an AC service (ACS), which allows the physician to delegate day-to-day details of AC management to another provider dedicated to AC care, and (2) incorporating into the treatment plan patient self-testing (PST) under which, after completing a training program, patients perform their own blood testing (typically, using a finger-stick blood analyzer), have dosage adjustments guided by a standard protocol, and forward test results, dosing and other information to the provider. Studies have suggested that PST can improve the quality of AC and perhaps lower TE and bleed rates.The purpose of Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) #481, “The Home INRStudy” (THINRS) is to compare AC management with frequent PST using a home monitoring device to high quality AC management (HQACM) implemented by an ACS with conventional monitoring of prothrombin time by international normalized ratio (INR) on major health outcomes. PST in THINRS involves use of an INR monitoring device that is FDA approved for home use.Study design: Sites are VA Medical Centers where the ACS has an active roster of more than 400 patients. THINRS includes patients with atrial fibrillation (AF) and/or mechanical heart valve (MHV) expected to be anticoagulated indefinitely.THINRS has two parts. In Part 1, candidates for PST are evaluated for 2 to 4 weeks for their ability to use home monitoring devices. In Part 2, individuals capable of performing PST are randomized to (1) HQACM with testing every 4 weeks and as indicated for out of range values, medication/clinical changes, or (2) PST with testing every week and as indicated for out of range values, medication/clinical changes.The primary outcome measure is event rates, defined as the percent of patients who have a stroke, major bleed, or die. Secondary outcomes include total time in range (TTR), other events (myocardial infarction (MI), non-stroke TE, minor bleeds), competence and compliance with PST, satisfaction with AC, AC associated quality of life (QOL), and cost-effectiveness.To assess the effect of PST frequency on TTR and other outcomes, at selected sites patients randomized to perform PST are assigned one of three test frequencies (weekly, twice weekly, or once every four weeks).

Improving Antithrombotic Management in Patients With Atrial Fibrillation: Current Status and Perspectives

Despite overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation (AF), there is still considerable undertreatment. A multidisciplinary expert group was formed to discuss issues surrounding anticoagulant treatment of patients with AF to try and achieve consensus on various aspects of the implementation of guidelines on oral anticoagulation therapy in AF. Panel members were cardiologists, hematologists, and laboratory and primary care physicians with specific expertise from Europe and the United States. One of the most important conclusions of the meeting was to enhance guideline adherence by better communication of the data showing that the benefits of stroke reduction outweigh the risk of bleeding associated with treatment with vitamin K antagonists. Management of oral anticoagulation therapy by dedicated centers, such as anticoagulation clinics, or by patient self-management may improve the quality of anticoagulation and facilitate the management of these patients and thereby further facilitate optimal antithrombotic management in patients with AF.

Patient Self-Management of Oral Anticoagulant Therapy: An International Update.

The clinical use of oral anticoagulant therapy has been complicated by the necessity for frequent determinations of the prothrombin time (PT) to ensure safety and therapeutic efficacy. This requirement has often imposed a significant burden on both providers and patients. In 1985 a German patient, Heike Möller-Jung, initiated her own patient self-testing (PST) and patient self-management (PSM). Today there are over 15,000 patients in Germany managing their oral anticoagulant therapy with PSM options. Pilot PST and PSM programs are in place in many other countries. In the United States, two devices have recently been approved for PST. This method of monitoring has been shown to be as accurate as that of traditional central laboratory PT determinations, to improve the amount of time patients are within the therapeutic INR range, and to decrease the incidence of adverse events associated with anticoagulant therapy.

Heart Rate Control in Patients With Chronic Atrial Fibrillation and Heart Failure

The goal of this study was to determine whether aggressive heart rate (HR) control in patients with both chronic atrial fibrillation (AF) and heart failure (HF) is associated with improved outcomes. HR control is one of the mainstays in management of patients with AF. However, rate control can be challenging in patients with HF. This study was designed as an interventional clinical trial, using patients with chronic AF and left ventricular systolic dysfunction with left ventricular ejection fraction ≤40% (n=20) as their own controls. Intervention consisted of increasing doses of metoprolol succinate to achieve target resting HR <70 beats per minute. Clinical data were collected at baseline and after intervention, with paired t test used to evaluate statistically significant change. After 3 months of intervention, average resting HR decreased from 94±14 beats per minute to 85±12 beats per minute. Average metoprolol succinate dose at the end of the study was 121 mg. None of the outcomes improved significantly after the intervention, including exercise tolerance (meters walked on 6-minute walk test 326±83 vs 330±86), quality of life (Minnesota Living With Heart Failure Questionnaire score of 42.5±19 vs 38±21), and brain natriuretic peptide (242±306 pg/mL vs 279±395 pg/mL). Aggressive HR control was difficult in this group of patients with chronic AF and HF due to patient intolerance of increasing doses of β-blockade, and not associated with improved outcomes. Further studies are needed to establish guidelines for target HR in patients with chronic AF who also have significant HF.

Predictors of anticoagulation quality in 15 834 patients performing patient self-management of oral anticoagulation with vitamin K antagonists in real-life practice: a survey of the International Self-Monitoring Association of Orally Anticoagulated Patients.

Although patient self‐management (PSM) of oral anticoagulation with vitamin K antagonists is recommended for patients requiring long‐term anticoagulation, important aspects are still unclear. Using data from a large international survey (n = 15 834; median age 72 years; 30·1% female), we studied predictors of poor anticoagulation control (percentage of International Normalized Ratio values within therapeutic range below 75%) and developed a simple prediction model. The following variables were identified as risk factors for poor anticoagulation control and included in the final model: higher intensity of therapeutic range (odds ratio [OR] on every level 1·9; 95% confidence interval [CI] 1·8–2·0), long intervals between measurements (>14 d; 1·5; 95% CI 1·3–1·7), female sex (OR 1·3; 95% CI 1·2–1·4), and management other than PSM (OR 1·4; 95% CI 1·2–1·6). At a threshold of 0·2 (at least one variable present), the model predicted poor anticoagulation control with a sensitivity of 85·3% (95% CI: 84·0, 86·4) and a specificity of 28·5% (27·6, 29·5). The area under the receiver operated characteristic curve was 0·65. Using the proposed prediction model, physicians will be able to identify patients with a low chance of performing well, considering additional training, regular follow‐up, or adjustment of therapeutic ranges.

Warfarin monitoring: point-of-care INR testing limitations and interpretation of the prothrombin time.

Long-term anticoagulant therapy with warfarin (Coumadin) has been demonstrated to be highly effective in preventing thromboembolic complications in a variety of conditions and disease states. Unfortunately, the therapeutic effect of a given dose of warfarin is highly unpredictable and can change over time due to a variety of factors, such as changes in diet or concomitant medications. Therefore, safe and effective utilization of chronic warfarin therapy requires frequent monitoring. The traditional goal has been to have monitoring performed at least once every four weeks in stable patients. The requirement for ongoing monitoring has frequently been a barrier that has limited the utilization of warfarin in patients who might otherwise benefit from anticoagulation. This has resulted in a strong research effort to not only develop alternative anticoagulant agents, but also to develop novel methods of monitoring warfarin that could reduce the burden on both patients and on their care providers. Point-of-care INR monitoring has been proposed as a means of providing more flexible monitoring options. Point-of-care INR monitoring can either be provided in the professional practice setting of a hospital or physician office, or can be utilized for patient self-testing in the home environment. Point-of-care testing in the professional setting provides the opportunity for immediate feedback and interaction but still requires the patient to travel to a centralized provider. Patient self-testing provides the opportunity for increased frequency of testing by providing improved access to testing. It has long been known that the routine Quick Prothrombin Time test demonstrates a high degree of variability depending on the thromboplastin reagent utilized. The INR (International Normalized Ratio) method of reporting the prothrombin time was implemented in the late 1980s with the hope that the test results could be standardized worldwide, regardless of the thromboplastin or coagulometer. As originally proposed, it was hoped that the INR would be highly effective, and that by knowing the ‘‘sensitivity’’ of any particular thromboplastin, it would be possible to provide a result that would be essentially interchangeable with the result obtained on any other test system. Unfortunately, the reality is that while the INR method of reporting has reduced the variability across different test systems, significant variation still remains. This inherent variability increases with higher INR values and can be clinically significant. In the late 1990s our lab performed a series of investigations in which we drew venipuncture samples from patients on warfarin, split the samples into multiple aliquots, and then used a variety of different test systems (different thromboplastin reagents and different coagulometer devices) to determine the INR on each aliquot. We observed that for a patient with an average INR of 2.0, the variation in INR across the different test systems was approximately ±0.4 INR units. For an average INR of 3.0, the variation was ±0.8 INR units. In other words, even though the average INR from the multiple test systems was 3.0, the range was from 2.2 to 3.8, potentially of clinical significance. The variation continued to increase as the average INR increased, such that for an averaged INR of 4.0, the observed variation was ±1.2 INR units. Similar results were observed with either central laboratory coagulometers or if point-of-care INR devices were evaluated. Similar variations are also seen in the College of American A. K. Jacobson (&) Loma Linda VA Medical Center, 11201 Benton Street, Loma Linda, CA 92354, USA e-mail: akjacobson@linkline.com