New In Coagulation

ISMP Medication Safety Alert! Warfarin by Generic Name. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/linkwarning/linkwarning.cfm?link=http%3A%2F%2Fwww%2Eismp%2Eorg%2Fnewsletters%2Facutecare%2Farticles%2F20080925%2D1%2Easp
A recent report by the Institute for Safe Medication Practices (ISMP) notes that some health professionals and patients may not realize that Jantoven is a brand name for the drug warfarin. That could result in inadvertently prescribing and dispensing two warfarin-containing medications for the same patient. ISMP cites the case of a patient who had been taking warfarin at home and continued the drug while in the hospital. On discharge, the physician instructed that the patient continue warfarin at home, and he wrote a new warfarin prescription. The community pharmacy dispensed Jantoven without discussing the nature of the drug with the patient or asking whether the patient was already taking warfarin. The patient, not realizing that the newly prescribed drug was warfarin by another name, took both medications, and that resulted in a severely elevated INR.
More Heparin Dosing Errors with Neonates

ISMP Medication Safety Alert! Heparin Errors Continue Despite Prior, High-Profile, Fatal Events. July 17, 2008.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/linkwarning/linkwarning.cfm?link=http%3A%2F%2Fwww%2Eismp%2Eorg%2Fnewsletters%2Facutecare%2Farticles%2F20080717%2Easp
The Institute for Safe Medication Practices (ISMP) reports that serious dosing errors continue to occur when heparin is administered to neonates. ISMP cites an incident in Texas where as many as 17 infants in a neonatal intensive care unit received heparin overdoses. According to ISMP's analysis, the infants may have received up to 100 times more heparin than intended. ISMP notes that when preparing solutions in the pharmacy, calculation errors are especially prone to occur when heparin is stocked in unfamiliar concentrations e.g., for example, if the pharmacy were to switch from vials containing 1,000 units per mL to vials containing 10,000 units per mL. The possibility of a dosing error increases if the pharmacy fails to verify the concentration of a solution before dispensing.Another problem, according to ISMP, is that there is no standard dosing protocol when it comes to using heparin for maintaining the patency of venous and arterial lines in neonates. This means a hospital might have to stock heparin solutions in several concentrations ranging from 0.5 units per mL to 10 units per mL, and this can make errors more likely. ISMP notes that some hospitals use a refractometer to measure the specific gravity of the solutions as they are prepared, and that spectroscopy equipment can also be used to check accuracy. This can differentiate between abnormally high concentrations and the lower concentrations needed for babies. According to ISMP, other hospitals are choosing to outsource the preparation of neonatal heparin flush products, using commercial manufacturers who meet FDA Good Manufacturing Practices and assay their solutions before distribution.


CDC Provides Details on Heparin Contamination Investigation
http://www.medscape.com/viewarticle/584709Investigators from the US Centers for Disease Control and Prevention (CDC), in partnership with academic researchers, have published the results of their investigation linking the adverse reactions reported during the heparin contamination scare earlier this year to specific vials of the drug, contaminated with oversulfated chondroitin sulfate (OSCS) [1]. Previous work identified OCSC as the likely contaminant in heparin and its biological effects in the laboratory setting.
According to the FDA, 93 deaths and hundreds of adverse reactions following heparin administration were reported between January 1, 2008 and March 31, 2008, although cause of death was uncertain in 45 of these deaths. On January 17, 2008, the FDA issued the first heparin recall of vials manufactured by Baxter Healthcare. A second, broader Baxter heparin recall took place at the end of February, and since then, the FDA has issued a total of 13 recalls of medical products containing heparin. The problem, however, has not completely gone away: as recently as November 6, the FDA seized 11 lots of heparin from Celsus Laboratories in Cincinnati, OH, after products were found to contain OSCS.
How to Test for Heparin Safety
According to an FDA spokesperson, the agency, working with "academic partners," has helped develop two methods to test for heparin contamination, based on nuclear magnetic resonance, capillary electrophoresis, enzymatic kinetics, and bioassays. The major heparin suppliers to the US market have committed to using these tests to screen heparin sources before distributing heparin products in the US.
A letter also appearing in this week's Journal describes the use of prothrombin time to detect OSCS contamination in both unfractionated and low-molecular-weight heparins [4]. The writers note that OSCS at certain threshold concentrations affects prothrombin time and that a test based on prothrombin time might provide a simpler, more sensitive screening tool for quality control of heparins and an easy, fast assay in the clinical setting to check for heparin safety when patients
Heparin made by Baxter Healthcare was found at every single one of the affected facilities but was present at only 4.3% of the control facilities. Vials collected at the facilities also were found to contain OSCS. According to Patel, the CDC investigation confirmed that there was a "strong epidemiological association" linking the initial findings--which suggested that OSCS was the culpable contaminant in Baxter Healthcare heparin--and the symptoms seen clinically. Although OSCS had already been accepted to be the likely source of the problem, the CDC investigation provides a missing link.

ASH 2008: Prophylaxis Halves Risk for Thromboembolic Events in Cancer Patients on Chemotherapy
http://www.medscape.com/viewarticle/584897
Cancer patients receiving chemotherapy are known to be at high risk for thromboembolic events, but at present little is done about this. Now a large trial showing that prophylaxis with an anticoagulant can halve this risk, presented here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition, might encourage oncologists to think about taking some action. The results come from PROTECHT, a placebo-controlled study of nadroparin (Fraxiparine, Sanofi) for the prophylaxis of thromboembolic events in more than 1000 cancer patients receiving chemotherapy.
PROTECHT was conducted in 1166 patients with metastatic or locally advanced cancer, and they were randomized 2:1 to receive nadroparin or placebo, both administered by subcutaneous injection.The primary outcome of the study was a clinically overt thromboembolic event, either venous or arterial, which included deep vein thrombosis of the upper and lower limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infraction, ischemic stroke, acute peripheral thromboembolism, and unexplained deaths of possible thromboembolic origin.
The risk of having 1 of these events was nearly halved, from a rate of 3.9% in the placebo group (15 events in 381 patients) to a rate of 2.1% in the nadroparin group (16 events in 769 patients). The relative risk reduction was 49.6%, with an interim-adjusted P value of .024,The incidence of minor bleeding was similar in both groups - 7.4% with nadroparin and 7.9% with placebo - and the risk for a major bleed was increased only slightly in the nadroparin group (5 episodes in 769 patients; 0.7% vs 0% in the placebo group.).


ASH 2008: Addition of Rituximab Doubles Response in ITP
http://www.medscape.com/viewarticle/584895
In the treatment of idiopathic thrombocytopenic purpura (ITP), the addition of rituximab (MabThera, Roche) to dexamethasone doubles the response rate, compared with dexamethasone alone, which is currently the standard treatment. The combination regimen offers an effective option prior to splenectomy for some patients, and could offer the possibility of a cure for others,
Rituximab is not currently approved for use in ITP, but the results from this trial could lead to it being used, off label, for such patients. "This is an important finding and it will definitely change clinical practice," commented J. Evans Sadler, MD, PhD, from the Division of Hematology at Washington University, in St. Louis, Missouri. "It could save some patients from having to undergo a splenectomy," he added. Dr. Sadler, who was not involved in trial, is a cochair of the ASH Scientific Program Committee.
Rituximab is a monoclonal antibody targeting CD20 on the surface of B cells, and is approved for use in non-Hodgkin's lymphoma and for severe rheumatoid arthritis in combination with methotrexate. Another potential use is in the treatment of chronic lymphocytic leukemia. Two large trials showing its efficacy in this patient population, when used in combination with fludarabine and cyclophosphamide, were presented at this year's ASH meeting, and were also predicted to change clinical practice.
Dexamethasone was administered at a dose of 40 mg over 4 days, a regimen that has become the standard first-line treatment for adult patients with chronic ITP. Rituximab was added on, at a standard dose of 375 mg/m2 administered intravenously on days 7, 14, 21, and 28.The primary end point was sustained response rate (i.e., a platelet count of more than 50 x 10x9/L after 6 months). This was significantly higher in patients treated with rituximab and dexamethasone than in those treated with dexamethasone alone (63% vs 36% [P = .004] on an intention-to-treat analysis and 85% vs 39% [P < .001] on a per-protocol analysis). Of the 52 patients who were initially allocated to receive dexamethasone alone, 27 failed to achieve an initial or sustained response, and they received salvage treatment with rituximab plus dexamethasone. They achieved a sustained response rate of 56% on an intention-to-treat analysis and 59% on a per-protocol analysis.The response to treatment was rapid, with an initial response (i.e., a platelet count of 50 times 109/L or more by day 30) in 44% of patients on the combination and in 25% on dexamethasone alone in an intention-to-treat analysis. American Society of Hematology (ASH) 50th Annual Meeting and Exposition: Abstract 1. Presented December 7, 2008. Abstract


ASH 2008: Dose of Platelet Transfusions Can Be Halved
http://www.medscape.com/viewarticle/584894
The dose of platelets given by transfusion to cancer patients who become thrombocytopenic can be halved without increasing the risk of bleeding, according to the results of a large study reported here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition. Several experts have predicted that this finding will change clinical practice.
The PLADO study involved 1350 patients, and "the size of this trial permits us to say that this is what we should be doing now," Dr. Slichter commented at an official ASH press conference. "I will be recommending that clinicians reduce the dose of platelets in transfusions, as the risk is not there."The PLADO trial set out to determine the optimal prophylactic platelet-dose strategy to prevent bleeding in thrombocytopenic patients. It compared 3 different doses of platelets given by transfusion: a low dose (1.1 x 1011 platelets/m2), a medium dose (2.2 x 1011 platelets/m2), and a high dose (4.4 x 1011 platelets/m2). The medium dose corresponds most closely to the standard dose currently used.Patients enrolled in the trial had hypoproliferative thrombocytopenia and were expected to be hospitalized with platelet counts of 10,000 mL or less for more than 5 days. This was the trigger for a platelet transfusion, which was given prophylactically on days when platelet counts reached or fell to below this level.
The results show that there was no significant difference in the risk of bleeding across any of these doses, either in World Health Organization grade 2 bleeding, which was the primary end point, or in the more severe cases.
American Society of Hematology (ASH) 50th Annual Meeting and Exposition: Abstract 285. Presented December 6, 2008.


Transfusions Linked to Venous, Arterial Thrombotic Events in Cancer Patients
http://www.medscape.com/viewarticle/584511
Anemia is observed in 30% to 90% of patients with cancer. Erythropoiesis-stimulating agents have been restricted in their use because of the risk for thromboembolic complications and reduced survival, and RBC and platelet transfusions have been used as an alternative, but their safety has not been well studied.
This is a retrospective cohort study of patients in a large database from 60 US medical centers to examine the association between RBC and platelet transfusions and the risk for venous thromboembolism, arterial thromboembolism, and mortality in patients with cancer who were admitted to the hospital between 1995 and 2003.
Study Highlights
Included were discharge summaries of patients admitted to hospitals that were accessed via the University HealthSystem Consortium.
Only data reporting RBC transfusions in at least 2% of admissions and platelet transfusions in at least 0.1% of admissions during every year were included in the analysis.
This represented the lowest quartile of all consortium medical centers.
The International Classification of Diseases, Ninth Revision, code classification was used to identify cases of venous thromboembolism, arterial thromboembolism, and treatment and cancer diagnoses.
Patients with multiple hospitalizations were identified, and only a single randomly chosen hospitalization per patient was included.
The study population consisted of 504,208 patients with cancer admitted to 60 US medical centers.
More than one third were 65 years or older, more than two thirds were white, 12.3% were black, and 4.6% were Hispanic.
Venous thromboembolism occurred in 4.2%, with 3.5% having deep vein thrombosis and 1.1% having pulmonary embolism.
Arterial thromboembolism occurred in 3.3% of patients.
Within the study population, 14.7% received either packed RBCs or platelet transfusions.
14.0% received at least 1 RBC transfusion, and 3.0% received at least 1 platelet transfusion.
2.3% received both RBC and platelet transfusions.
0.6% received autologous whole-blood or RBC transfusions.
Venous thromboembolism occurred in 7.2% receiving RBC transfusions only, 6.6% receiving both RBC and platelet transfusions, and 6.4% receiving platelet transfusions only.
These rates were higher vs the 3.7% venous thromboembolism rate and 3.0% arterial thromboembolism rate in hospitalized patients who did not receive transfusions.
Rates of venous thromboembolism and arterial thromboembolism were low in those who received autologous transfusions.
For venous thromboembolism, RBC transfusion was associated with an OR of 1.60 and platelet transfusions with an OR of 1.20.
Other variables significantly associated with venous thromboembolism were older age (> 65 years), female sex, use of chemotherapy, primary cancer site, use of venous catheters, and comorbidities.
For arterial thromboembolism, RBC use was associated with an OR of 1.53 and platelet transfusion with an OR of 1.55.
Other variables increasing the risk for arterial thromboembolism were older age, male sex, primary cancer site, use of venous catheters, and comorbidities.
Death during hospitalization occurred in 33,924 patients (6.7%).
The in-hospital mortality rate was higher in those receiving RBC transfusions (11.9%) and platelet transfusions (23.1%).
The in-hospital mortality rate was also significantly higher for those with venous thromboembolism (16.7%) and arterial thromboembolism (19.3%).
RBC transfusions (OR, 1.34) and platelet transfusions (OR, 2.40) were independently associated with an increased risk for in-hospital mortality after adjusting for variables.
Other variables for mortality included older age, primary site, nonwhite race, venous thromboembolism, arterial thromboembolism, and the presence of comorbidities.
The authors concluded that use of RBC or platelet transfusions in patients with cancer was associated with an increased risk for venous thromboembolism, arterial thromboembolism, and in-hospital mortality.


Tinzaparin Mortality Risk Not Limited to Patients Older Than 90 Years
http://www.medscape.com/viewarticle/584647
The increased risk for mortality associated with tinzaparin sodium (Innohep, Pharmion Corp) may not be limited to patients aged 90 years and older, the US Food and Drug Administration (FDA) said yesterday in a news release. The warning was based on data from the European Innohep in Renal Insufficiency study of patients aged 70 years and older with renal insufficiency - a sample group that is often underrepresented in clinical trials. The study was terminated early in February 2008 after 13% of tinzaparin-treated patients died compared with 5% of those receiving unfractionated heparin.
Currently available information has revealed no clear pattern as to the causes of death, but they do not appear to be related to either over- or underdosing, according to an alert sent from MedWatch, the FDA's safety information and adverse event reporting program. Although they have not been ruled out, manufacturing issues likewise seem unlikely. Information on the study is still being collected by the FDA for analysis, and relevant changes to the safety labeling for tinzaparin are expected to ensue.
In the interim, healthcare professionals are advised to consider alternative treatments to tinzaparin when treating patients aged 70 years and older with renal insufficiency. Tinzaparin is a low-molecular-weight heparin product indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium.
Adverse events related to use of tinzaparin should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.


Doppler Screening Program Cuts Strokes in Children With Sickle Cell Disease
http://www.medscape.com/viewarticle/585030
Transcranial Doppler (TCD) screening of children with sickle cell disease and treatment of those at high risk can markedly reduce the stroke rate in this patient population, according to study findings presented at the American Society of Hematology annual meeting in San Francisco.
With the screening protocol, annual TCD follow-up is recommended for patients with a normal result (<170 name="Supporter">
ACS, Deep-Vein Thrombosis Linked to Idiopathic Pulmonary Fibrosis
http://www.medscape.com/viewarticle/585067
Clinical Context
Previous evidence suggests that IPF may be associated with an increased risk for cardiovascular disease and that median survival after diagnosis is approximately 3 years, with no treatments shown to improve survival. IPF is a significant cause of morbidity and mortality in the United States and Europe, mostly from progression of underlying lung disease.
The associations of IPF with lung cancer, cardiovascular disease, and other conditions may help clarify the cause and/or pathophysiology of IPF. Understanding these associations may help determine whether heightened surveillance and/or prevention strategies are required in people with IPF and whether management guidelines should be updated accordingly.
Study Highlights
The goal of this study was to quantify the risk for cardiovascular disease before and after the diagnosis of IPF.
The investigators analyzed computerized primary care data from the Health Improvement Network to quantify the relative risk of having a cardiovascular event before or after receiving a diagnosis of IPF.
Cardiovascular events were defined as ACS, angina, atrial fibrillation, DVT, and cerebrovascular accident.
Rates of cardiovascular events in 920 patients with IPF were compared vs events in 3593 general-population control subjects matched for age, sex, and community.
For participants with IPF, mean age at diagnosis was 71 years, and 62% were men.
Compared with control subjects, case patients with IPF were less likely to be prescribed statins and beta-blockers and were more likely to be prescribed ACE inhibitors, amiodarone, and warfarin.
In the period before the diagnosis of IPF, case patients vs matched control subjects had an increased risk for ACS (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.15 - 2.03), angina (OR, 1.84; 95% CI, 1.48 - 2.29), and DVT (OR, 1.98; 95% CI, 1.13 - 3.48).
During the follow-up period after the diagnosis of IPF, the risk for ACS was markedly increased (rate ratio [RR], 3.14; 95% CI, 2.02 - 4.87), as was the risk for DVT (RR, 3.39; 95% CI, 1.57 - 7.28).
These increased risks for cardiovascular events before and after the diagnosis of IPF were not confounded by smoking habit or affected by age or sex.
If a cohort of 100 people with newly diagnosed IPF were observed for 3 years, they would have 6 acute coronary events and 2 DVTs, whereas matched control subjects would have 3 acute coronary events and 1 DVT.
The investigators concluded that people with IPF have an increased risk for vascular disease vs the general population and that this effect was most pronounced for ACS and DVT after IPF was diagnosed.
The investigators suggest that these findings provide further support for a possible trial of anticoagulation in people with IPF.
Limitations of the study include possible ascertainment bias, which may have led to an overestimate of the association between cardiovascular disease events and the presence of IPF.

Testing and Acting on Clopidogrel Nonresponsiveness: Intense Interest and Confusion
http://www.medscape.com/viewarticle/585595
Variable responsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is the "minifocus" of the December 2008 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions. The collection of studies, several of which test a course of action based on tests of low responsiveness, speaks to the intense interest in the topic but also to the lack of large randomized trials validating the different assays and pointing the way forward.
"The majority of studies--although certainly not all--suggest that clopidogrel nonresponsiveness seems to correlate with a higher risk of ischemic events down the road," he said. But the question is whether clopidogrel nonresponsiveness is a risk marker, like CRP, or a modifiable risk factor, Bhatt continued. "That part is not so clear. It's logical to make that leap and think that if a patient is hyporesponsive, improving their degree of response should help. For many clinicians, that's their gut feeling, but the thing missing in the chain of evidence is a clinical trial showing that you can define, with an easy test, the patient population that is hyporesponsive to antiplatelet therapy and then modify their therapy based on that test in a way that improves their outcomes."
In another study, Dr Thomas Cuisset (CHU Timone, Marseille, France) and colleagues report that patients with low responsiveness to clopidogrel who were given a GP IIb/IIIa inhibitor during PCI had lower rates of cardiovascular events within the first 30 days postprocedure than low responders who were randomized to usual care (600-mg clopidogrel pre-PCI) [3]. Again, researchers report no increased major bleeding risk among patients given the GP IIb/IIIa inhibitor boost.
In two separate papers [4,5] also appearing in this issue, Dr Patrick Gladding (Auckland City Hospital, New Zealand) and colleagues report that increased loading and maintenance doses of clopidogrel appear to improve overall platelet responsiveness but that a strategy of increasing the doses might benefit only patients with a decreased ability to metabolize the drug. Their second paper identifies carriers of specific genetic variants--the CYP2C19*2 and CYP2C19*4 alleles--who showed reduced platelet inhibition after a 600-mg loading dose of clopidogrel but responded to higher loading and maintenance doses. They propose that genotyping for specific gene polymorphisms may help physicians to individualize clopidogrel treatment.
According to Bhatt, there are probably a dozen different tests currently available for assessing antiplatelet-therapy responsiveness and no consensus on which one might be preferable in any given circumstance, leading to "intense confusion" over the whole issue of clopidogrel responsiveness.
Several large and small studies are under way looking specifically at different assays and tests, he said, pointing in particular to the Gauging Responsiveness with a Verify Now Assay-Impact on Thrombosis and Safety (GRAVITAS) trial, randomizing patients deemed nonresponsive to clopidogrel on point-of-care testing to receive higher dosing of clopidogrel.
Important information will also come from studies like CURRENT-OASIS 7 (standard vs a higher dose of clopidogrel), A Study of Platelet Inhibition and Patient Outcomes (PLATO) (AZD6140 [AstraZeneca] vs clopidogrel), and Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) (looking at the more potent drug, cangrelor [the Medicines Company], vs standard therapy, with Bhatt as a co-principal investigator), Bhatt said.
"These other trials will help to indirectly answer this question, even though they are not specifically examining resistance," he explained. "If a broad strategy of using more intense agents or higher doses is better than less intense antiplatelet agents, then there would be no need to first test for responsiveness. On the other hand, if they come back with a mixed picture, then that would argue in favor of testing."

One in 10 Stops Taking Clopidogrel Because of "Nuisance Bleeding"
http://www.medscape.com/viewarticle/586019 New observational data highlight the problem of "nuisance bleeding" on clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) therapy following stent implantation, with as many as 85% of patients experiencing easy bruising, bleeding from small cuts, and minor hemorrhages from broken capillary vessels [1].Importantly, more than one in 10 of patients stops taking clopidogrel as result of this superficial, or nuisance, bleeding, report investigators.
Nuisance bleeding, defined as easy bruising, bleeding from small cuts, petechia, and ecchymosis, is often not on a clinician's radar despite the adverse impact on a patient's quality of life. Among 2360 unselected patients who underwent successful stent implantation at their center, 32.4% reported bleeding events. Of these events, more than 85% of patients reported nuisance bleeds, whereas 13.6% were internal and 0.7% alarming bleeds. Among patients who reported nuisance bleeding, 70% experienced bleeding on a daily basis. As a result of nuisance bleeding, 11% of patients discontinued clopidogrel.

Abciximab Not Beneficial in Patients With Stroke Symptoms on Awakening
http://www.medscape.com/viewarticle/586003
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To assess the safety and possible efficacy of abciximab in the treatment of patients with wake-up stroke, the researchers analyzed data from the Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II). Of 801 patients randomized in AbESTT-II, 43 had wake-up strokes; of these, 22 received abciximab and 21 received placebo.The rate of symptomatic intracranial hemorrhage within 5 days or at discharge was higher among abciximab-treated patients in the wake-up group (13.6%) than abciximab-treated patients in the non-wake-up group (4.0%, p = 0.07). The bleeding rate exceeded the prespecified safety margins and resulted in early termination of recruitment into the wake-up group.
Even so, those patients already enrolled completed regularly scheduled assessments. The researchers found that the rate of favorable outcomes at 3 months was significantly lower among abciximab-treated patients in the wake-up group compared to abciximab-treated patients in the non-wake-up group (9.3% versus 29.2%, respectively; p = 0.005).
Stroke 2008;39:3277-3282.

Warfarin Cuts Risk of Systemic Embolism in Patients With Atrial Fibrillation
http://www.medscape.com/viewarticle/585919While the value of warfarin for stroke prevention in patients with AF is well documented, a possible effect of anticoagulants on the risk of systemic embolism has not been examined, Dr. Ljubica V. Andersen from Aarhus University Hospital, Denmark, and co-investigators note in the December issue of the journal Heart.
The clinicians conducted a meta-analysis of 15 relevant studies, published between January 1989 and November 2007, including a total of 16,058 patients with 128 systemic embolic events and 371 major bleeding events.
Compared with antiplatelet agents, warfarin therapy lowered the risk of systemic embolism by 50% (odds ratio, 0.50) without increasing the risk of major bleeding (odds ratio, 1.07).
Warfarin compared with placebo resulted in a risk reduction of 71% (OR, 0.29) but with a higher risk of major bleeding with warfarin (OR, 3.01).
Results of a comparison of warfarin with low-dose warfarin (OR, 1.52) or low-dose warfarin with aspirin (OR, 1.00) were inconclusive, the investigators say, owing to a small number of events in the warfarin versus low-dose warfarin trial and the combination of low-dose warfarin and aspirin trials.
Heart 2008;94:1607-1613.



Genetic Variant Linked With Worse Clinical Outcomes in MI Patients Treated With Clopidogrel
http://www.medscape.com/viewarticle/585914
Acute-MI patients who possess the genetic variant linked previously with variability in the antiplatelet response to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) are at an increased risk of death, recurrent MI, and urgent coronary revascularization when placed long-term on the antiplatelet regimen. The variability in the gene that encodes the cytochrome P450 2C19 enzyme is thought to contribute to the effectiveness of clopidogrel as an antiplatelet agent. This enzyme is active in the biochemical pathway that converts clopidogrel into an active metabolite, and the loss-of-function polymorphism, known as CYP2C19*2, is associated with reduced clopidogrel responsiveness.
Publishing findings from the French Registry of Acute ST-Segment Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) study online December 22, 2008 in the New England Journal of Medicine, the investigators show that patients carrying any two of the CYP2C19 loss-of-function alleles, which included CYP2C19*2, CYP2C19*3, CYP2C19*4, or CYP2C19*5, were at a significantly greater risk of death, MI, or stroke.
A third study, from the Thrombolysis in Myocardial Infarction (TIMI) study group, showed that, among clopidogrel-treated subjects, carriers of the reduced-function CYP2C19 alleles had a more than 50% increased risk in the primary end point of death from cardiovascular causes, MI, or stroke, when compared with noncarriers, as well as a threefold increase in the risk of stent thrombosis [3].
The CYP2C19 variant is extremely common, occurring in 30% of individuals of European ancestry, 40% of individuals of African ancestry, and in more than 50% of individuals of Asian ancestry.
Sources
Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2008; DOI:10.1016/S0140-6736(08)61845-0. Available at: http://www.thelancet.com/.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; DOI 10.1056/NEJMoa0808227. Available at: http//www.nejm.org.
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; DOI: 10.1056/NEJMoa0809171. Available at: http://www.nejm.org/.
Storey R. Clopidogrel in acute coronary syndrome: to genotype or not? Lancet 2008; DOI:10.1016/S0140-6736(08)61846-2. Ava


ASH 2008: Anticoagulants: A New Therapy for Cancer?
http://www.medscape.com/viewarticle/585751
Heparin has been used as an anticoagulant for decades, but growing evidence suggests that the anticoagulant might have anticancer properties. Preliminary experiments have shown that it may reduce the metastatic spread of some types of cancer. Experimental evidence has consistently demonstrated that a single dose of heparin given at the right time attenuates metastasis in mice. Retrospective studies and other analyses have also shown that heparin therapy likely improves prognosis in humans.But whether the antimetastatic properties of heparin would ever be fully investigated in a prospective study remains unknown.
The association between cancer and activation of blood coagulation was first described more than 100 years ago. The hypercoagulable state that is frequently seen among cancer patients appears not only to act as an important risk factor for thrombosis but might also play a role in disease progression. It has thus been hypothesized that anticoagulants may have an antineoplastic effect in this setting.
Experience with the effects of heparin on human malignancy is primarily limited to settings in which it was given either to prevent or to treat thrombosis in cancer patients. Meta-analyses comparing unfractionated heparin and low-molecular-weight heparin (LMWH) for treatment of deep-vein thrombosis have shown substantial improvement in cancer outcome in the subset of patients randomly assigned to receive LMWH.
Heparin is a natural product that is composed of a complex polydisperse mixture of highly sulfated glycosaminoglycan chains, of which only a fraction bind to antithrombin. Previously, Dr. Varki and colleagues reported that heparin has an unrelated biological effect in inhibiting P- and L-selectin binding to their natural ligands. Clinical trials using vitamin-K antagonists showed no major effect on cancer survival in most studies, so the heparin effect on cancer may not be due primarily to its anticoagulant function but rather to inhibition of P- and L-selectin. Also, other known heparin effects, such as cytokine binding, inhibition of thrombin generation, and inhibition of heparinases, may also be beneficial in cancer.
Researchers in the United Kingdom are conducting a heparin study with patients who have both small-cell and non-small-cell lung cancer. An ongoing Canadian trial is examining the efficacy of heparin in ovarian cancer, and researchers in Amsterdam are studying heparin in prostate, pancreatic, and non-small-cell lung cancer.
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American Society of Hematology 50th Annual Meeting and Exposition. Presented December 7, 2008.