 |
FAQs | Contact Us | Shopping Cart  |
|
|
 |
 |
Learning CenterNew In CoagulationThursday, July 8, 2010
WHAT'S NEW IN COAGULATION: JULY 2010WHAT’S NEW IN COAGULATION: JULY 2010 Researchers Detect Blood-Clotting Mechanism Ever wonder how your blood miraculously stops flowing and forms a scab after a cut? Researchers have now pinpointed the mechanism down to the molecular level. If people have too much hemostatic activity, they can develop an excess of blood clots, resulting in thrombosis, which is a potentially deadly condition. On the other hand, if there is too little hemostatic activity, people could bleed to death, according to background information in the news release. To achieve and maintain the right hemostatic balance, the body has a feedback system controlled by miniscule forces in the circulation system. The forces are applied to the highly-sensitive A2 domain of the blood-clotting protein called von Willebrand factor (VWF), which acts as a “force sensor”. By manipulating single molecules, the researchers found that the tiniest force causes A2 molecules to unfold and lose much of their complex, three-dimensional organization. After the unfolding, the enzyme ADAMTS13 comes into play. The enzyme cuts the molecule, hence controlling the size of the blood clot, according to the study, in the June 5 issue of Science.In the body, these cutting events decrease hemostatic potential and also enable blood clots to be trimmed in size. A better understanding of the mechanism of blot clotting could lead to new treatments for injuries or bleeding disorders, such as type 2A von Willebrand disease, the researchers noted. New Score Can Identify ACS Patients at High Bleeding Risk
ACS patients at increased risk for bleeding and subsequent one-year mortality can be identified with a simple risk score based on six baseline measures plus anticoagulation regimen, and these patients can then be targeted for appropriate treatment strategies, a new study has shown. Hemorrhagic complications are an independent risk factor for subsequent mortality in ACS patients and in those undergoing PCI and represent a hazard equivalent to or greater than that for MI. While certain characteristics are known to be associated with an increased risk of bleeding--for example, old age, female sex, impaired renal function, and/or baseline anemia--the relative hazard of these factors and their interaction have been incompletely characterized. They suggest that the development of a simple-to-use risk score for bleeding could standardize quality of care and patient outcomes. Risk stratification could also be employed to compare outcomes across clinical studies and institutions. The risk score differentiated patients with a 30-day rate of non–CABG-related major bleeding ranging from 1% to over 40%. Other results showed that major bleeding was an independent predictor of a 3.2-fold increase in mortality, and this link to mortality risk was strongest for non–CABG-related TIMI-defined major bleeding followed by non-TIMI major bleeding with or without blood transfusions, whereas isolated large hematomas and CABG-related bleeding were not significantly associated with subsequent mortality. They point out that the rates of non–CABG-related major bleeding were higher in patients enrolled with STEMI than with NSTEMI (6.2% vs 3.8%, respectively), although major bleeding was increased in NSTEMI patients with raised biomarkers at baseline. They suggest that the increased rate of bleeding in patients with STEMI might reflect the urgency of care provided, more frequent use of venous sheaths, unadjusted patient comorbidities, the more frequent use of a 600-mg loading dose of clopidogrel, or different GP-IIb/IIIa-blocker regimens. CABG-related major bleeding did not significantly predict subsequent mortality is important, because medications that might decrease PCI-related ischemic complications but increase surgical bleeding (eg, thienopyridines) are often withheld from patients with ACS until angiography confirms a likely nonsurgical management strategy. They suggest that with this new information, thienopyridine agents should be administered as early as possible before cardiac catheterization (in the ambulance or emergency room), so they might reach their maximal effect in patients undergoing PCI. But they add that the relationship between the severity of CABG-related bleeding and nonfatal clinical outcomes should be further assessed in future studies. PPIs, Clopidogrel, and Stent Implantation: No Risk? FDA Data Coming Soon
Yet another attempt to understand the risk of using a proton-pump inhibitor (PPI) in patients taking clopidogrel--this time in patients who'd undergone stent implantation--has found no significant increase in the risk of mortality, rehospitalization for ACS, stent thrombosis, or all outcomes combined out to 12 months. Outcomes in 1210 consecutive patients taking dual antiplatelet therapy after undergoing stent implantation between January 2003 and December 2006 were reviewed. After a mean of eight months (range one to 12 months), rates of death, ACS, stent thrombosis, or all three combined were numerically higher in the patients taking PPIs, but the difference was not statistically significant for any of the end points. Differences in event-free survival remained statistically similar after adjustment for baseline differences. Subgroup analyses failed to identify a single subpopulation in which PPIs appeared to translate into a higher risk of adverse events. 75% of the patients in the study had received pantoprazole (Protonix, Wyeth), which "doesn't inhibit cytochrome p450, and it may be that in patients who need a PPI, pantoprazole can be administered. Previous research has suggested that patients treated with pantoprazole had a significantly better platelet response to clopidogrel than those treated with omeprazole. Moreover, Tentzeris noted, while stent-thrombosis numbers were higher in PPI-treated patients, mortality rates were not increased in this group. The study didn't exactly support the notion of "no problems" with PPIs. The highly discordant data, both pharmacodynamic and clinical (albeit retrospective), has led to considerable confusion over what should be done. Indeed, experts responding to the only randomized controlled trial of clopidogrel with and without concomitant PPI use, COGENT (which saw no signal of harm from the combination) warned that more harm would come from not prescribing a PPI. As to the argument that some patients taking clopidogrel do need gastroprotection, Angiolillo conceded that it might be okay to "go with pantoprazole, which does not interfere with 2C19 or has minimal interference, or use an H2 receptor blocker." The skepticism over the FDA’s warning stems largely from the fact that the agency has yet to release the data that convinced it of a problem, he notes. But interventionalists have to have faith that the data are sound. “Obviously, there were many people who had access to these data, and the decision was made based on that. And the data will likely be out in the second half of this year.
Sleep Disordered Breathing ups Prothrombotic Markers
A community-based study of people with sleep apnea and their families showed significant linear relationships between severity of apnea or hypopnea and levels of two prothrombotic markers, fibrinogen and plasminogen-activator inhibitor-1 (PAI-1) [1]. The links between sleep disordered breathing (SDB) and the two biomarkers were observed even at mild to moderate SDB levels and support abundant other evidence linking sleep apnea and similar disorders to markers of thrombosis and thrombus-mediated cardiovascular events such as MI and stroke. In overnight sleep studies, levels of fibrinogen, PAI-1, and D-dimer (another thrombotic marker) were obtained from 537 participants of the Cleveland Family Study, consisting of adults with diagnosed sleep apnea and their families, as well as control individuals drawn from their neighborhoods. The study, conducted from 2001 to 2006, excluded people with severe chronic diseases, those on oral corticosteroids or anticoagulants, and anyone who regularly used continuous positive airway pressure therapy for sleep apnea. In the adjusted analyses, no relationships were observed between apnea-hypopnea index (AHI) and D-dimer levels or between hypoxia severity and any of the three thrombosis biomarkers. AHIs exceeding 15 were not related to levels of any of the markers. But for every five-point rise in AHI in the cohort, up to an AHI of 15, levels of PAI-1 rose 10% (p<0.01) and morning fibrinogen levels rose a mean of 8.4 mg/dL (p=0.002)
Management of Bleeding Following Major Trauma: An Updated European Guideline . Abstract and IntroductionIntroduction Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes.
INTERSTROKE: Ten Modifiable Risk Factors Explain 90% of Stroke Risk
A large case-control study evaluating risk factors for stroke has shown that 10 risk factors are associated with 90% of the risk of stroke and that of these modifiable risk factors, hypertension is the most important for all stroke subtypes and is a particularly dangerous risk factor for intracerebral hemorrhage [1]. The results of the study, known as INTERSTROKE, were presented at the World Congress of Cardiology (WCC) and are published online June 18, 2010 in the Lancet. Not unlike the previously published INTERHEART study of coronary heart disease, a trial led by Dr Salim Yusuf (McMaster University, Hamilton, ON) that identified nine modifiable risk factors accounting for 90% of disease, this study showed that many strokes can be predicted and that relatively simple measures, such as blood-pressure control, could reduce the burden of disease. At the WCC meeting, organizers and presenters have highlighted the global burden of stroke, noting that countries of low and middle income are disproportionately affected by the disease. These low- and middle-income countries, for example, account for more than 85% of stroke mortality worldwide. The contribution of various risk factors to stroke burden is not entirely known, however, particularly in lower-income countries, because most of the data from clinical trials are derived from developed or Westernized countries. INTERSTROKE is a standardized, case-control study looking at the importance of established and emerging risk factors for the common stroke subtypes in different regions. In total, 3000 first acute-stroke cases and 3000 controls from 22 countries were included in the analysis. Of the stroke patients, just 14% were from a high-income country, while 81% were from Southeast Asia, India, or Africa. Overall, self-reported hypertension was the strongest risk factor for stroke and was stronger for intracerebral hemorrhage than for ischemic stroke. A history of hypertension was associated with a more than 2.5-fold increased risk of stroke. When a stricter definition of hypertension was used--blood pressure >160/90 mm Hg--the strength of the association increased. Along with hypertension, current smoking, abdominal obesity, diet, and physical activity accounted for 80% of the global risk of stroke, explaining 80% of the risk of ischemic stroke and 90% of the risk of hemorrhagic strokes. When additional risk factors were included in the model, including diabetes mellitus, alcohol intake, psychosocial factors, the ratio of apolipoprotein B to A1, and cardiac causes (atrial fibrillation or flutter, previous MI, and valve disease), these 10 risk factors accounted for 90% of the risk of stroke. Hypertension, smoking, abdominal obesity, diet, and alcohol intake were the most important risk factors for intracerebral hemorrhagic stroke. Epidemiological studies have failed to show a consistent relationship between total cholesterol and stroke risk, a finding confirmed in the INTERSTROKE study. In this analysis, the researchers found no association with total and non-HDL cholesterol for ischemic stroke risk but did observe a strong association between apolipoprotein and HDL-cholesterol levels and the risk of ischemic stroke. Interestingly, the group observed that the reduction in risk of ischemic stroke associated with elevated apolipoprotein A1 and HDL cholesterol was larger than the increase in risk associated with increased levels of apolipoprotein B or non-HDL cholesterol.INTERSTROKE confirms that hypertension, a well-known risk factor for stroke in developed countries, is also a risk factor in developing nations. Tranexamic Acid May Be Used To Stop Bleeding In Recently Injured Accident Patients.Investigators "enrolled more than 20,000 accident victims at 274 hospitals in 40 countries." Patients "were randomly chosen to receive either a 1-gram dose of tranexamic acid [TXA] and another gram over the next eight hours, or a placebo given the same way." The researchers "found that, in the four months after the accident, tranexamic acid reduced deaths from all causes by 10%, compared with the placebo and the risk of death from excessive bleeding by 15%." The trial also showed no evidence of complications or unwanted clotting, which doctors had feared."Currently, TXA is not generally used in emergency rooms to treat trauma patients, but" the study's lead researcher "believes that this study could change that." The product costs about $4.43 a dose, with one given as an immediate injection and the second delivered intravenously over an eight-hour period. If the drug "became widely available and was used promptly, it could save as many as 100,000 lives a year, 13,000 of them in India and 12,000 in China, where road deaths are surging. Patients With Excess Bacteria In The Small Intestine May Need More Warfarin.An excess of bacteria in the small intestine may increase the amount of warfarin necessary to achieve a therapeutic anticoagulant effect." Before reaching that conclusion, researchers randomized 30 patients "evenly between individuals requiring low (≤17.5 mg/wk), high (35–70 mg/wk), and very high (≥70 mg/wk) doses of VKA [vitamin K antagonists] to maintain stable anticoagulation." Investigators eventually discovered that "of the five of the six patients with a breath test indicating" small-intestine bacterial overgrowth "required very high doses of warfarin," according to the paper in Thrombosis Research. The "remaining patient with an abnormal breath test required a high dose of warfarin, and none of the patients receiving low doses of warfarin had an abnormal breath test."
Low Response to Clopidogrel Linked to Increased Risk of Cardiac Death After PCI
In patients undergoing PCI, a low response to clopidogrel assessed by the vasodilator-stimulated-phosphoprotein (VASP) flow cytometry test is an independent predictor of cardiovascular death, a new study show. The deleterious impact of a low response to clopidogrel was significantly higher in patients who received a drug-eluting stent. The main message is that if platelets are not correctly inhibited, the risk of cardiac death increases. The current study used the VASP test to measure platelet inhibition. Although it is not available as a bedside test and blood samples must be sent to a specialized laboratory for measurement. This test has advantages over some other tests in that it is selective for the P2Y12 receptor and so is a good indicator of responsiveness to clopidogrel; it is not sensitive to IIb/IIIa blockers; and it is convenient in that it uses whole blood, so the sample does not need to be centrifuged. In addition, the test can be done any time within 48 hours of the blood sample being taken. The VASP test is the most reliable test for platelet inhibition with regard to thienopyridine use. Light-transmission tests may be best if you want to look for hyperreactive platelets in general, as these cover several different pathways of platelet aggregation. The VASP test looks only at the activation of the P2Y12-receptor pathway, but as this is the pathway used by clopidogrel to block platelet activation, it is ideal for testing responsiveness to clopidogrel. In the paper, the researchers explain that the VASP test is a new assay specific to the P2Y12 adenosine-diphosphate-receptor pathway. In this test, platelet activation is expressed as platelet-reactivity index (PRI), and low responders to clopidogrel were defined as having a PRI >60%. In the study, 461 unselected patients undergoing urgent or planned PCI were classified as low responders or responders to clopidogrel, depending on their PRI as measured by the VASP test. The patients were followed for a mean of nine months. The median value of the PRI in the 277 clopidogrel responders was 41.37, and in the 184 low responders it was 73.15. There was a significantly higher proportion of diabetic and obese patients in the low-responder group.At follow-up, the rate of dual antiplatelet therapy was equivalent between groups. Results showed that cardiac mortality rates and stent thrombosis rates were higher in patients classified as low responders to clopidogrel. Low response to clopidogrel was one of four factors identified by multivariate analysis as independent predictors of cardiac death. The others were reduced creatinine clearance, use of a drug-eluting stent, and raised CRP. The deleterious impact of a low response to clopidogrel on cardiovascular death was significantly higher in patients implanted with drug-eluting stents. While they say this result should be taken with great caution, given the inherent limitation of registry data, the limited size of the cohort, and the possible contribution of unmeasured confounding factors, they also point out that this finding supports the view that the delayed endothelium healing after drug-eluting-stent placement requires a more robust and sustained platelet inhibition than after a bare-metal stent. RE-NOVATE II: Venous-Thromboembolism-Related Deaths Halved With Dabigatran vs Enoxaparin
Major venous thromboembolism (VTE) and VTE-related mortality occurred in 2.2% of patients receiving oral dabigatran and in 4.2% of patients receiving subcutaneous enoxaparin, according to results of the RE-NOVATE II trial of patients undergoing total hip replacement. The previous trial demonstrated that dabigatran 150 mg or 220 mg orally once daily was noninferior to enoxaparin 40 mg subcutaneously once daily for the prevention of VTE and all-cause mortality after total knee and hip arthroplasty. Major VTE events included proximal deep-vein thrombosis, nonfatal pulmonary embolism, and VTE-related death. "The most important finding relates to major VTE and VTE-related death. The difference was 2.2% to 4.2% in the dabigatran vs enoxaparin groups, respectively [P = .03]. In the RE-NOVATE II trial, oral dabigatran 220 mg was given once daily for an average of 32 days after total hip replacement. In all, 1010 patients received dabigatran and 1003 received a subcutaneous injection of enoxaparin 40 mg. In terms of efficacy, the primary end point was a combination of total VTE and all-cause mortality. The main secondary end point was major VTE plus VTE-related death. Major bleeding during treatment was assessed as the key safety outcome measure. Oral dabigatran 220 mg was found to be as effective and safe as injected enoxaparin 40 mg in the prevention of total VTE. "The overall rates for all VTEs, including distal and all-cause mortality, were 7.7% vs 8.8% for patients on dabigatran and enoxaparin, respectively. This means a noninferiority margin with P <.0001. It did not meet the P value for superiority. Dabigatran is not approved by the US Food and Drug Administration for use in the United States. Major bleeding events classified as fatal, in a critical organ, or associated with a 20 mg/L drop in hemoglobin in excess of expected levels were comparable between both treatment groups. 1.4% of patients in the dabigatran group and 0.9% of those in the enoxaparin group had episodes of major bleeding (P = .40).
Risk of Cancer With Prasugrel Raised Again
During the daylong discussion of last year's controversial Food and Drug Administration (FDA) advisory panel on prasugrel (Efient, Lilly/Daiichi Sankyo), one agency official asked: "Does prasugrel cause cancer?" While his answer, as well as the consensus reached by the expert panel, was that prasugrel did not appear to cause cancer, a couple of researchers continue to warn about the possibility that prasugrel might be a promoter of cancer and that physicians should be aware of these risks, especially in patients prescribed the drug long term. TRITON-TIMI 38 show that use of prasugrel was associated with an increase in cancer risk, particularly a 62% increase in the rate of new and worsening cancers. The analysis documents all solid cancers, including nonhematologic malignant cancers, and excludes nonmelanoma skin cancer, which carries a benign prognosis and is usually excluded from clinical trials, and brain tumors. Overall, there were 92 new solid cancers among patients treated with prasugrel and 64 new solid cancers among the patients treated with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), a significant 44% increase in risk. Excluding nonmelanoma skin cancers and brain tumors, there were 112 treatment-emergent cancers in the prasugrel arm and 69 treatment-emergent cancers in the clopidogrel-treated patients, a difference that translates into a significant 62% increase in risk of these new and worsening solid cancers. In addition to these findings, there was a nonsignificant 57% increase in deaths from cancer among patients treated with prasugrel. The data show that in the CHARISMA trial, in the combination group, the patients treated with clopidogrel and aspirin, there was less cancer than in the clopidogrel-group only, even though the combination patients had more bleeding. "If the pattern is there, if there is really something going on with thienopyridines, where bleeding will cause the increased detection of cancer signal, this didn't happen with clopidogrel. In response to the new report, Lilly and Daiichi Sankyo pointed out that the FDA has already concluded it is unlikely prasugrel caused cancer and that the drug's label highlights the imbalance of newly diagnosed malignancies, which primarily occurred in the colon and lung. Also, preclinical data are "not indicative of tumor-growth enhancement," while "oncology experts have concluded that there is no biologic plausibility that prasugrel would be a tumor stimulator," according to the company.
Donna Castellone
|
About the Author
Donna Castellone, LinksPrevious Posts
Archives
|
 |
This website contains information on products which is targeted to a wide range of audiences and could contain product details or information otherwise not accessible or valid in your country. Please be aware that we do not take any responsibility for accessing such information which may not comply with any legal process, regulation, registration or usage in the country of your origin. | ||
 | ||
| ||
|
