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| | | | | ASH 2004 | | | | | | The American Society of Hematology
46th Annual Meeting and Exposition
December 4-7, 2004
San Diego, California
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| | | |  | Bridging Therapy for Patients on Long-term Oral Anticoagulants
The clinical outcomes of bridging therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) were the topic of a key, oral presentation during the "Antithrombotic therapy/clinical studies" session on the final day of the meeting.
Alex C. Spyropoulos, MD, FACP, FCCP, Lovelace Medical Center, Albuquerque, New Mexico, presented data on behalf of the REGIMEN investigators, who studied the optimal perioperative management of patients on long-term oral anticoagulant (OAC) therapy. REGIMEN, a prospective multicenter patient registry in the USA and Canada, is the first large patient registry to compare UFH with LMWH in this setting.
Centers involved in the REGIMEN registry enrolled patients who were receiving chronic anticoagulation and required perioperative bridging therapy for an elective procedure or surgery. Primarily, the REGIMEN investigators compared the efficacy and safety of in-hospital UFH with LMWH (mostly given on an outpatient basis) for bridging in patients on long-term OAC. Data on patient characteristics from 1077 patients with primary clinical adverse events up to 30 days postprocedure were compared between UFH and LMWH.
Dr Spyropoulos reported that patients on LMWH spent less time in the hospital. Similar rates for adverse events were seen in both treatment groups, and these were confined, primarily, to minor bleeding. Statistical analysis for procedure variables showed that use of UFH compared with LMWH, intraprocedural anticoagulants/thrombolytics, procedure duration > 45 minutes, and general anesthesia were associated with an increased risk of a major adverse event.
The REGIMEN investigators concluded that, in selected outpatients, bridging therapy with LMWH was at least as safe and effective as in-hospital UFH.
Reference
Spyropoulos AC, Turpie AGG, Dunn AS, et al. Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients with long-term oral anticoagulants: results from the REGIMEN registry [abstract]. Blood. 2004;104(11 Pt 1):203a. Abstract 709.
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| | | | | Risk Factors for Bleeding in Patients with Nonvalvular Atrial Fibrillation Receiving Ximelagatran or Warfarin: Findings from SPORTIF III and V
During the "Antithrombotic therapy" presentations on December 6, 2004, James D. Douketis, MD, of McMaster University, Ontario, Canada, updated the audience on the latest results of data analyses of risk factors for bleeding from the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials. Of interest, Dr Douketis presented the list of risk factors for bleeding common to patients taking either warfarin or ximelagatran. Univariate analysis demonstrated each of the following risk factors to have an odds ratio and 95% confidence interval >1.0: increasing age, diabetes mellitus, and concomitant low-dose aspirin. There were also 2 novel findings: Asian race was a risk factor for bleeding and, surprisingly, statin use appeared to offer some protection against bleeding. In consideration of these 2 unexpected findings, Dr Douketis suggested that further clinical studies on racial or ethnic variation as a risk factor, as well as studies to determine the protective effects offered by the statin group of medications, would be of interest.
Reference
Douketis JD, Arneklev K, Goldhaber S, et al. Risk factors for bleeding in patients with nonvalvular atrial fibrillation who are receiving anticoagulant therapy with ximelagatran or warfarin: findings from the SPORTIF III and V trials [abstract]. Blood. 2004;104(11 Pt 1):153a. Abstract 528
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| | | | | Current Dosing Recommendations for Direct Thrombin Inhibitors in Patients with Heparin-induced Thrombocytopenia May Be Too High.
Gerald A. Soff, PhD of Northwestern Memorial Hospital in Chicago, Illinois, and colleague, used the opportunity of the poster sessions to present their findings on an important safety issue concerning a frequently elevated activated partial thromboplastin time (aPTT) found in some patients administered the direct thrombin inhibitors (DTIs) lepirudin or argatroban according to the respective product inserts. The investigators reviewed their institution's experience with these drugs to determine whether the stated dosing guidelines needed modification.
A chart review of their pharmacy data for all patients that received lepirudin or argatroban from September 2002 to March 2004 revealed 66 patients who were treated with the DTIs for heparin-induced thrombocytopenia (HIT) or for HIT with thrombosis (HITT). HIT was confirmed by a decline in platelet count of 50%, a drop to <100,000 platelets/mcL, and/or a positive heparin-induced platelet aggregation enzyme-linked immunosorbent assay (HIPA ELISA).
Of these 66 patients, 39 received lepirudin and 27 received argatroban. The mean dose of DTI that resulted in a therapeutic aPTT (55-80 seconds) was calculated for each patient. The mean lepirudin dose resulting in a therapeutic aPTT was 0.071 mg/kg/h, which was less than the recommended dose of 0.15 mg/kg/h. While only 10% of the patients had a mean dose at or above the recommended dose, 49% of the patients required 0.05 mg/kg/h or lower. For argatroban, the mean dose resulting in a therapeutic aPTT was 1.52 mcg/kg/min. While 67% of patients required less than the recommended dose, only 15% of the patients studied had a dose equal to the recommended dose, and only 18% had a mean dose above the recommended dose. Even though the dosing of the 2 DTIs was lower overall than the recommended dosing, aPTT levels were therapeutic or supratherapeutic the majority of the time in both patient groups.
Investigators also noted a poor correlation between the dose of DTI and the resulting aPTT. This made it difficult to predict the resulting aPTT for a given dose adjustment of DTI. Further compounding the discrepancies, 20 written prescription errors were found in 5 patients receiving argatroban. Most likely, these errors may have been due to dosing confusion, with argatroban prescribed using mcg/kg/min, rather than mg/kg/h.
The DTIs lepirudin and argatroban, used for the anticoagulation therapy in patients with or at risk for HIT/HITTS, require careful dosing and close monitoring for safe use. Yet, they lack specific titration guidelines and carry a significant risk of life-threatening hemorrhage. This study supports anecdotal reports and case-report experience that suggests the current dosing recommendations for both drugs are too high. For safer use with a lower risk of hemorrhage, the investigators concluded that the dosing guidelines need to be lowered. These medications should be high-alert medications when being prescribed, and improved physician education, along with modification of the product insert, will help to avoid costly and potentially deadly outcomes.
Reference
McDaniel M, Soff GA. Decreasing adverse drug events associated with lepirudin and argatroban for the treatment of heparin-induced thrombocytopenia [abstract]. Blood. 2004;104(11 Pt 1):495a. Abstract 1787.
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| | | | | What Are the Barriers to Prescribing Oral Anticoagulants to Patients with Atrial Fibrillation?
An interesting poster presentation of an analysis of both the perceived and actual barriers to warfarin prescription in patients with atrial fibrillation, included a discussion of the importance of patient preference, capabilities, and clinical contraindications. The analysis noted that, although prior studies had assessed either physicians' general perceptions of barriers to oral anticoagulation or actual barriers in a sample of patients, they had yet to both be evaluated within a single study.
By identifying 45 barriers to warfarin use from literature, from input of clinical experts, and from a physician focus group, the authors evaluated physicians' general perception of barriers to warfarin use and actual critical barriers to prescribing warfarin in their patients. They devised a new study instrument, whereby physicians were asked to rank their reluctance to prescribe warfarin if perceived barriers were present in a patient on a scale of 1 to 10 (with 10 being very reluctant). These barriers were classified as patient medical characteristics, health-care system factors, patient capability, and patient preference. A sample of US physicians who treat patients with atrial fibrillation (AF) took part in the analysis. Physicians then indicated critical barriers to prescribing warfarin in their own specific AF patients not receiving warfarin.
The analysis revealed that recent severe bleeding, an inability to rely on patient adherence to medication in general and to complex instructions for warfarin in particular, unwillingness to undergo repeat laboratory testing and risk of fall were considered by physicians as the primary factors influencing their decision not to prescribe warfarin. It was shown that the critical barriers to prescribing warfarin in specific AF patients included: patient unwillingness to undergo repeat testing, inability to rely on the patient to adhere to medication instructions in general or to complex instructions for warfarin in particular, difficulty getting to monitoring appointments, and bleeding episode more than 3 months ago.
The investigators concluded that patient preference and capabilities are at least as important as clinical contraindications as barriers to prescribing warfarin in AF patients.
Reference
Hollowell J, Ingelgard A, Reddy P, Gold K, Fitzmaurice D. Patient preference and capabilities are at least as important as clinical contraindications as barriers to prescribing warfarin in patients with atrial fibrillation [abstract]. Blood. 2004;104(11 Pt 1):606a. Abstract 2204.
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| | | | | Positive Results for Fondaparinux from the MATISSE Trials
Fondaparinux is at least as safe and effective as standard therapies for the treatment of venous thromboembolism (VTE)—that was the message from the MATISSE Investigators in an oral presentation session at the American Society of Hematology 46th Annual Meeting and Exposition.
Presented by Harry R. Buller, MD, of the Academic Medical Center of Amsterdam, the Netherlands, the session provided an update on the MATISSE trials, which were set up to evaluate fondaparinux in the treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE).
Fondaparinux is the first in a new class of anticoagulants that inhibit thrombin generation by indirect targeting of factor Xa. It is a completely synthetic pentasaccharide with a selective action and a well-defined pharmacologic target. The MATISSE trials were designed to address 2 main issues: the MATISSE-DVT trial compared fondaparinux with a low-molecular-weight heparin, enoxaparin, in 2205 patients with DVT, while the MATISSE-PE trial compared fondaparinux with dose-adjusted intravenous unfractionated heparin (UFH) in 2213 patients with PE. In both trials, the aim was to compare the recurrence of VTE during the 3-month follow-up period and major bleeding and death during the initial treatment period.
Fondaparinux was administered as a once-daily subcutaneous dose of 7.5 mg (adjusted to 5 mg and 10 mg for patients <50 kg and >100 kg, respectively), while enoxaparin was administered as a twice-daily subcutaneous dose of 1 mg/kg. As fondaparinux and enoxaparin can be self-injected without laboratory monitoring, outpatient treatment was presented as an option but ultimately left to the discretion of the physician. Treatment of PE with UFH, however, required in-hospital care because of the intravenous nature of UFH administration and prerequisite for laboratory monitoring. All patients received anticoagulant therapy for at least 5 days.
New drug compares well
The investigators found that the rates of recurrent VTE and major bleeding in fondaparinux outpatients were similar to those in enoxaparin outpatients or UFH inpatients. About 1% of patients in each group had a major bleeding complication during initial treatment, while about 4% in each group had a recurrence of VTE within 3 months.
As outpatient treatment was encouraged but left to the physician’s discretion, it was interesting to note that almost one-third of the fondaparinux- and enoxaparin-treated patients in the MATISSE-DVT trial received therapy on an outpatient basis. This fell to about one-seventh in MATISSE-PE (understandable considering the relative severity of the condition) but comparing favorably with the UFH group where no patients could be treated on an outpatient basis. For both trials, outpatient treatment showed comparable safety and efficacy data compared with in-hospital treatment.
From these studies, the investigators concluded that the initial outpatient treatment of DVT and PE with once-daily fondaparinux would appear as safe and effective as therapy with enoxaparin and UFH—drugs that are well-established treatment options for VTE with proven safety records.
Reference
Buller HR, and the MATISSE Investigators. Initial outpatient treatment of venous thromboembolism with fondaparinux (Arixtra®): The MATISSE Trials [abstract]. Blood. 2004;104(11 Pt 1):202a. Abstract 705.
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| | | | | Bedridden Acutely Ill Medical Outpatients Treated at Home Have a High Risk of VTE
One of the many thrombosis-related topics selected for presentation at the American Society for Hematology 46th Annual Meeting and Exposition was a study by Jean-Luc Bosson, MD, PhD, and his group from France. The investigating team said that, on the basis of the results of the MEDENOX study, venous thromboembolism (VTE) prophylaxis in hospitalized acutely ill medical patients has been rigorously employed, making it much more common in France. However, the group continued to express concern over the risk for VTE in bedridden acutely ill medical outpatients treated at home by general practitioners, because that number remains unknown.
Bosson went on to describe the goals of the group's study. He stated that the aim of the "Evaluation de l'incidence des evenements Thromboemboliques veineux et des modalites Ambulatoires de Prevention du risque thrombo-Embolique en medecine generale" (ETAPE study) was to determine the incidence of clinical VTE in bedridden acutely ill medical outpatients treated at home.
The study prospectively enrolled patients of > 40 years of age with an acute medical illness that reduced mobility > 48 hours and justified at least one home medical visitation. Patients were enrolled prospectively at multiple centers for this epidemiological study. Clinical deep-vein thrombosis (DVT) between days 1 and 21 was the primary outcome measure. The secondary outcome was the incidence of VTE (DVT or pulmonary embolism).
With 17,194 patients enrolled, 16,532 (96.1%) were evaluated; 61% were female, 13% were totally bedridden. Each patient had one or more of the following medical conditions: hypertension, venous insufficiency of lower limbs with varicose veins, severe infection, acute rheumatologic episode, and diabetes. Overall, 35% of patients received VTE prophylaxis. The incidences of clinical DVT were 1.9%, 0.9%, and 0.7% in patients with major, moderate, or low risk of DVT, respectively. Table 1 is a summary of VTE events at follow-up.
Bosson concluded that any population of bedridden acutely ill medical outpatients being treated at home had a high risk of VTE, with a rate of clinical VTE of 1.1%. This rate was similar to the one observed in orthopedic surgery patients (1.3% to 3.3%). This is a finding that should be considered by physicians when making the decision to provide prophylaxis.
Table 1. Incidence of Clinical VTE Events at Follow-up
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Patients, N
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16,532
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Median duration of follow-up, days
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20
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Median time to DVT diagnosis, days
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7
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DVT diagnosed, % (95% CI)
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0.99 (0.84-1.14)
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DVT confirmed by ultrasonography or venography, %
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78
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PE, %
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0.20
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Clinical VTE, % (95% CI)
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1.1 (0.94-1.26)
| CI = confidence interval; DVT = deep-vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
References
Bosson J-L, Pouchain D, Dubroca I, Bergmann J-F. The incidence of clinical venous thromboembolism and use of ambulatory prophylaxis methods in bedridden acutely ill medical outpatients: the ETAPE study [abstract]. Blood. 2004;104(11 Pt 1):488a. Abstract 914.
Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients With Enoxaparin Study Group. N Engl J Med. 1999;341:793-800.
Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358:9-15.
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| | | | | Air Travel Found to Be Independent Risk Factor for DVT
The potential link between venous thromboembolism (VTE) and prolonged periods of travel, particularly air travel (or "economy-class syndrome"), has been the subject of intensive media scrutiny over the past few years. While in physiological terms it is entirely plausible that prolonged travel is an independent risk factor for VTE, epidemiological data have so far been inconclusive, indeed often conflicting.
In the largest case-control study of its kind, a research group from Montreal, Canada, has attempted to shed some light on this gray area by asking: what is the significance of travel as a deep-vein thrombosis (DVT) risk factor?
The multicenter study enrolled 359 consecutive patients admitted to hospital with objectively confirmed DVT, plus an equivalent-sized control group for whom DVT had been ruled out. Body mass index, smoking status, and patient location (inpatient vs outpatient) were all comparable between groups. On admission to hospital, patients were surveyed for recent travel history, medications, and clinical characteristics using a detailed questionnaire, and subjects were also screened for factor V Leiden and prothrombin gene mutations. At the end of the study, results were analyzed using logistic regression to test the relationship between DVT and (a) the mode of travel, ie plane compared with car, and (b) the duration of travel.
A high flying risk
Analyzing plane and car travel separately showed that the adjusted odds ratio (OR) for plane travel was 2.28 (95% confidence interval [CI], 0.94-5.50) and for car travel was 1.00 (95% CI, 0.54-1.83). The researchers also found that in patients presenting with DVT, plane travel of > 12 hours' duration was associated with an increased DVT risk compared with shorter travel durations (2.92; 95% CI, 0.54-15.73 vs 1.29; 95% CI, 0.62-2.66).
From these results, the authors concluded that plane travel, but not car travel, appears to be a mild independent risk factor for DVT, while flights of 12 hours' duration or more are associated with a 7-fold rise in the risk of DVT. As the largest case-control study to date looking at the relationship between DVT and travel (and that takes into account concurrent DVT risk factors), the findings raise interesting questions regarding the value of thromboprophylaxis during long-haul travel, particularly in high-risk groups. This question is particularly apt in the light of recent American College of Chest Physicians guidelines, which have, for the first time ever, offered specific recommendations for long-distance travelers.
References
Opatrny L, Shapiro S, Miron M-J, Monczak Y, Kahn SR. A Canadian multicenter case-control study of the risk of venous thrombosis in car and airplane travelers [abstract]. Blood. 2004;104(11 Pt 1):143a. Abstract 491.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.
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