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New In Coagulation
Tuesday, October 7, 2008
What is new in Coagulation - OCTOBER
DARK CHOCOLATE CAN REDUCE LEVELS OF C-REACTIVE PROTEIN.
September 30 - A new Italian study has shown, for the first time, that consuming moderate amounts of dark chocolate can significantly reduce levels of C-reactive protein (CRP) [1]. Dr Romina di Giuseppe October 2008 issue of the Journal of Nutrition. The reduction induced by moderate consumption of dark chocolate corresponds in clinical terms to a significant reduction in the risk of cardiovascular disease. The lowering of CRP that we saw corresponds to a shift from medium risk of cardiovascular disease to low risk and is the first time an association between consumption of dark chocolate and inflammation has been found in a population study.
Of 4849 subjects in good health and free of risk factors in the Moli-sani Project, the researchers identified 1317 who did not eat any chocolate and 824 people who ate dark chocolate regularly. They related the levels of CRP in their blood to their usual chocolate intake. After adjustment for age, sex, social status, physical activity, systolic blood pressure (BP), body-mass index (BMI), waist/hip ratio, food groups, and total energy intake, dark-chocolate consumption was inversely associated with CRP (p=0.038). Mean serum CRP concentrations were 1.32 mg/L in nonconsumers of dark chocolate and 1.10 mg/L in those who ate dark chocolate (p<0.0001).>INFORMATION ABOUT HEPARIN IN PLASMA DERIVED PRODUCTS:
http://www.fda.gov/cder/drug/infopage/heparin/default.htm.
Following reports of serious allergic-type hypersensitivity reactions and cases of severe hypotension in association with the use of intravenous bolus doses of heparin sodium for injection, FDA identified a contaminant, in heparin sourced from pigs raised in China. More recently, questions have been raised concerning the potential risk to recipients of products where heparin may have been used in manufacturing or is present in the final product. These products include plasma-derived clotting factors, including United States licensed Antihemophilic factor (Factor VIII), Factor Nine complex concentrate, and other plasma-derived products such as immune globulins and albumin.
In response to these questions, FDA contacted manufacturers of plasma-derived products to find out what measures they were taking to reduce or eliminate potential risks of exposure to contaminated heparin. Based on the information received, FDA believes the risk of adverse reactions due to contaminated heparin to patients who receive US licensed plasma-derived products is likely to be extremely small.
- All heparin currently used for therapeutic treatment and manufacturing is tested for the contaminant, oversulfated chondroitin sulfate using sensitive FDA developed assays.
- Plasma derivative manufacturers reported one or more of the following:
o heparin was not used in their products
o heparin was used in early stages of manufacture and was not present in the final product
o heparin used in manufacturing and in small amounts in the final product was tested and found not to be contaminated
o where small amounts of heparin are in the final product, there have been no reports of an increase in allergic reactions
Importantly, the amount of heparin received by patients who had adverse events is much greater than the amount in plasma-derivative products. September 25, 2008
ASPIRIN RESISTANCE: CLINICAL INDICATIONS AND DISPARITIEShttp://www.medscape.com/viewarticle/578713
Anita Airee, Pharm.D.; Heather M. Draper, Pharm.D.; Shannon W. Finks, Pharm.D.
Pharmacotherapy. 2008;28(8):999-1018. ©2008 Pharmacotherapy Publications
09/12/2008
Aspirin is one of the most widely prescribed drugs for the prevention of thrombosis in patients with vascular disease. Yet, aspirin is
unable to prevent thrombosis in all patients. The term "aspirin resistance" has been used to broadly define the failure of aspirin to
prevent a thrombotic event. Whether this is directly related to aspirin itself through biochemical aspirin resistance or treatment failure,
or if it is because of aspirin's inability to overcome the thrombogenic aspects of the disease process itself, has not been elucidated.
This can have dramatic clinical implications for a variety of vascular disease subsets and is cause for concern, considering the high
prevalence of aspirin use for both primary and secondary prevention. Disparities exist in the rates of aspirin resistance among certain
patient populations, such as women, patients with diabetes mellitus, and those with heart failure, and across clinical conditions,
such as cardiovascular and cerebrovascular disease. Clinical trial data from studies observing resistance have revealed that
regardless of study size, dose of aspirin, control for drug interactions and adherence, or assay used to measure platelet function,
aspirin resistance is associated with an increased risk for adverse events. Although the evidence is mounting, there has yet to be a
consensus on the appropriate clinical response to aspirin resistance.
A standard definition of aspirin resistance and the clinical relevance of such have been the subject of much debate, and a clear,
distinct definition and treatment strategy are lacking. The term "aspirin resistance" has been coined to most broadly define failure of
aspirin to prevent a thrombotic event, and the rate of aspirin resistance is widely variable, ranging from 5-60% of the population
affected by cardiovascular and cerebrovascular diseases.[2,4] Failure of aspirin therapy can be multifactorial and includes clinical an
d biochemical failure. Laboratory confirmation of aspirin resistance by platelet function assay was recently described to be as high as
24%[5] and has been described in a Caucasian population as well as African-Americans and those from the Indian
subcontinent.[5-7]
Aspirin resistance appears to be more prevalent in women than in men, both in coronary artery disease and stroke.
In a case-control study examining the relationship between biologic measurements of aspirin resistance in patients with stable coronary
artery disease and myocardial infarction, being female was independently associated with 4 times the rate of aspirin resistance
participants taking aspirin 75-325 mg/day found an overall 28% rate of aspirin resistance, yet a higher prevalence was noted in women (OR 2.08, p=0.001).[66]
Rates of aspirin resistance ranging from 5.2-45% have been implicated as a cause of cardiovascular events in several studies
These studies demonstrate an increase in adverse effects in patients with laboratory defined aspirin resistance. Many studies reflect
that although the variables affecting treatment failure such as adherence and drug interactions were controlled for, there was
nonetheless a statistically significant increase in adverse events in those patients with aspirin resistance as defined by platelet function
tests.Doses across the studies were widely variable as was the time of measurement of platelet function; however, the impact of these
variables is as of yet undefined. Cardiovascular events occurred regardless of the index event (e.g., myocardial infarction, percutaneous coronary intervention [PCI]),[79-86] and two studies
found an increase in events, although atherosclerotic risk factors such as tobacco use or drug therapy according to guidelines were
equal across both groups.Individuals found to have more aspirin resistance included those of advanced age, women, those with
increased body mass index, and patients with a history of peripheral vascular disease. Independent predictors of worse outcomes
were aspirin resistance, heart failure,increased age,diabetes,history of peripheral vascular disease, elevated platelet count and lower
hemoglobin level. Limitations to these studies, however, include small patient populations, some with differing baseline characterist
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Thrombolysis Appears to Be Safe Up to 4.5 Hours After Stroke Onset http://www.medscape.com/viewarticle/580655
Observational data from a large European registry suggest that thrombolysis may be safe up to 4.5 hours after stroke onset, an hour and a half longer than current recommendations of a 3-hour limit. Results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry (SITS-ISTR), an observational audit of patients treated with intravenous alteplase, a tissue plasminogen activator (tPA), for acute ischemic stroke showed no significant difference in outcomes between patients treated between 3 and 4.5 hours after symptom onset and those treated before the recommended threshold of 3 hours. If these findings are confirmed in the soon-to-report European Cooperative Acute Stroke Study 3 (ECASS 3) randomized trial comparing tPA treatment vs placebo in patients presenting between 3 and 4.5 hours after symptom onset, more patients with ischemic stroke may be eligible for therapy.l
Subsequent to results of the major clinical trials of tPA during the 1990s, alteplase was approved for use in the United States in 1996 and in Canada in 1999 for patients with ischemic stroke treated within 3 hours of symptom onset. However, the European Medicines Evaluation Agency was more conservative, giving only provisional approval in 2002. One of 2 conditions for licensing was that an observational study be implemented to assess the safety of tPA in routine practice.
- Study data were drawn from the SITS, which combines observational patient data from more than 700 clinical centers in 35 countries. All patients in the database received alteplase intravenously for the treatment of acute ischemic stroke between 2002 and 2007. Patients older than 80 years and those with severe strokes were not included in the study.
- The dose of alteplase used was 0.9 mg/kg administered for 60 minutes, with an upper limit of 90 mg; 10% of the dose was given as a bolus.
- The current study compared patients receiving alteplase within 3 hours of symptom onset vs patients treated at 3 to 4.5 hours.
- The main outcomes of the study were the rates of symptomatic intracerebral hemorrhage at 24 hours and functional independence and mortality at 3 months after the stroke. Functional independence was defined by a modified Rankin scale of 2 or less at 3 months.
- 11,865 patients treated within 3 hours of symptom onset were compared with 664 patients treated between 3 and 4.5 hours. Treatment was started at a median of 55 minutes later in the cohort receiving later administration of alteplase.
- Comparing the late treatment vs early treatment groups, median age was 3 years younger (65 vs 68 years, respectively), stroke severity was slightly decreased, and rates of hypertension and hyperlipidemia were lower. More patients in the late treatment group were treated in centers with experience in thrombolysis.
- Half of patients in the late treatment group received alteplase within 15 minutes of the 3-hour treatment recommendation, indicating that most patients and centers were trying to adhere to the recommendations to treat within 3 hours. This relatively early treatment could blunt the effect of the main result of the study.
- There was a slight difference between the late treatment and early treatment groups in the rate of intracerebral hemorrhage (2.2% and 1.6%, respectively; adjusted odds ratio, 1.32), but this result failed to achieve statistical significance.
- There was also no significant difference between the early treatment and late treatment groups in mortality rate (12.7% and 12.2%, respectively; adjusted odds ratio, 1.15) and independence (58% and 56.3%, respectively; adjusted odds ratio, 0.93).
- There was no difference between the early treatment and late treatment groups in the primary cause of death, with cerebral infarction being the most common reason for death in both groups.
- Most patients with acute ischemic stroke do not receive thrombolysis, in large part because of failure to present to the emergency department within 3 hours of symptom onset. A previous pooled analysis suggested that thrombolysis at 3 to 4.5 hours after symptom onset was associated with a favorable outcome, whereas treatment after more than 4.5 hours was not.
- In the current study, thrombolysis for acute stroke with alteplase at 3 to 4.5 hours after symptom onset appeared to be similarly safe and effective as treatment within 3 hours of symptom onset.
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Thromboembolic Consequences of Subtherapeutic Anticoagulation in Patients Stabilized on Warfarin Therapy: The Low INR Study
http://www.medscape.com/viewarticle/578712
Nathan P. Clark, Pharm.D.; Daniel M. Witt, Pharm.D.; Thomas Delate, Ph.D.; Melissa Trapp, Pharm.D.; David Garcia, M.D.; Walter Ageno, M.D.; Elaine M. Hylek, M.D.; Mark A. Crowther, M.D.
Pharmacotherapy. 2008;28(8):960-967. ©2008 Pharmacotherapy Publications
Posted 09/10/2008
Abstract
Study Objective: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin.
Design: Retrospective, matched cohort analysis.
Setting: Centralized anticoagulation service in an integrated health care delivery system.
Patients: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age.
Measurements and Main Results: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05).
Conclusion: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.
PROFESS: Combination Therapy Falls Short of Noninferiority vs Clopidogrel News Author: Susan Jeffrey
Results of the largest secondary stroke prevention trial comparing the combination of aspirin and extended-release dipyridamole (Aggrenox/Asasantine, Boehringer Ingelheim) did not meet prespecified noninferiority criteria vs clopidogrel (Plavix, sanofi-aventis; Iscover, Bristol-Myers Squibb) in preventing stroke recurrence after a first event, although the difference between the agents was not statistically significant for the primary outcome of recurrent stroke.In a factorial design, the trial also examined the effect of early blood pressure lowering after a stroke using telmisartan (Micardis, Boehringer Ingelheim) vs placebo in the same patients and found there was no benefit with the addition of the angiotensin receptor blocker in prevention of stroke recurrence, at least during the 2.5 years of follow-up in this trial.
Finally, a third analysis showed no neuroprotective effect of either dipyridamole or telmisartan that were on board when recurrent strokes did occur in this trial, despite suggestive results from previous preclinical studies. Current guidelines in Europe and the United States recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole and clopidogrel are options for prevention of stroke recurrence, but there are no direct comparisons of the latter agents available to guide choices, Dr. Sacco said. The European and Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and European Stroke Prevention Study 2 (ESPS2) trials had previously compared aspirin vs aspirin and dipyridamole and shown the combination to be more effective than aspirin alone.
"In conclusion, for the antiplatelet part of this large trial, we were not able to meet our prespecified noninferiority criteria for the combination vs clopidogrel," Dr. Sacco said. The agents had similar rates of recurrent stroke and the composite of stroke, MI, or vascular death he noted. Major hemorrhagic events including intracranial bleeds were more frequent in the combination group, "however, the absolute risks were low and partially offset by fewer ischemic events, primary outcomes," he concluded. "The net benefits and risks were similar with the 2 agents."
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High-Risk Patients With Atrial Fibrillation Not Anticoagulated Before Stroke
http://www.medscape.com/viewarticle/580035
Results of a new study show that among high-risk patients with atrial fibrillation admitted to the hospital for a stroke, the vast majority were either not taking warfarin or were in subtherapeutic ranges at the onset of the stroke. In fact, only 10% of patients admitted with a first ischemic stroke were found to be receiving warfarin and were in a therapeutic range at the time of their stroke.
Cardioembolism resulting from atrial fibrillation accounts for approximately 1 in 6 ischemic strokes (1 in 4 in elderly patients) and is a potentially preventable cause of stroke-related disability, dementia, and death, the study authors write. Warfarin has been shown to reduce the risk for ischemic stroke by 67% and death by 25% vs a 22% reduction in stroke seen with aspirin.
To describe the problem of underuse, they analyzed data from the Registry of the Canadian Stroke Network, a prospective database of consecutive patients admitted to 12 designated stroke centers in Ontario between 2003 and 2007. Patients were included in this analysis if they were admitted with an acute ischemic stroke and had a known history of atrial fibrillation, were classified as high risk for systemic emboli according to published guidelines, and had no known contraindications to anticoagulation therapy.
The primary endpoints were the use of prestroke antithrombotic medications and international normalized ratio (INR) on admission. Among 597 patients admitted with a first ischemic stroke during this period, the strokes were disabling in 60% and fatal in 20%.In these patients, preadmission medications were either antiplatelet therapy or no medication in almost 60%.
- In patients with atrial fibrillation who present with a first ischemic stroke, 39% are receiving warfarin (29% subtherapeutic and 10% therapeutic), 30% are receiving a single antiplatelet agent, 2% are receiving dual antiplatelet therapy, and 29% are not receiving antithrombotic therapy.
- In patients with atrial fibrillation and a history of stroke or transient ischemic attack who present with a subsequent ischemic stroke, 57% are receiving warfarin (39% subtherapeutic and 18% therapeutic), 25% are receiving a single antiplatelet agent, 3% are receving dual antiplatelet therapy, and 15% are not receiving antithrombotic therapy.
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Anticoagulant and Antiplatelet Therapy for Endoscopic Procedures Reviewed
http://www.medscape.com/viewarticle/574397
Guidelines have been issued regarding proper anticoagulant and antiplatelet treatment of patients who undergo endoscopic procedures. The new recommendations, which were commissioned by the British Society of Gastroenterology in collaboration with the British Committee for Standards in Haematology and the British Cardiovascular Intervention Society, are reported in the May 9 issue of Gut.
:Anticoagulants are frequently prescribed, and use of antiplatelet agents is also increasing for ischemic heart disease and for patients with coronary artery stents. Many endoscopic procedures are associated with risk for hemorrhage, which may be further increased by patients receiving anticoagulant or antiplatelet therapy.
Although the American Society for Gastrointestinal Endoscopy has issued excellent guidelines, they offer limited guidance regarding the management of cardiac patients on antiplatelet agents. To supplement these guidelines and extend their scope, the British Society of Gastroenterology, in collaboration with the British Committee for Standards in Haematology and the British Cardiovascular Intervention Society, has issued guidelines regarding proper anticoagulant and antiplatelet treatment of patients who undergo endoscopic procedures.
- In acute GI hemorrhage, the immediate risk from bleeding may outweigh the risk for thrombosis from stopping anticoagulant or antiplatelet therapy. Each patient must be evaluated individually, and there is no unequivocal guidance that would apply to all situations.
- Depending on hemorrhage severity and the risk of stopping anticoagulation for patients with high-risk conditions, warfarin may be stopped with or without substitution of heparin.
- In patients with GI hemorrhage and coronary stents, clopidogrel should not be stopped without first consulting with a cardiologist, and interruption should be limited to 5 or fewer days.
- The first goal in acute GI hemorrhage should be early therapeutic endoscopic intervention to achieve hemostasis with minimal or no interruption of anticoagulant or antiplatelet therapy.
- Low-risk procedures are diagnostic endoscopic procedures, with or without biopsy, biliary or pancreatic stenting, and diagnostic EUS.
- High-risk procedures are colonoscopic polypectomy, ERCP with sphincterotomy, biliary or pancreatic stenting, endoscopic mucosal resection or endoscopic submucosal dissection, endoscopic dilatation of upper or lower GI strictures, endoscopic therapy of varices, percutaneous gastrostomy, and EUS with fine-needle aspiration.
- For discontinuation of anticoagulant therapy, low-risk conditions are prosthetic metal aortic valve, xenograft heart valve, AF without valvular disease, and more than 3 months after venous thromboembolism. High-risk conditions are prosthetic metal mitral valve, prosthetic heart valve and AF, AF and mitral stenosis, less than 3 months after venous thromboembolism, and thrombophilia syndromes.
- For discontinuation of clopidogrel, low-risk conditions are ischemic heart disease without coronary stents, cerebrovascular disease, or peripheral vascular disease. High-risk conditions are drug-eluting coronary artery stents within 12 months of placement and bare metal coronary artery stents within 1 month of placement.
- For low-risk endoscopic procedures, anticoagulation or antiplatelet therapy should be continued, but if warfarin is continued, INR should not exceed the therapeutic range.
- For high-risk endoscopic procedures in low-risk conditions, warfarin should be temporarily discontinued. Clopidogrel should be discontinued 7 days before the procedure, but aspirin should be continued. If the patient is not already taking aspirin, prescribing aspirin may be considered while clopidogrel is stopped.
- For high-risk endoscopic procedures in high-risk conditions, warfarin should be temporarily discontinued and substituted with LMWH. Patients should be told that risk for postprocedure bleeding is increased vs that in nonanticoagulated patients.
- Stopping clopidogrel should only be considered after discussion with the patient's cardiologist, and a gastroenterologist or surgeon should confirm that the endoscopic procedure is essential.
- If bare metal coronary stents were placed more than 1 month before endoscopy, clopidogrel could be temporarily discontinued.
- If drug-eluting coronary stents were placed more than 12 months before endoscopy, clopidogrel could be temporarily discontinued.
- If drug-eluting stents were placed more than 6 months before endoscopy and the procedure is deemed to be essential, then it may be safe to discontinue clopidogrel temporarily.
- Clopidogrel should be stopped 7 days before the procedure, but aspirin therapy should be continued. On the day following the procedure, clopidogrel should be restarted.
- In patients receiving anticoagulant or antiplatelet agents, acute GI hemorrhage is a high-risk situation in which the immediate risk to the patient from bleeding may outweigh the risk for thrombosis from stopping anticoagulant or antiplatelet therapy. However, each patient must be evaluated individually, and there is no unequivocal guidance that would apply to all situations.
- For low-risk endoscopic procedures, anticoagulation or antiplatelet therapy should be continued, but if warfarin is continued, INR should not exceed the therapeutic range. In high-risk endoscopic procedures in low-risk conditions, warfarin should be temporarily discontinued. For high-risk endoscopic procedures in high-risk conditions, warfarin should be temporarily stopped and substituted with LMWH. Stopping clopidogrel should only be considered after discussion with the patient's cardiologist.
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Novel Thrombolytic Microplasmin Safe in Acute Ischemic Stroke
http://www.medscape.com/viewarticle/581466
Phase 2 results with microplasmin, a novel thrombolytic agent that is thought perhaps to have some neuroprotective properties, have shown that the treatment was well tolerated and demonstrated "reasonable safety" when given out to 12 hours after symptom onset, researchers report.
In the thrombolytic system, plasminogen is activated into plasmin by tissue plasminogen activator (tPA), Dr. Thijs explained. Plasmin then further decreases fibrin into degraded peptides.
"In order to bypass this system, you could infuse plasmin directly," he said, but noted that plasmin is difficult to produce in sufficient quantities. "Therefore, the sponsor of this trial designed a recombinant drug called microplasmin, which is a truncated form of plasmin," he said. The drug retains all protease activity and is able to degrade fibrin.
In preclinical tests, microplasmin reduced infarct size in different stroke models "and was potentially less neurotoxic than tPA," Dr. Thijs noted. "Some studies suggest less breakdown of the blood-brain barrier, and this may lead to possible increased safety."
In this phase 2a trial, 40 patients with ischemic stroke from 8 centers in Austria, Germany, and Belgium were enrolled between 3 and 12 hours after symptom onset and randomized to receive placebo or 1 of 3 ascending doses of microplasmin. Treatment was given as a 15-minute intravenous bolus infusion of 1 mg/kg, followed by a 1-hour infusion of 1, 2, or 3 mg/kg, respectively. The first 8 patients enrolled received the lowest dose (6 active, 2 placebo); the next 16 received 2 mg/kg (12 active, 4 placebo); and the last 16 patients received the highest dose (12 active, 4 placebo). .
In terms of safety, there was 1 symptomatic intracerebral hemorrhage in the highest-dose group, which was fatal, and none with placebo. A second death occurred in the treated group, from pneumonia, toward the end of follow-up. There were no deaths in the placebo group. There were no cases of systemic bleeding with treatment vs placebo.
Although underpowered to look at efficacy, they did examine some surrogate biomarkers that might give some hint of the drug's activity, including fibrinogen and MMP, he noted. They found significant depletion of fibrinogen with treatment in a dose-dependent fashion vs placebo. MMPs increased significantly in the placebo group, while in the treated group there was an again dose-dependent reduction.
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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