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Learning Center
New In Coagulation
Monday, August 3, 2009
WHATS NEW IN COAGULATION: AUGUST 2009
Reducing Bleeding Risk in Patients Who Need Triple Antithrombotic Therapy
http://www.medscape.com/viewarticle/705565?sssdmh=dm1.497244&src=nldne
Strategies aimed at reducing bleeding risk in patients who need treatment with dual antiplatelet therapy as well as an anticoagulant such as warfarin are examined in the Journal of the American College of Cardiology. Dual antiplatelet therapy (aspirin plus clopidogrel is given routinely in the treatment of ACS and after coronary stent deployment, and anticoagulant therapy might be indicated for stroke prevention in a variety of conditions that include atrial fibrillation and profound left ventricular dysfunction as well as after mechanical prosthetic heart valve replacement. Triple antithrombotic therapy may be needed when a patient has multiple diseases, the most common situations being patients with AF and or mechanical prosthetic heart valves who also have coronary artery disease and require a stent. The significant bleeding hazards associated with triple antithrombotic therapy is a real issue.
Data that are available suggest that up to 21% of patients receiving triple antithrombotic therapy need a transfusion (a figure that might increase with longer treatment durations), and the relative risk of major bleeding is three- to fivefold higher than in patients receiving dual antiplatelet therapy alone. But this is confounded by the fact that patients receiving triple therapy are typically older and have multiple comorbidities, which might increase bleeding potential. Short-term use of triple therapy (for one month) is associated with at least a twofold lower risk of major bleeding compared with prolonged use (more than six months). But patients receiving dual antiplatelet therapy only after PCI (prolonged warfarin interruption) have a threefold increase in stroke or thromboembolic events, compared with patients receiving triple therapy or warfarin plus a single antiplatelet agent.
Severe or life-threatening bleeding usually requires reversal of warfarin therapy and, in some cases, platelet transfusions to counteract clopidogrel therapy. If dual antiplatelet therapy requires urgent discontinuation, the patient should be closely monitored for the risk of stent thrombosis. In patients with mild or moderate bleeding, every effort should be made to maintain the INR as close to 2.0 as possible, and the aspirin dose should be kept at <100 mg.
If bleeding persists, they advise that aspirin be discontinued first, as clopidogrel seems to be more important than aspirin in preventing stent thrombosis after PCI.
Travel Increases Risk of VTE Threefoldhttp://www.medscape.com/viewarticle/705542?sssdmh=dm1.497244&src=nldne
A new meta-analysis of studies on travel and the risk of venous thromboembolism (VTE) has found that any mode of transportation increases this risk. For all modes of travel, the risk of VTE increases with the duration of the journey. We found an 18% increase in risk per two-hour increase in travel duration.Tthe association between travel and VTE was studied for people using any mode of transportation and used nontraveling persons for comparison. Included were 14 studies--11 case-control, two cohort, and one case-crossover--with more than 4000 cases of VTE in total.
Overall, a twofold higher risk for VTE was identified in travelers than in nontravelers. But they discovered that a significant amount of heterogeneity was present in six case-control studies with biased selection of control participants. These case-control studies included "referred controls," people who were referred with the suspicion of VTE--like the case patients--but who tested negative for VTE. Looking at these six studies alone showed a relative risk of 1.2 for VTE with travel. When these six studies were excluded from their overall analysis, they found a relative risk of 2.8 for VTE with travel.A greater risk of VTE with air travel than with surface travel was noted, around a 60% higher risk, but this was not statistically significant. Likewise, the elevated risk with greater journey time was slightly higher for flying: they found a 26% increase in risk of VTE per two-hour increase in flight time.
For healthy adults, the current recommendations for those traveling for long periods are simply to ensure good leg mobility and adequate hydration. It is unclear whether compression stocking are effective.
Good and Bad News for Possible Warfarin Competitorshttp://www.medscape.com/viewarticle/706114?sssdmh=dm1.502297&src=nldne
An investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested as a once-daily drug in a phase 3 trial in over 16 000 patients with atrial fibrillation, following unexpected results from a pharmacokinetic analysis of the agent in a phase 2 study. Once-daily dosing caused less bleeding than twice-daily dosing, even when you used the same total dose. Delivering a compound twice a day generally allows for more consistent drug levels in the blood, Consequently, in the multinational phase 3 study, known as ENGAGE-AF TIMI 48, patients will be randomized either to 30 mg or 60 mg of edoxaban once daily or to warfarin, dosed once daily with adjustments to maintain an internalized normalized ratio (INR) between 2.0 and 3.0. The primary end point of ENGAGE-AF will be the prevention of stroke and systemic embolic events (SEE), and the primary safety assessment will be the incidence of bleeding. The trial is expected to conclude in the first half of 2012.
You don't have to monitor [edoxaban], it doesn't have a lot of drug-drug interactions, and it doesn't matter what you eat, so it's easier to use.Another investigational, once-daily factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is currently in limbo in the US after the FDA declined to approve it for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- or knee-replacement surgery, despite a recommendation for approval from its Cardiovascular and Renal Drugs Advisory Committee earlier this year . Bristol-Myers Squibb also has a factor Xa inhibitor in development, apixaba. Tecarfarin (Aryx Therapeutics), another new potential competitor to warfarin, has disappointed in a recent phase 2/3 trial [3]. Tecarfarin, like warfarin, is a selective inhibitor of vitamin-K epoxide reductase (VKOR), but unlike warfarin, it is not dependent upon cytochrome P450 enzymes for metabolism.In the study, EmbraceAC, in 600 patients with a variety of underlying conditions--such as AF, implanted prosthetic heart valves, and a history of venous thromboembolic disease--tecarfarin failed to show superiority (as measured by time in the therapeutic INR range) over warfarin. The company says this is because the warfarin patients did much better than expected in the trial, due to the centralized dosing control center employed. It is still analyzing the data to determine a future strategy for tecarfarin.
Antithrombotic Drug Use Linked To Cerebral Microbleedshttp://www.medscape.com/viewarticle/705593?src=mp&spon=17&uac=123046FG
Cerebral microbleeds or hemosiderin deposits in the brain suggesting the presence of microangiopathy have been linked to a condition known as cerebral amyloid angiopathy when the microbleeds are present only in lobar brain regions. To determine whether antithrombotic drug use may predispose to cerebral microbleeds, the investigators in this population-based, cross-sectional analysis used magnetic resonance imaging to evaluate the presence and location of cerebral microbleeds.
The study cohort consisted of 1062 persons enrolled in the Rotterdam Scan Study, a population-based imaging study in The Netherlands, who were at least 60 years of age, had no dementia at baseline, and who underwent brain magnetic resonance imaging between August 15, 2005, and November 22, 2006. Automated pharmacy records were used to determine prescription of platelet aggregation inhibitors and anticoagulant drugs before magnetic resonance imaging. Cerebral microbleeds were about 70% more prevalent in users of platelet aggregation inhibitors than in non-users of antithrombotic drugs (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21-2.41). However, there was no significant association between microbleed presence and anticoagulant drug use (OR, 1.49; 95% CI, 0.82-2.71). Compared with users of carbasalate calcium, aspirin users had a higher prevalence of strictly lobar microbleeds (adjusted OR for aspirin users vs non-users, 2.70; 95% CI, 1.45-5.04; adjusted OR for carbasalate calcium users, 1.16; 95% CI, 0.66-2.02). Comparing use of similar dosages of aspirin vs carbasalate calcium made this difference in prevalence of strictly lobar microbleeds even more dramatic.
However, the benefits of antithrombotic drugs in persons at increased risk for myocardial infarction or ischemic cerebrovascular disease have been shown to exceed any risks of bleeding. In certain patients, such as those with evidence of cerebral amyloid angiopathy, physicians should consider the risk-benefit ratio for drugs such as aspirin before deciding on an optimal course of treatment.
Adding UFH to Enoxaparin for PCI Is Unnecessary, Ups Bleeding Risk
http://www.medscape.com/viewarticle/706407?sssdmh=dm1.503977&src=nldne
Administering unfractionated heparin (UFH) to patients already receiving enoxaparin--a common practice in the cath lab known as stack-on--results in overanticoagulation, putting patients at increased risk of bleeding, and therefore should be avoided.In addition, the results demonstrate that the anticoagulation test commonly used in cath labs--activated clotting time (ACT)--does not detect this excessive anticoagulation.
Current guidelines for non-ST-segment and ST-segment elevation acute coronary syndromes (ACS) recommend complex regimens combining the use of different anticoagulants, but the effects of these are not well documented. To examine the effects of this strategy, he and his colleagues recruited 72 healthy subjects aged 40 to 60 (middle-aged volunteers were chosen as their ages most closely approximate those of ACS patients, Drouet explained). They received a standard, subcutaneous (sc) enoxaparin dose of 1 mg/kg every 12 hours for 2.5 days and were then randomized to receive a 70-IU/kg intravenous UFH bolus four, six, or 10 hours after the final enoxaparin dose. Anticoagulation levels were assessed in subjects receiving enoxaparin alone and after the UFH bolus by monitoring ACT, anti-Xa and anti-IIa activities, and thrombin generation (endogenous thrombin potential [ETP]).
After the final enoxaparin dose, ETP levels decreased by 40%; anti-Xa and anti-IIa activities increased, as expected; and ACT levels did not indicate any anticoagulation effect. Stack-on UFH at four, six, or 10 hours after the last enoxaparin dose significantly increased anti-Xa and anti-IIa activities (p<0.0001) to well above accepted therapeutic levels and resulted in total inhibition of thrombin generation for two hours or more. But ACT levels remained within the range commonly observed in subjects who are receiving only UFH (despite the fact they were also on enoxaparin).
The results show that an additional intravenous UFH bolus given to healthy subjects already receiving standard enoxaparin therapy resulted in complete inhibition of ETP, and this effect was consistent regardless of whether UFH was given four, six, or 10 hours after the last sc enoxaparin dose, say the researchers. This effect was correlated to and was explained by an immediate and prolonged inhibition of factor-Xa and factor-IIa.
In contrast, measurement of ACT levels reflected only the changes in anticoagulation levels associated with UFH alone and poorly predicted the cumulative effects of enoxaparin and UFH.
Continued Warfarin Seems Okay for High-Thrombotic-Risk Device Procedureshttp://www.medscape.com/viewarticle/706480?sssdmh=dm1.505375&src=nldne
Patients with an indication for warfarin therapy, such as atrial fibrillation (AF) or a history of stroke, can be safely implanted with pacemakers and implantable cardioverter defibrillators (ICDs) without going off their oral anticoagulation regimen.Such continued warfarin, compared with an alternative strategy of warfarin interruption while bridging with a low-molecular-weight heparin (LMWH), didn't seem to promote serious complications and may have prevented some hematomas and pocket revisions.Not surprisingly, the likelihood of a hematoma went up with the number of leads on the implanted device. The group saw about a 23% rate of hematoma associated with procedures that were bridged with LMWH, which is in line with rates described in the literature. That's three times the rate seen in the patients who continued on warfarin.
Ongoing oral anticoagulation is increasingly an issue at device implantations, partly because of rapid growth in ICD and biventricular pacemaker use and the ranks of people with AF or other warfarin indications. . About a quarter of such device recipients are on warfarin, he said, and about a third of those have markers of increased thrombotic risk that support keeping them on the drug during procedures.
Of 447 patients on chronic warfarin who received pacemakers or ICDs at one center over 18 months (29% of total device recipients during that time), 155 were prospectively classified at high thrombotic risk and therefore as potential candidates for bridge therapy with the LMWH dalteparin (Fragmin, Eisai/Pfizer). Markers of high risk included AF with a CHADS2 score of at least 2, recent venous thromboembolism, presence of a mechanical heart valve, or a history of stroke or transient ischemic attack.
Of those 155 patients, 117 stayed on warfarin during their device implantations and 38 were bridged with dalteparin for reasons that included concomitant clopidogrel therapy, renal dysfunction, known coagulopathy, or planned submuscular device insertion. A third comparison group consisted of 117 historical control patients not on anticoagulation but matched by age, gender, type of implanted device, and implantation procedure (whether new device implantation or replacement/revision).
Association of Aspirin Dosage to Clinical Outcomes After Percutaneous Coronary Intervention: Observations From the Ottawa Heart Institute PCI Registryhttp://www.medscape.com/viewarticle/705112?src=mp&spon=17&uac=123046FG
Derek So, MD; E. Francis Cook, MD; Michel Le May, MD; Chris Glover, MD; William Williams, MD; Andrew Ha, MD; Richard Davies, MD; Michael Froeschl, MD; Jean-Francois Marquis, MD; Edward O'Brien, MD; Marino Labinaz, MD
Published: 07/21/2009
Abstract and Introduction
Abstract
Background: Dual antiplatelet therapy, with aspirin and a thienopyridine, is the accepted treatment after percutaneous coronary intervention (PCI). No clear evidence exists regarding the ideal dosage of aspirin. Recent guidelines recommend higher-dose aspirin because of the possible decrease in stent thrombosis. The purpose of this study was to test the hypothesis that high-dose aspirin of 325 mg decreases death and myocardial infarction (MI) compared to a lower dose of 81 mg in patients undergoing PCI.
Methods: An observational cohort study of 1,840 consecutive patients who underwent PCI was conducted. Patients who did not survive to discharge were excluded. The primary endpoint was a composite of all-cause mortality and MI at 1 year.
Results: Nine-hundred and thirty patients (50.5%) were discharged on 325 mg of aspirin and 910 (49.5%) were discharged on 81 mg. The risk of all-cause mortality or MI was not significantly different between patients: low-dose 5.49% (50/910) vs. high-dose 4.19% (39/930); adjusted odds ratio [OR], 1.16; 95% confidence interval [CI], 0.73-1.85). In a multivariable analysis, the Charlson comorbidity score (OR, 1.37; 95% CI, 1.18-1.58) and urgent PCI (OR, 1.75; 95% CI, 1.03-3.00) were associated with increased death or MI. Among patients with drug-eluting stents, the use of low-dose aspirin did not predispose them to death or MI (adjusted OR, 1.12, 95% CI, 0.53-2.34).
Conclusions: In this large contemporary analysis of PCI patients, no differences in death or MI were observed at 1 year between patients discharged on low-dose aspirin 81 mg compared to patients on a higher dose.
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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