New In Coagulation

FDA Seizes Contaminated Heparin from a Cincinnati Manufacturer

As part of the U.S. Food and Drug Administration's ongoing efforts to ensure that heparin for patients remains safe, the government today seized 11 lots of heparin from Celsus Laboratories Inc. in Cincinnati, Ohio. The five lots of Heparin Sodium Active Pharmaceutical Ingredient (API) and six lots of Heparin Lithium were seized at the FDA's request by U.S. Marshals. These products, which were manufactured from material imported from China, had been found by the agency to be contaminated with over-sulfated chondroitin sulfate (OSCS), a substance that mimics heparin's anticoagulant activity.
OSCS contaminant in injectable drug products containing heparin has been linked to multiple adverse events and deaths initially reported to the FDA in January 2008. Since then, the FDA has put in place a comprehensive inspection and import controls program and has acted to remove from the market heparin materials and products contaminated with OSCS. The seized Celsus heparin - which had entered the United States before the establishment of import controls for the drug - was tested for the presence of OSCS as part of this FDA effort.
To date, the agency has initiated 13 recalls of multiple contaminated medical products containing heparin from several companies.

AHA 2008: Tailoring Clopidogrel Loading on the Basis of Responsiveness Testing Reduces Stent Thrombosis
http://www.medscape.com/viewarticle/583332
Shelley Wood A strategy of measuring platelet responsiveness and tailoring clopidogrel as needed can reduce the rate of early stent thrombosis in patients undergoing PCI, new research shows. The results support a strategy of stratifying patients into one of three groups--good responders, low responders, or "resistants"--whose clopidogrel dose could be tailored as needed.
Others, however, point out that cardiologists have not yet agreed what test is the best in terms of measuring how well patients are responding to antiplatelet therapy or on the best strategy for acting on any information gleaned.
Paganelli et al screened 1122 patients undergoing nonemergent PCI for clopidogrel responsiveness, after they'd received their 600-mg loading dose (plus 250-mg aspirin). Responsiveness was defined by a vasodilator-associated stimulated phosphoprotein (VASP) index of 50% or greater, based on a test that measures the extent to which clopidogrel binds, in vivo, to the P2Y12 platelet-surface chemoreceptor. In all, 429 patients deemed to have reduced responsiveness were ultimately randomized to the control group, receiving a maintenance dose of clopidogrel (75 mg), or to a VASP-guided loading dose of up to three additional loading doses of 600 mg every 24 hours until VASP was reduced below 50% pre-PCI.
Thirty-day definite stent thrombosis postprocedure--the primary end point of the study--was significantly reduced in patients in the VASP-guided group as compared with controls, with almost all stent thromboses occurring in the first seven days. There were statistically nonsignificant trends toward reduced cardiovascular death and reduced repeat revascularizations and a significantly reduced risk of MI in the VASP-guided group. Overall MACE was, as a result, significantly lower in the VASP-guided arm of the study. There were no differences in bleeding rates in the VASP-guided group


AHA 2008: New Factor Xa Inhibitor Rivaroxaban Moves Into Phase 3 for ACS
http://www.medscape.com/viewarticle/583315
Lisa Nainggolan : A phase 2 trial with a novel oral factor Xa inhibitor rivaroxaban (Johnson & Johnson/Bayer) has demonstrated the feasibility of triple therapy for patients with acute coronary syndromes, showing a trend toward improved efficacy with the drug in addition to aspirin and clopidogrel. But there was a dose-dependent increase in bleeding using this approach, The ATLAS ACS-TIMI 46 trial identified two doses of rivaroxaban--2.5 mg and 5 mg twice daily--that will be taken forward into a phase 3 trial, Gibson said. This study is slated to begin next month, will enroll up to 16 000 patients, and is estimated to last around 33 months. Rivaroxaban is one of several potential new oral anticoagulants in development that are set to become the long-awaited replacements for warfarin. First indications will be in preventing venous thromboembolism after surgery, but these agents are also being developed for the prevention of stroke in atrial fibrillation patients and, as in this study, for the treatment of ACS. Warfarin has not been used in clinical practice in the setting of ACS, because of the difficulty of keeping patients in the target bleeding range.
The phase 2 ATLAS ACS-TIMI 46 trial, in which 3491 recent ACS patients (who were stabilized one to seven days after the index event) were treated with aspirin alone (n=761) or aspirin plus clopidogrel (n=2730), depending on the preferences of the treating physician. Patients were then further randomized to placebo or rivaroxaban in a number of dosing regimens and treated for six months: 5 mg, 10 mg, or 20 mg of rivaroxaban once daily or 2.5 mg, 5 mg, or 10 mg twice daily.


AHA 2008: JPAD: No Effect of Aspirin Primary-CV-Event Prevention in Diabetics
Steve Stiles
http://www.medscape.com/viewarticle/583346.

Study Highlights
This was a prospective, multicenter, randomized, open-label, controlled trial with blinded end point assessment.
2539 Japanese patients with diabetes without a history of CV disease were randomized to receive low-dose aspirin 81 to 100 mg daily (n = 1262) or no aspirin (n = 1277) for a mean of 4.37 years.
Mean age was 65 years, 55% were men, 20% were current and 40% were past smokers, mean body mass index was 24 kg/m2; median duration of diabetes was 7.3 years in the aspirin and 6.7 years in the nonaspirin group.
Diabetes was well-controlled in both groups with mean glycated hemoglobin levels of 7.1% in the aspirin and 7.0% in the nonaspirin group.
The primary end point was a composite of atherosclerotic events that included fatal and nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease.
Secondary end points consisted of individual events and mortality from CV and all causes.
Although the study was originally powered to detect a difference in events in the 2 groups, the overall rate of CV events was less than one third of the expected event rate of 52 per 1000 patients.
The dropout rate was 10% in the aspirin group.
The rate if CV events were 5.4% in the aspirin and 6.7% in the nonaspirin group with an HR of 0.80, which was not statistically significant.
Combined fatal coronary and cerebrovascular events were lower in the aspirin group with an HR of 0.10 (P = .0037).
There were no other significant differences in CV outcomes between the 2 groups.
In the subgroup of patients aged 65 years or older, the composite of CV events was 6.3% in the aspirin and 9.2% in the nonaspirin group for a significantly reduced risk (HR, 0.68; P = .047).
In patients younger than 65 years, there was no significant difference in the composite of CV events.
There was no increase in risk for hemorrhagic stroke in the aspirin vs nonaspirin group.
Risk for gastrointestinal bleeding was increased (12 events in the aspirin vs 4 events in the nonaspirin group with 4 cases of severe bleeding requiring transfusion in the aspirin group).
There was no increase in death from hemorrhagic stroke or gastrointestinal bleeding in the aspirin group.
The authors concluded that in contrast to patients without diabetes, use of aspirin for primary prevention was not associated with reduced risk for atherosclerotic events and larger trials with adequate power are needed to confirm this finding.
This finding extends the results of a previous meta-analysis showing lower benefit for CV protection among patients with diabetes vs those without diabetes.
The authors suggested that aspirin use for CV prophylaxis in patients with diabetes should be reexamined.

Cardiologist Questions Safety of Lilly's Prasugrel
http://www.medscape.com/viewarticle/583377\\\
Researchers have overestimated the ability to administer Eli Lilly and Co's experimental antiplatelet agent prasugrel without causing dangerous bleeding, a prominent cardiologist said on Monday.U.S. regulators in recent months have twice delayed a decision on whether to approve prasugrel, which is being developed in partnership with Daiichi Sankyo that would compete with Bristol-Myers Squibb Co's Plavix (clopidogrel).
Prasugrel proved far better able than Plavix to prevent dangerous blood clots in a large trial called Triton whose results were unveiled last year. However, it was associated with a far higher degree of serious bleeding than Plavix, raising concern whether the U.S. Food and Drug Administration would deem its potential benefits worth the risks.The Triton study involved patients who underwent percutaneous coronary interventions.
Researchers of the Lilly-sponsored trial had theorized that prasugrel could be safely given, as long as it was not taken by three groups shown to have the highest bleeding risk in the trial: patients weighing less than 130 pounds, those aged 75 or older, or those who had previous strokes or TIAs.In Triton, prasugrel was 19% more effective than Plavix in preventing cardiovascular death, nonfatal heart attacks and strokes, but it was 32% more likely to cause serious

THINRS: Home INR Monitoring as Effective as Clinic-Based Care
http://www.medscape.com/viewarticle/583500
Susan Jeffrey
Results of a new randomized comparison shows that weekly home international normalized ratio (INR) monitoring is safe but did not reduce stroke, major bleeds, or death when compared with monthly clinic-based INR testing. Home monitoring did increase the amount of time spent in the target therapeutic range as well as patient satisfaction with anticoagulation therapy, the researchers note.
Warfarin is an effective therapy but only if managed well, Dr. Jacobson pointed out during his presentation. Warfarin is often underutilized, and the quality of management can be poor. Frequent home INR monitoring with weekly patient self-testing is a promising strategy to improve outcomes, he said, because it increases test frequency, which might allow more rapid identification and correction of out-of-target-range INRs, and promotes engagement of patients with their own care.
In this trial, the researchers compared these 2 strategies, weekly patient self-testing (PST), using an interactive voice-response reporting system and Web-based local monitoring, and currently recommended practice: high-quality anticoagulation management (HQACM), with testing carried out monthly at a clinic.
The primary end point was an aggregate of stroke, major bleeds, and death. Over an average of 54 months and 8370 patient-years of follow-up, there were 544 primary end-point events - 237 deaths, 263 major bleeds, and 44 strokes - but there was no statistical difference in the number of events between the intervention groups.
In many cases, INR testing is done by off-site labs without point-of-care testing, and the coordination of how results are communicated first to the physician and then back to the patient is often suboptimal. Ideally, patients should get immediate feedback with this type of point-of-care device to minimize the risk for over- and undercoagulation and allow immediate correction of any problems. To compare patient self-care with a better standard of care than is often offered in the community is to potentially underestimate its benefit.


Experts Identify New Risk Factors for Perioperative Death and Stroke
http://www.medscape.com/viewarticle/583666
Study Highlights
The New York Carotid Artery Surgery Study is a population-based cohort of 9308 carotid endarterectomies performed by 482 surgeons in 167 hospitals on Medicare patients from January 1998 through June 1999 in New York State.
Exclusion criteria included patients with no carotid endarterectomy performed, same-side operations for restenosis, carotid endarterectomy combined with other major procedures, and patients without complete clinical risk factor data.
Detailed clinical data were abstracted from medical charts to assess sociodemographic, neurologic, and comorbidity risk factors.
Deaths and strokes within 30 days of surgery were confirmed by clinicians.
Multivariable logistic regression was used to identify independent patient risk factors.
Results demonstrated that the mean age was 74.6 ± 6.8 years (age range, 40 - 98 years), and 44.3% were women.
The indications for surgery included 71.5% of patients were asymptomatic, 18.9% had a carotid TIA, 9.3% had a stroke, and 0.3% had an acute syndrome.
95.4% underwent surgery for high-grade carotid stenosis (70% - 99%).
Within the 30 days of surgery, there were 106 deaths (1.14%) and 305 (3.28%) strokes.
The 30-day rate of death or stroke in asymptomatic patients was 3.01% vs 6.44% for symptomatic patients (P < .0001; OR for symptomatic patients, 2.22; 95% CI, 1.80 - 2.74). The 30-day rate of death or stroke was 2.71% in asymptomatic patients with no history of stroke or TIA, 4.06% in asymptomatic patients with a history of stroke or TIA, 5.62% in those undergoing surgery for carotid TIA, 7.89% of those with stroke, and 13.33% in those with crescendo TIA or stroke-in-evolution. In asymptomatic patients, those with a history of stroke or TIA had higher risks for combined death or stroke vs those with no history of cerebrovascular disease (4.06% vs 2.71%; P < .007). In symptomatic patients, those with stroke as the indication for surgery had a higher risk for complication vs those with TIA (7.89% vs 5.62%; P < .02; OR, 2.44; CI, 1.04 - 1.98). Significant multivariable predictors of death or stroke included age 80 years or older (OR, 1.30; 95% CI, 1.03 - 1.64), nonwhite (OR, 1.83; 95% CI, 1.23 - 2.72), admission from the emergency department (OR, 1.95; 95% CI, 1.50 - 2.54), asymptomatic but with a history of stroke or TIA (OR, 1.40; 95% CI, 1.02 - 1.94), TIA as an indication for surgery (OR, 1.81; 95% CI, 1.39 - 2.36), stroke as the indication (OR, 2.40; 95% CI, 1.74 - 3.31), crescendo TIA or stroke-in-evolution (OR, 3.61; 95% CI, 1.15 - 11.28), contralateral carotid stenosis 50% or more (OR, 1.44; 95% CI, 1.15 - 1.79), severe disability (OR, 2.94; 95% CI, 1.91 - 4.50), coronary artery disease (OR, 1.51; 95% CI, 1.20 - 1.91), and diabetes with insulin treatment (OR, 1.55; 95% CI, 1.10 - 2.18). The presence of a deep carotid ulcer was of borderline significance (OR, 2.08; 95% CI, 0.93 - 4.68). Limitations to this study were bias associated with an observational cohort study and no standard approach to presurgical or postsurgical assessment. Genomewide Association Study Finds Genetic Predictors of Warfarin Required Dose
http://www.medscape.com/viewarticle/583686

Genomewide association studies have identified another gene variant that influences individual variations in response to warfarin dosage. Warfarin, described as the 11th most widely prescribed drug worldwide, is an effective anticoagulant used in patients with stroke, myocardial infarction, and pulmonary embolism. However, among whites, the required dosage varies 10- to 20-fold between individuals. A dose that creates bleeding problems in some patients may fail to protect others against clotting disorders.
The clinical index of appropriate warfarin dose is a coagulation level known as the prothrombin time international normalized ratio (INR). The INR for a healthy person is 1.0, but for patients taking warfarin to reduce clotting, the target INR is 2.0 to 3.0. Lacking predictive information about genetic and nongenetic factors influencing a patient's warfarin response, physicians determine doses empirically and initially may err in either direction.
Polymorphisms in VKORC1, the drug target of warfarin, may alter gene expression and explain approximately 30% of variation in warfarin response. Variants in CYP2C9, a gene coding for a liver enzyme that metabolizes warfarin, account for about 12% of the dose variation. Factors such as age and sex explain another 15% of the variation. A study in press, involving 1523 Swedish patients, assessed patient benefits of forecasting the required warfarin dose.
The current GWAS genotyped 1053 Swedish patients in the Warfarin Genetics (WARG) cohort and determined the mean warfarin dosage required to establish an INR of 2.0 to 3.0 in each subject. Doses ranged from 5.0 to 107.0 mg/week. Univariate regression analysis found VKORC1 and CYP2C9, previously identified, and multiple regression analysis identified a third gene associated with response to warfarin: CYP4F2 (P = 8.3 x 10î º10). The single-nucleotide polymorphism (SNP) alters the coding sequence for the gene product.
Clinical trials are currently underway to determine whether genetic prediction of dose benefits patients, and there is evidence that it does. The FDA recommends, but does not mandate, that genetic information should be considered in deciding the warfarin dose. "Our GWAS, at this point, lays out what the genetic landscape looks like, and gives more impetus to conducting trials showing that CYP2C9, VKORC1, [and] CYP4F2 are the major genetic predictors," said Dr. McGinnis. "There may be some other ones that we will find ... It's not perfect, but it's a lot better than doing it empirically, adjusting by trial and error."
Genetic coding in the genes VKORC1, CYP2C9, and CYP4F2 explain 30%, 12%, and 1.5%, respectively, of the variance in the warfarin dose required to achieve an INR of 2.0 to 3.0, while other genes may account for 3% to 5% more of the variance.
The other factors that account for about 15% of the variation in warfarin dosage to achieve an INR of 2.0 to 3.0, which can be a dosage that ranges from 5.0 - 107.0 mg/week, include age and sex.

Admission INR Inversely Associated With Infarct Volume in Ischemic Stroke
S. Andrew Josephson, M.D.
http://www.medscape.com/viewarticle/583094
Current treatment of acute stroke focuses on administration of lytic medications and endovascular techniques meant to restore blood flow quickly in order to decrease the volume of irreversible tissue injury. An alternative strategy is for patients at high risk for ischemic stroke to be taking medications at the time of the event that will reduce infarct size. A recent trial aimed to study whether the preadmission international normalized ratio (INR) in patients taking warfarin was associated with decreased stroke severity.
The authors performed a single institution retrospective analysis of consecutive patients taking warfarin at the time of admission for ischemic stroke, all of whom received diffusion-weighted brain MRI within 24 h of symptom onset. A total of 93 patients were identified and another 93 patients not taking warfarin during the same time period, matched for stroke subtype, served as a control. The indication for warfarin use in the cohort was most commonly nonvalvular atrial fibrillation (61 patients, 66%). The median time to INR measurement from stroke symptom onset was 6.1 h, and the median time from INR measurement to MRI was 1.6 h.
The median INR in patients with warfarin use at the time of stroke was 1.7 (IQR, 1.3-2.3) and the mean admission infarct volume on MRI was 7.9 mL (IQR, 1.9-25.1 mL). There was a significant inverse correlation between INR values on admission and infarct volume (r = -0.38, p < .001), which remained significant after a linear regression model accounted for other predictors (p = .014). When patients were dichotomized into those with INR ≤ 2.0 and those ≥ 2.0, those ≤ 2.0 were found to have 3.5 times (95% CI, 2.9-4.2) greater lesion volume than those with INR ≥ 2.0. Patients with therapeutic (≥ 2.0) INR levels on admission had a significantly smaller lesion volume than the control group not taking warfarin (p =.001). However, the difference between lesion volume in all patients taking warfarin, regardless of INR, and the control group did not quite reach statistical significance (p = .072). Additional secondary analyses demonstrated that admission INR was inversely correlated with final infarct volume seen on follow-up MRI performed between days 5 and 75 (n = 40, r = -0.42, p = .007). The severity of stroke at admission, measured by the National Institutes of Health Stroke Scale (NIHSS), and the degree of disability at discharge, measured by the modified Rankin Scale (mRS), were also inversely correlated with admission INR in the group taking warfarin. Currently, there are few evidence-based indications for use of warfarin for primary or secondary stroke prevention outside of atrial fibrillation. However, even in patients with atrial fibrillation, only about half of patients with an indication for warfarin are prescribed for it, and in those who are, the INR is frequently found to be subtherapeutic. This study once again emphasizes that these patients should be taking warfarin at the appropriate dose, not only to prevent stroke, but also to limit the size and severity of stroke when it occurs. For the clinician, this important study provides further convincing information to discuss with patients and their physicians who are considering initiating warfarin therapy for evidence-based indications. Zosia Chustecka http://www.medscape.com/viewarticle/583771
Bevacizumab is a monoclonal antibody that neutralizes vascular endothelial gro
Bevacizumab Significantly Increases Venous Thromboembolism Risk
wth factor (VEGF), which results in the inhibition of angiogenesis.The angiogenesis inhibitor bevacizumab (Avastin, Genentech/Roche) significantly increases the risk for venous thromboembolism (VTE), a new meta-analysis concludes. Because the drug is being increasingly used in the routine treatment of cancer patients, the authors suggest that this new finding might merit a black-box warning.Currently, the product information includes only arterial thromboembolic events in its warnings section. That finding comes from a meta-analysis of 5 clinical trials involving 1745 patients, which did not find an increase in the risk of VTE (J Natl Cancer Inst. 2007;99:1232-1239).

The new meta-analysis examined 15 randomized controlled clinical trials involving 7956 patients with various advanced cancers, and found that the risk of developing VTE for patients taking bevacizumab was 33% greater than for controls (relative risk, 1.33; 95% confidence interval, 1.13 - 1.56; P < .001). The other issue for clinicians and researchers is whether the background rate of VTE (independent of any increase related to bevacizumab) justifies the prophylactic use of anticoagulants more broadly, Dr. Hurwitz said. This is an issue that merits further study, he added. It is also a rather controversial subject, and is hotly debated by oncologists, most recently at the 33rd European Society of Medical Oncology Congress in Stockholm, Sweden, as reported at the time by Medscape Oncology. According to Genentech/Roche, the manufacturer of bevacizumab, the incidence of VTEs reported in this meta-analysis is consistent with the drug's safety profile as documented in the product label and in previously presented data. "VTEs are typically managed with anticoagulant medication and can occur in people with cancer, regardless of the treatment they are receiving for their cancer," the company sai The meta-analysis found that bevacizumab increased the risk not only for all-grade VTE, but also for clinically significant high-grade VTE, the authors point out. The incidence was 11.9% for all-grade VTE and 6.3% for high-grade VTE. In addition, the risk was significantly and similarly increased by both the low dose (2.5 mg/kg per week) and the high dose (5 mg/kg per week). However, there was difference in the risk seen among patients with different types of tumors. The highest incidence of all-grade VTE was observed among patients with colorectal cancer (19.1%), whereas the lowest risk was seen in patients with renal cancer (3%). In between were patients with non-small-cell lung cancer (14.9%) and patients with breast cancer (7.3%). A similar pattern across these tumor types was seen with the incidence of high-grade VTE. This difference in VTE by cancer may be related to biology (for example, higher incidence in aerodigestive malignancies), but may also reflect other factors, such as previous treatment and performance status, say the authors.The authors point out several limitations to their meta-analysis, including potential overlap between the various grades of VTE, and the fact that the incidence of VTE varied greatly across the individual clinical trials (ranging Thrombolytic Therapy Can Improve Survival for Some Patients With Acute Embolism
http://www.medscape.com/viewarticle/583818
Thrombolytic therapy improves survival for some patients with massive acute pulmonary embolisms (PE), but may increase mortality for others, according to a report in the November 10th issue of the Archives of Internal Medicine.Only 356 (2.4%) of the 15,116 patients in the database received thrombolytic therapy for acute PE, the results indicate.
Overall, the unadjusted 30-day mortality rate was 2.2-fold higher among patients who received thrombolytic therapy (17.4%) than among those who did not receive this treatment (8.6%), the authors report.Results were similar for in-hospital mortality rates, which were 2.3-fold higher for patients who received thrombolytic therapy (19.6 per 1000 person-days) than for those who did not receive thrombolytic therapy (8.3 per 1000 person-days).
There was, however, a trend toward lower mortality rates among patients in the highest risk categories (based on the predicted probability of receiving thrombolysis), the researchers note. Major bleeding rates were only slightly higher among patients who received thrombolytic therapy (5.3%) than among those who did not (3.5%), the report indicates."
Arch Intern Med 2008;168:2183-2190.

Dipyridamole and Aspirin Combo Reduces Vascular Events
http://www.medscape.com/viewarticle/583873
According to pooled data from randomized controlled trials, dipyridamole and aspirin are more effective than aspirin alone in the secondary prevention of transient ischemic attack (TIA) or minor stroke, researchers report in the November issue of the Journal of Neurology, Neurosurgery and Psychiatry.Compared to the use of aspirin alone, the adjusted hazard ratio for the composite end-point of vascular death, non-fatal myocardial infarction or non-fatal stroke was 0.82 in the combination group.
This continued to be true in a variety of subgroups, including those based on age, sex, hypertension, diabetes, and previous stroke. The researchers, however, point out that data on risk factors were not available for all five trials, thus reducing the numbers available for analysis.
The combination was also more effective than aspirin alone in preventing recurrent stroke (hazard ratio, 0.78).
The superiority of the agents in concert, the investigators observe, is backed by sound evidence. Combination therapy, they conclude, "should be preferred over aspirin after a TIA or minor stroke of presumed arterial origin, as supported by several national guidelines."
J Neurol Neurosurg Psychiatry 2008;79:1218-1223.

Lower-Than-Expected Bleeding in CABG Patients Taking Clopidogrel Within Five Days Preop
http://www.medscape.com/viewarticle/584123
Shelley Wood
A new comparison of CABG patients who did and did not receive clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) within five days prior to their surgeries is challenging some of the long-held concerns about bleeding risks in CABG patients. Authors of the analysis found that clopidogrel within five days of CABG was "weakly associated" with an increased need for red blood cell transfusions, but they were no more likely to require reoperation for bleeding than people who had taken it more than five days beforehand.
What's more, many other factors, including which surgeon performed the procedure, female sex, and whether cardiopulmonary bypass was used, were all bigger determinants of bleeding risk than clopidogrel use five days or less before surgery.
The dilemma is posed in part by existing AHA/ACC guidelines, which give clopidogrel a class 1 recommendation for patients with non-ST-elevation ACS but also advise, as a class 1 recommendation, that clopidogrel be withheld for five days before CABG, if clinical circumstances permit it. Surgeons at many centers are resistant to performing what are more dangerous and technically demanding procedures when patients have recently taken clopidogrel.
Bleeding Events, With and Without Recent Clopidogrel

Clopidogrel <5 days (%)
No clopidogrel <5 days (%)
Reoperation for bleeding
Clopidogrel at five days or less was significantly associated with a 40% increased need for red cell transfusion, but this association was weaker than other things assessed by the investigators. In a statistical analysis that assessed the relative statistical strength of different predictive factors, which surgeon performed the procedure was by far the strongest predictor of whether a patient required red blood cell transfusion.
Kim JH-J, Newby K, Clare RM et al. Clopidogrel use and bleeding after coronary artery bypass graft surgery. Am Heart J 2008; 156:886-892.

Antithrombin III, Human (Thrombate III)
Misleading Safety Claims
Food and Drug Administration's Center for Biologics Evaluation and Research has reviewed sell sheet Thrombate III (Antithrombin III, Human) submitted by Talecris Biotherapies, Inc. (Talecris) . This sell sheet misbrands Thrombate III.
The FDA-approved professional labeling (PI) for Thrombate III states that it is indicated for the treatment of patients with hereditary antithrombin III (AT) deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. These are specific high risk situations for patients with clotting deficiencies. To underscore this limited indication, the Indications and Usage section describes how to determine accurately the existence of hereditary AT deficiency.
The sell sheet presents safety and efficacy superiority claims for Thrombate III versus fresh frozen plasma (FFP) based on comparison of Thrombate III's PI with anecdotal evidence. There are no adequate and well-controlled clinical trials or substantial clinical experience to support such superiority claims.
Specifically, the backside of the sell sheet includes a table comparing Thrombate III and FFP (fresh frozen plasma). The headings for the table read:
"Thrombate III ... the Necessary Therapy"
"Fresh frozen plasma (FFP) is contraindicated for a coagulopathy when the missing protein is available as a concentrate."
The table continues with the comparison of Thrombate III and FFP on efficacy, dosing, "safety processing," adverse events, side effects, storage, and "convenience." The overall presentation of the table misleadingly suggests that Thrombate III is safer and more effective than FFP when none of these characteristics have been compared in an adequately and well-controlled manner.
The sell sheet is misleading because it suggests that Thrombate III is safer than has been determined by substantial evidence or substantial clinical experience. There are significant safety risks involved with the use of Thrombate III for hemostasis, particularly involving the interaction of Thrombate III and heparin. Heparin is commonly used in high risk situations for which Thrombate III is indicated. The Warnings section of the PI states that the anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Concomitant use of heparin and Thrombate III requires careful monitoring. Therefore, the following statement, on page 2 of the sell sheet, is misleading: "Thrombate III reduces the risk of thrombotic events without increasing the risk of bleeding."

FDA Licenses Drug to Prevent Joint Damage in Children with Hemophilia A http://www.fda.gov/bbs/topics/NEWS/2008/NEW01900.html
The U.S. Food and Drug Administration today approved a new use for the blood product Kogenate FS to reduce the frequency of bleeding episodes and prevent joint damage in children with the most severe form of hemophilia.
Hemophilia A is a rare, hereditary, bleeding disorder in which a protein needed to form blood clots, factor VIII, is missing or its level is reduced. The disorder affects about 15,000 individuals in the United States, nearly all of whom are male.
"Administering Kogenate FS to children with hemophilia A on a daily basis before a bleeding event occurs will reduce bleeding into joints and help prevent joint damage, a major cause of disability in hemophiliacs," said Jesse Goodman, M.D., M.P.H., director, FDA's Center for Biologics Evaluation and Research.
When individuals with hemophilia are injured, they bleed longer than a person without hemophilia. As a result, these individuals may experience serious bleeding episodes, often in the joints and muscles. Repeated bleedings increase the chance of joint damage.
Kogenate FS is a genetically engineered version of factor VIII. It was first licensed in the United States in 1993 for use during surgery and to prevent or control other bleeding episodes.
In a clinical trial, 65 boys under 30 months of age with severe hemophilia A and normal joints were observed for five years. The patients received either one daily dose of the drug, or three doses at the time of a bleeding episode. Joint damage during a bleeding episode was 6-fold lower, and the rate of bleeding 8-fold lower, in those boys who received the drug on a daily basis compared to those who received the drug only when a bleeding episode occurred. Most patients received the drug intravenously through a catheter.
The most common adverse events were infection at the catheter site and fever.

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750

Clinical Context
Two-point ultrasonography is frequently used in the evaluation of patients with suspected DVT, but whole-leg color-coded Doppler ultrasonography has emerged as another diagnostic option as well. Two-point ultrasonography is relatively simple to perform and is associated with better access, particularly during weekends and nights. In addition, it does not require sophisticated ultrasound equipment and has a high rate of reproducibility.
However, the use of 2-point ultrasonography to diagnose DVT frequently requires repeated testing in 1 week to detect calf DVT, which can extend to the proximal veins. Whole-leg Doppler ultrasonography generally obviates this requirement, making 1-day testing possible. The current study examines the 3-month outcomes of patients tested for suspected DVT of the lower extremities with 2-point ultrasonography or whole-leg color-coded Doppler ultrasonography.
Study Highlights
14 centers in Italy participated in the study. Patients were eligible for study participation if they were 18 years or older and were presenting for evaluation of their first episode of suspected DVT of the lower extremities. Patients with a history of VTE were excluded from study participation.
Participants were randomly assigned to a diagnostic strategy of 2-point or whole-leg ultrasonography. Study subjects in the 2-point ultrasound group underwent an ultrasound examination focused on the common femoral and popliteal veins. Patients with normal results on 2-point ultrasound testing then underwent D-dimer testing, and, if the result of the D-dimer was negative, no additional testing was performed. Patients with abnormal D-dimer levels were scheduled to undergo another ultrasound test at 1 week.
Participants who received negative results on whole-leg testing did not receive any additional workup.
The main outcome of the study was the prevalence of objectively proven VTE during the 3 months after testing in patients with negative results on workup for DVT.
2098 patients underwent randomization. Baseline data were similar between diagnostic groups.
The mean age of the participants was 63 years, and 41% of subjects were men.
Many patients had significant risks for DVT, with 28% having a history of cancer and 25% having a history of leg trauma or fracture.
The rates of abnormal findings on initial ultrasonography were 22.1% in the 2-point ultrasound group and 26.4% of the whole-leg ultrasonography group.
In participants with abnormal results on D-dimer testing in the 2-point ultrasonography group, 5.5% had abnormal results on repeated ultrasonography at 1 week.
In participants with positive testing results on whole-leg ultrasonography, 76.6% had proximal DVT, 13% had isolated DVT of the posterior tibial or peroneal veins, and 10.4% had isolated muscular vein thrombosis.
Approximately one quarter of study participants had a clinical visit at 3 months after the initial evaluation, and the rest were contacted by telephone.
At 3 months, the mortality rates in the 2-point and whole-leg ultrasound groups were 1.1% and 0.9%, respectively.
16 participants had suspected DVT during follow-up in the 2-point ultrasound group, and DVT was confirmed in 7 of these patients. 21 participants had suspected DVT during follow-up in the whole-leg ultrasound group, and DVT was confirmed in 9 of these patients.
The overall rates of symptomatic VTE during follow-up were 0.9% and 1.2% in the 2-point and whole-leg ultrasound groups, respectively. The difference between groups was not significant.


Preliminary Data Suggest Spiriva Not Linked to Increased Stroke Risk
http://www.medscape.com/viewarticle/581756

October 8, 2008 - Preliminary data from a large, 4-year, company-sponsored study of about 6000 patients suggest that the inhaled, long-acting anticholinergic agent tiotropium bromide (Spiriva HandiHaler, Boehringer Ingelheim Pharmaceuticals, Inc) is not linked to an increased risk for stroke relative to placebo, the US Food and Drug Administration (FDA) announced yesterday in an updated early communication.
Complete results of the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study are expected to be available in November 2008, according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program. At that time, they will be subjected to an agency review that may take several months.
Thus far, however, the findings contradict those of 2 recent publications, which have reported an increased risk for mortality and/or cardiovascular events in patients receiving tiotropium and other inhaled anticholinergic agents for the treatment of chronic obstructive pulmonary disease (COPD).
One study was a systematic review and meta-analysis of 17 clinical trials involving inhaled anticholinergic agents (n = 14,783), and the other was a case-control study of inhaled medications that included an anticholinergic (n = 32,130 case patients and 320,501 control patients).
In March 2008, Boehringer Ingelheim had also reported findings from a meta-analysis of 28 placebo-controlled studies that suggested an annual excess risk for stroke of about 2 cases per 1000 patients. At that time, the FDA advised that these results be interpreted with caution.
Tiotropium is indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysima.

Societies Confront GI Risks of Antiplatelets, NSAIDS in Consensus Document
:http://www.medscape.com/viewarticle/581682

News Author: Steve StilesCME Author: Charles Vega, MD
Clinical Context
Upper gastrointestinal tract ulceration and bleeding are important complications of treatment with ASA and other NSAIDs. The annual incidence of ulceration related to NSAIDs is 2% to 4.5%. However, the rate of hospitalization from ulcerative events declined between 1992 and 2000, possibly because of the use of lower doses of NSAIDs and/or the increased use of antisecretory therapy. The use of NSAIDs in addition to regular ASA increases the risk for gastrointestinal tract adverse events to a greater degree than the risk associated with either medication alone.
The current Expert Consensus Document from the American College of Cardiology Foundation, American College of Gastroenterology, and American Heart Association describes the best practice to mitigate the risk for gastrointestinal tract adverse events associated with the use of ASA, NSAIDs, and antiplatelet agents.
Study Highlights
The use of low-dose ASA increases the risk for symptomatic or complicated upper gastrointestinal tract ulcers by 2- to 4-fold, to a level of 5 cases of ulceration for every 1000 ASA users per year. Enteric-coated ASA preparations do not reduce this risk, but higher doses of ASA promote an increased risk for ulceration. Therefore, ASA at doses higher than 81 mg daily should not be routinely prescribed for long-term therapy.
The combination of ASA with heparin or warfarin is synergistic in promoting upper gastrointestinal tract bleeding. When ASA is used with warfarin, the international normalized ratio should be maintained between 2 and 2.5.
The risk for gastrointestinal tract hemorrhage associated with clopidogrel is not significantly lower vs ASA, and a strategy of replacing ASA with clopidogrel only to reduce gastrointestinal tract risk is not recommended.
In patients with a history of ulcer complication or ulcer disease, patients should be tested for evidence of H pylori infection before initiation of antiplatelet therapy. If results of this testing are positive, patients should receive eradication therapy before antiplatelet therapy.
Patients with a history of previous ulcer, gastrointestinal tract bleeding, or who are to receive dual antiplatelet therapy or an antiplatelet medication plus an anticoagulant should receive gastrointestinal tract prophylaxis during treatment with an antiplatelet medication. In addition, patients with 2 or more of the following risk factors should receive gastrointestinal tract prophylaxis during antiplatelet therapy:
Age 60 years or older
Corticosteroid use
Dyspepsia or symptoms of gastroesophageal reflux disease
PPIs are the preferred medications for the therapy and prophylaxis of NSAID- and ASA-associated gastrointestinal tract injury. Misoprostol is associated with adverse effects, which often lead to treatment discontinuation. Sucralfate and H2 receptor antagonists are not adequately effective in the prevention of NSAID-related gastric ulcers.
The decision whether to discontinue ASA in the setting of acute ulcer bleeding must be made on an individual basis. One trial found that discontinuation of ASA after a bleeding ulcer was associated with a higher risk for mortality but no reduction in the risk for recurrent ulcer bleeding. It should be noted that patients received treatment with PPIs in this study.
ASA does not need to be discontinued before most endoscopic procedures, but each case should be evaluated individually.


Warfarin Warning: Shortfalls in Anticoagulation for AF Up Risks of ICH and Embolic Stroke
http://www.medscape.com/viewarticle/581882

News Author: Steve StilesCME Author: Charles Vega, MD
October 10, 2008 - Most patients with atrial fibrillation (AF) aren't getting prescriptions for warfarin, and of those who are on warfarin, most aren't being anticoagulated to the proper therapeutic extent; their international normalized ratios (INRs) are frequently outside the recommended range of 2.0 to 3.0, which puts them at significantly increased risk of intracranial hemorrhage or embolic stroke, suggest data gleaned retrospectively from prescription reimbursement claims, hospital records, and similar sources from the years 1999 to 2005 [1]. There was no record of a prescription for an antiplatelet agent for almost half the patients in the analysis.
Overall in the analysis:
Only 45% of the population was prescribed warfarin.
A total of 52% had insurance claims for an anticoagulant or antiplatelet agent.
Men were significantly more likely than women to be dispensed an anticoagulant (odds ratio [OR], 1.46; 95% CI, 1.40 - 1.52).
Patients aged 60 to 74 years were significantly more likely than those aged 40 to 59 years to be dispensed an anticoagulant (OR, 1.68 - 1.73; 95% CI lower limit ≥ 1.57, 95% CI upper limit ≤ 1.85, depending on age subgroup).
In a substudy of the 13,115 patients for whom INRs were recorded, the median during follow-up was within the therapeutic range (2.2 INR). However, about one third of the group was in the therapeutic range <> 3.0 were far less common.
Alarmingly, but not surprisingly, INR levels <>Clinical Context
Compared with normal sinus rhythm, nonrheumatic AF increases the risk for embolic stroke by 4- to 7-fold. This risk increases with age; AF accounts for nearly one quarter of strokes in persons between the ages of 80 and 89 years. In patients undergoing cardioversion for AF, nearly all thromboembolic events occur within 10 days of treatment. Other factors that promote embolic events in AF include female sex, hypertension, poor myocardial function, previous myocardial infarction, and a previous thromboembolic event.
Warfarin is indicated to prevent embolic stroke in patients with AF, particularly older adults with other cardiovascular risk factors. However, warfarin therapy can be difficult to manage for both patient and clinician alike. The current study uses a large patient database to examine the treatment of AF.
Study Highlights
Study data were drawn from a database of a large health plan in the United States. The database contains information on medical diagnoses used for billing, pharmacy claims, and laboratory work, with approximately 30% of outpatient laboratory values appearing in the database.
The current research focused on adults age 40 years or older who had at least 1 diagnostic code for AF between 1999 and 2005. Patients with diagnoses of mitral stenosis or heart valve replacement were excluded from study analysis.
The main outcome of the study was the prevalence of treatment of AF with warfarin. Researchers also examined INR levels within the study cohort and how these levels affected subsequent outcomes.
116,969 patients with AF were evaluated. 35% of cases appeared to be newly developed between 1999 and 2005, and the remainder were chronic AF.
59% of patients were men. The mean age of male subjects was 66 years, and the mean age of women was 70 years.
45% of subjects received a prescription for warfarin, and 48% had no claim for warfarin or an antiplatelet medication. 82% of participants had no INR recorded in the database.
Patients in the youngest age group, between 40 and 59 years, were the most likely to receive warfarin.
More than 30% of patients were hospitalized during the study period.
Risk factors for embolic stroke, such as age 75 years or older and hypertension, were far more common than risk factors for hemorrhage, such as coagulopathy.
Men were 46% more likely to receive warfarin vs women. In general, warfarin prescriptions were more common in patients at higher risk for embolic events. Older adults were more likely to receive warfarin, although subjects between ages 60 and 74 years were more likely to receive warfarin vs those age 75 years or older.
The median INR during follow-up was 2.2, but only 19% of subjects spent at least a large majority of the time in the therapeutic range of INR (between 2 and 3). Subtherapeutic INR results outnumbered supratherapeutic results.
There were 151 strokes, 62 intracranial bleeds, and 21 arterial thrombotic events during 13,200 person-years of INR monitoring. INR levels less than 2 were associated with an unadjusted relative risk of 2.39 for stroke and 5.68 for arterial thromboembolism vs therapeutic INR levels.
INR levels greater than 3 were associated with an unadjusted relative risk of 2.11 for intracranial hemorrhage vs therapeutic INR levels.
Current warfarin use was not a statistically significant risk factor for stroke, intracranial bleed, or arterial thromboembolism after accounting for INR level.

Black Patients May Be at Higher Risk for Microbleeds
http://www.medscape.com/viewarticle/582159
Allison Gandey
October 16, 2008 - African Americans have 32% more microbleeds after primary intracerebral hemorrhage than whites, a new study shows. The results are published in the October 7 issue of Neurology.
"Our study suggests that black patients with primary intracerebral hemorrhage have a far greater frequency of microbleeds compared with whites and that this may have important implications for diagnosis and treatment of risk factors," senior author Chelsea Kidwell, MD, from the Georgetown University Medical Center, in Washington, DC, told Medscape Neurology & Neurosurgery.
"However, we still need to better understand the contributions of various underlying risk factors in these populations," she said.
In this retrospective study, the researchers looked at patients diagnosed with primary intracerebral hemorrhage at 2 metropolitan stroke centers. Clinical and neuroimaging data were available for each patient. The investigators compared baseline characteristics and imaging findings by race.
The researchers report that age and hypertension were not significantly associated with microbleeds. However, race and heavy alcohol consumption were.
.Neurology. 2008;71:1176-1182. Abstract

Coffee and Tea May Protect Against Stroke
News Author: Pauline Anderson
http://www.medscape.com/viewarticle/576548
June 24, 2008 - High consumption of coffee or tea every day appears to protect male smokers against at least 1 type of stroke, a new study suggests.
This large, prospective, observational study showed that Finnish smokers who consumed 8 or more cups of coffee per day had a 23% lowered risk for cerebral infarction, whereas those who drank 2 or more cups of black tea daily had a 21% lowered risk for this type of stroke vs those who drank little or none of these beverages. The associations were independent of risk factors such as a history of coronary heart disease.
Their report is published in the June 2008 issue of Stroke.

Antioxidant Health Benefits
Both coffee and tea are widely consumed caffeinated beverages, the study authors write, and both are known to have antioxidant health benefits. For example, observational research suggests that coffee drinking is inversely associated with inflammation and endothelial dysfunction and that it may improve insulin sensitivity and reduce the risk for type 2 diabetes. As for tea, it contains high amounts of polyphenols, which prevent oxidation of low-density lipoprotein cholesterol and may reduce platelet activation and plasma C-reactive protein levels, a marker of inflammation.
Some of these health benefits may extend to prevention of cerebral infarction, said the study authors. "Beneficial effects of consumption of coffee and tea with regard to risk of cerebral infarction are biologically plausible because coffee and tea contain phenolic compounds with antioxidant properties that may prevent atherosclerosis," they write.
However, although the relationship between consuming caffeinated beverages and the risk for coronary heart disease has been studied extensively, this current study is among the few to examine the association with stroke risk.
Subjects for this study were participants of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial originally designed to determine whether alpha-tocopherol, beta-carotene, or both could reduce cancer incidence in male smokers. The cohort consisted of 29,133 Finnish men aged 50 to 69 years who smoked at least 5 cigarettes per day and had no history of stroke. From 1985 to 1988, these men were recruited into the trial, which ended in 1993.At baseline, participants completed questionnaires gathering general background characteristics, including medical, smoking, and physical activity histories. Investigators measured height, weight, and blood pressure, calculated body mass index, and obtained levels of serum total cholesterol and high-density lipoprotein cholesterol.Also at baseline, the researchers used validated food frequency questionnaires to assess consumption of coffee and black tea for the previous year. This information was provided by 26,556 of the randomized participants. At 2 to 5 years after randomization, the researchers asked the men how they usually prepared their coffee: filtered, boiled, or instant. This information was available for 20,427 of the participants. Most used the filter (14,513 [71.1%]) or boiling (4232 [20.7%]) method.
Approximately 2.5% of the study sample reported never drinking coffee, and approximately 64% did not drink tea. The mean daily coffee consumption among drinkers was 5.7 cups. Men with higher coffee consumption were slightly younger, smoked more, had lower systolic and diastolic blood pressures, were less likely to have a history of diabetes or coronary heart disease, were more likely to be physically active, and consumed less alcohol and tea than men with low coffee consumption. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein, a marker of inflammation linked with an increased risk for ischemic stroke.
In their analysis, the researchers included strokes occurring from the time of randomization to December 31, 2004. During a mean follow-up of 13.6 years, there were 2702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes.
The association was similar regardless of whether the coffee preparation method was boiling or filtered. Results also were much the same whether subjects were observed for less than 10 years or for 10 years or more. For tea, the association between consumption and cerebral infarction also did not vary significantly by age or cardiovascular risk factors. Because the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study includes only male smokers, the study authors write, their results may not be generalizable to women or to nonsmokers. "These findings warrant confirmation in other populations, particularly women and nonsmokers," they conclude.
Stroke. 2008;39:1681-1687.


U.S. Lawmakers Expand Probe to Aspirin-Combo Ads
http://www.medscape.com/viewarticle/582049
By Susan Heavey
WASHINGTON (Reuters) Oct 14 - U.S. Democratic lawmakers are expanding their probe into direct-to-consumer drug advertisements to include Bayer AG's combination aspirin product, according to letters released on Tuesday.
Bayer's marketing of its Aspirin with Heart Advantage, a combination product that includes a dietary supplement, appears to go against a U.S. Food and Drug Administration's request not to advertise such products, said House of Representatives Energy and Commerce Chairman John Dingell.In the letter to Bayer HealthCare President Gary Balkema, the Michigan Democrats asked whether the company planned to seek FDA approval for the combination product. They also called on the company to provide lawmakers with all related records within two weeks.
In a separate letter to U.S. Health and Human Services Michael Leavitt, the lawmakers asked whether the FDA or its lawyers were aware of the aspirin marketing or advertisements for any other combination products that include dietary supplements.
Dingell and Stupak have been investigating whether drug companies have misled the public through consumer-targeted advertisements. Other companies with ads under review include Pfizer Inc, Johnson & Johnson, Merck & Co Inc and Schering Plough.


New Rofecoxib Data Will Help Inform Treatment Decisions With Other Coxibs, NSAIDs
http://www.medscape.com/viewarticle/581985

News Author: Lisa NainggolanOctober 14, 2008 - New results from the extended follow-up of the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial provide a more complete assessment of the cardiovascular toxicity of the cyclooxygenase 2 (COX-2) inhibitor rofecoxib (Vioxx, Merck), than previously reported, say Dr John A Baron (Dartmouth Medical School, Hanover, NH) and colleagues in a report published online October 13, 2008, in the Lancet
Clinical Context
COX-2 inhibitors have been associated with cardiovascular toxicity. Rofecoxib was withdrawn from the worldwide market because of this effect, demonstrated in the APPROVE trial, which examined the protective effect of rofecoxib on adenomatous polyps but was terminated early because of cardiovascular toxicity.
This is an analysis of adverse cardiovascular effects of rofecoxib during and 1 year after the APPROVE trial, which was conducted at 108 centers worldwide with recruitment in 2000 and 2001.
Study Highlights
Included were men and women 40 years or older with 1 or more histologically confirmed large-bowel adenomas removed within 12 weeks, with no remaining polyps after colonoscopy.
Excluded were those receiving NSAID treatment and those with hypertension, heart failure, cardiovascular surgery within 1 year, or a history of transient ischemic attack or stroke within 2 years.
Patients were randomly assigned to 25-mg rofecoxib (n = 1287) or placebo (n = 1300) once daily for 3 years.
The protocol was amended to include those who used aspirin after the trial began.
A single-blind run-in period of 6 weeks assessed adherence.
Those who were at least 80% adherent were included in analysis.
The primary outcome was the combined incidence of nonfatal MI, nonfatal stroke, and death from cardiovascular, hemorrhagic, and other causes.
The trial was terminated 2 months before the planned completion rate because of adverse cardiovascular effects.
Posttreatment extended follow-up was completed on 84% of those receiving rofecoxib and 83% of those receiving placebo.
Median posttreatment follow-up times were 537.5 days for rofecoxib and 550 days for placebo.
Mean age of the participants was 59.4 years, mean weight was 81.3 kg, 62% were men, and 84% were white.
High baseline cardiovascular risk was more common in those without extended follow-up (34%) vs those with extended follow-up (27%; P = .04).
The relative risk for thrombotic cardiovascular events during treatment or within 14 days of stopping medication was 1.89 for combined events.
The HR did not differ significantly with time.
After adjustment for baseline age, sex, aspirin use, and cardiovascular risk, the HR for MI was 1.94 and for stroke, 2.17.
In total, 59 participants in the rofecoxib group and 34 in the placebo group had a combined event (unadjusted HR, 1.79; P = .006).
The increase in risk was seen early, in the first 6 weeks of treatment.
The difference in cumulative risks for a combined event between the 2 groups grew with time, reaching 1.74% at 36 months.
Relative risks were higher in those with cardiovascular risk factors, especially diabetes.
After discontinuation of treatment, 52 participants in the rofecoxib group and 32 in the placebo group had a cardiovascular event.
The adjusted HR for the posttreatment period was 1.41 for the rofecoxib group and persisted to 1 year.
The authors concluded that rofecoxib use was associated with increased cardiovascular risk, which persisted

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750
News Author: Steve StilesOctober 8, 2008 - Two ultrasound-based evaluations, both with their advantages and disadvantages, are about equally effective at guiding the management of patients with suspected lower-extremity deep-vein thrombosis (DVT), conclude the authors of a randomized trial reported in the October 8, 2008, issue of Journal of the American Medical Association [1]. But the writer of an accompanying editorial [2] gives the edge to one of the techniques, the one that's been around longer and is simpler and probably more widely available, and notes that a clinical prediction rule not evaluated in the study can also play a role in the initial evaluation of DVT.
The study of more than 2000 patients with suspected DVT found comparably low three-month rates of confirmed venous thromboembolism (VTE) among those who were spared the burdens of anticoagulation therapy based on the results of either two-point compression ultrasonography with provisional D-dimer testing or whole-leg color-coded Doppler ultrasonography.
Compression ultrasonography, typically performed on proximal leg veins, plus D-dimer testing "is simple, convenient, and widely available but requires repeat testing in one-fourth of the patients," according to the authors, led by Dr Enrico Bernardi (Civic Hospital, Conegliano, Italy).
The Doppler method "offers a one-day answer [and is] desirable for patients with severe calf complaints, for travelers, and for those living far from the diagnostic service but is cumbersome, possibly more expensive, and may expose patients to the risk of (unnecessary) anticoagulation," they write. Whole-leg color-coded Doppler ultrasonography, unlike the other method, will disclose DVT of the calf, they explain; its clinical importance, and therefore the value of anticoagulation directed at it, has been questioned.
Still, both methods are "reliable diagnostic options," Bernardi et al conclude. "Either strategy may be chosen based on the clinical context, on the patients' needs, and on the available resources."
The trial's patients had been referred to one of 14 ultrasound laboratories in Italy with a first episode of suspected symptomatic DVT. Of the 1045 randomized to the two-point ultrasonography strategy, 217 had abnormal findings at the initial workup and were classified as having proximal DVT; 828 had normal findings and underwent D-dimer testing. That test was abnormal in 256, who were scheduled for repeat ultrasonography a week later. Repeat ultrasound yielded abnormal findings in 14 patients.
So, 814 patients were spared anticoagulation therapy and were followed for the prespecified three months; they included the 572 with normal findings at ultrasonography and D-dimer testing plus 242 with repeatedly normal ultrasonography despite a positive D-dimer result.
Whole-leg color-Doppler ultrasonography yielded abnormal findings in 278 of the 1053 assigned to it. Those patients received anticoagulation therapy while the 775 with a negative test were followed.
Venous thromboembolism was confirmed in seven of the 801 patients in the two-point ultrasonography group (0.9%) and in nine of the 763 in the whole-leg ultrasonography group (1.2%) who hadn't been anticoagulated and were available for the three-month follow-up. The difference met the trial's criteria for equivalence, the authors write.
In his editorial, Landefeld recommends that patients with a suspected first instance of DVT be initially evaluated using two of three methods: the clinical prediction rule, two-point ultrasonography, and D-dimer testing. "If both tests are negative, DVT is effectively ruled out, and anticoagulation can be withheld safely," he said.
"If the clinical evaluation using the Wells criteria [3] suggests low [DVT] probability, and if the [two-point] ultrasound or the D-dimer test is negative, you've essentially ruled out DVT," Landefeld explained to heartwire. "If the compression ultrasound is positive for proximal DVT, you've made the diagnosis. If the clinical evaluation suggests intermediate or high [DVT probability] and the compression ultrasound is negative, then you have to do something more. And that could be to do another test in a week or a more definitive one right then, which would be venography or color-coded Doppler."http://www.medscape.com/viewarticle/581682




Aspirin: Should It Be Used for Primary Prevention in Diabetics?
http://www.medscape.com/viewarticle/582320.
Study Highlights
Patients eligible for study participation were aged 40 years or older and had type 1 or 2 diabetes. All participants had evidence of PAD, as suggested by an ankle brachial pressure index of 0.99 or less.
Patients with a history of symptomatic cardiovascular disease were excluded from study participation, as were those who regularly used aspirin or antioxidants.
Participants were randomly assigned in a 2 x 2-factorial design to receive aspirin 100 mg daily plus an antioxidant tablet daily, either active treatment alone plus placebo, or double placebo. Each antioxidant capsule contained alpha-tocopherol 200 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulphate 10 mg, nicotinamide 10 mg, lecithin 9.4 mg, and sodium selenite 0.8 mg.
Participants received standard disease therapy as well, which was left to the discretion of the study investigator and other responsible clinicians.
Participants were followed up every 6 months during a median of 6.7 years.
The main outcome of the study was the composite of death from CHD or stroke, nonfatal MI or stroke, or above-ankle amputation for critical limb ischemia. Secondary outcomes included the individual components of the composite outcome.
1276 patients underwent randomization. Baseline characteristics were similar between randomly assigned groups. The mean age was 60 years, and slightly more than half of the study cohort were women. Nearly one third of patients were current smokers, and the median ankle brachial pressure index was 0.90.
233 participants experienced 1 of the primary composite endpoints, and a total of 638 primary events were reported. There was no significant interaction between aspirin and antioxidants for the primary endpoint.
Aspirin was not effective in reducing the rate of composite vascular events (HR, 0.98). Moreover, aspirin did not significantly reduce the risk for death from CHD or stroke (HR, 1.23). Rates of significant adverse events were also not different between aspirin and placebo.
In a similar fashion, antioxidants were not effective in the prevention of the composite endpoint (HR, 1.03), and they also did not reduce the risk for death from vascular events. More participants not receiving antioxidants experienced gastrointestinal tract symptoms vs participants receiving antioxidants.
Secondary endpoints related to vascular outcomes were not significantly affected by study therapy. The overall risk for mortality was higher in the antioxidant group vs the placebo group (HR, 1.49), whereas aspirin had no effect on the risk for mortality.
Subgroup analysis on the basis of age, sex, and ankle brachial pressure index values did not alter the study's main findings.

Warfarin Does Not Significantly Reduce Stroke Risk in Blacks With AF
http://www.medscape.com/viewarticle/582298NEW YORK (Reuters Health) Oct 20 - Analysis of a cohort of patients hospitalized for atrial fibrillation (AF) shows that warfarin is statistically effective in preventing ischemic stroke among whites, but not among nonwhites, particularly not in black patients.To see if this benefit extends to other racial groups, a cohort of 18,867 patients hospitalized between 1995 and 2000 with AF. The population was 78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian. Over a median of 3.3 years, or 63,204 person-years, of follow-up, there were 1226 ischemic strokes.
All patients were on warfarin for essentially the same amount of time. The overall percentage of time the international normalized ratio was between 2 and 3 was 54.5%, but it was lower in blacks at 47.8%.The rate ratios of ischemic stroke with on warfarin treatment versus no warfarin treatment was0.79 for whites, 0.92 for blacks, 0.71 for Hispanics and 0.65 for Asians, Dr. Shen and colleagues report in the October issue of Stroke.
In this cohort, we did not observe a statistically significant lower rate of stroke with warfarin therapy among nonwhites (in particular blacks) with previous AF hospitalizations,However, a protective effect of warfarin in nonwhites can not be completely ruled out due to the "relatively small number of events among nonwhites." In addition, the number of nonwhites in the cohort was fairly small, so the estimates should be "interrupted with caution," the researchers add.
Stroke 2008;39:2736-2743.

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.

WHAT'S NEW IN COAGULATION
FEIBA VH (Anti-Inhibitor Coagulant Complex, Vapor Heated)Background
According to the FDA-approved prescribing information (PI), FEIBA VH is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity and is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors. FEIBA VH is contraindicated in patients who are known to have normal coagulation mechanism.
FDA reported the following claim filed by the manufacturer Baxter is misleading and the email notification sent by the company be removed.:
"Controlled 78% of bleeds with 3 or fewer infusions-60% of which were controlled with 1 infusion within 12 hours"
The claim is misleading because it overstates the efficacy of FEIBA and the claimed efficacy rate of 60% with one infusion is inconsistent with the PI. According to the PI, "In 130 (78%) of the episodes, hemostasis was achieved with one or more infusions. of these, 36 % were controlled with one infusion within 12 hours" (Clinical Pharmacology). Additionally, the above claim is false or misleading because it only presents that FEIBA "controlled 78% of bleeds with 3 or fewer infusions," but omits important contextual information that the bleeds were controlled "within 36 hours." By omitting this information, the overall presentation of the claim misleadingly suggest that 60% of the bleeds were controlled within 12 hours, which is false.
"FEIBA is well tolerated in 96%-100% of infusions with a low thrombotic event incidence (0.008%)"
The safety claim that FEIBA is "well tolerated" in 96-100% of infusions and has a low incidence of thrombotic events (0.008%) is misleading because it minimizes the fact that serious thrombotic events can occur with FEIBA particularly following the administration of high doses and/or in patients with thrombotic risk factors," and "patients .must be monitored for the development of DIC [disseminated intravascular coagulation] and/or symptoms of acute coronary ischemia". Moreover, the following adverse events, but not limited to, that are reported in the referenced studies1-5 to support the safety claim are inconsistent with the term "well-tolerated":

Antihemophilic Factor, Human (RECALL)REASON:
CSL Behring L.L.C. is initiating a Voluntary Recall of four lots of Monoclate-P®, Antihemophilic Factor, Human. These lots are being withdrawn because they do not meet the potency specification when stored for three months at 5°C. CSL Behring is requesting that the use of these lots be immediately discontinued and the products be returned to the company. No adverse events or product complaints have been reported or associated with the use of this lot.
http://www.fda.gov/cber/recalls/anticsl081808.htm


http://www.medscape.com/viewarticle/561169_print
Guidelines Updated for Prevention of DVT and PE Linked With Gynecologic Surgery News Author: Laurie Barclay, MD
Désirée Lie, MD, MSEd
August 9, 2007 - The American College of Obstetrics and Gynecology (ACOG) has updated its guidelines for prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with gynecologic surgery. The evidence-based clinical management guidelines, which are published in the ACOG Practice Bulletin in the August issue of Obstetrics and Gynecology, are intended to update and replace those from the October 2000 Practice Bulletin.
- The most common mutations predisposing to VTE are factor V Leiden, and mutation G20210A is carried mainly in white patients; screening should be conducted in all white patients with a history of DVT.
- Elevated levels of homocysteine levels increase the risk for VTE and may be genetic or acquired.