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New In Coagulation
Wednesday, February 4, 2009
What's New in Coagulation - February 2009
U.S. FDA Staff Backs Two Hematologic Drugshttp://www.medscape.com/viewarticle/586450
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Two proposed therapies to treat rare blood disorders appear safe and effective for U.S. approval,
GTC Biotherapeutics Inc's drug Atryn for hereditary antithrombin deficiency, made from human proteins expressed in goat milk, and CSL Ltd's treatment Riastap for hypofibrinogenemria appeared to work in company studies..Both products would need further study after they begin sales, the agency reviewers said.
Summaries for both drugs were released on the FDA's website at www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4410B1-00-Index
FDA Warns That Tinzaparin Increases Mortality Risk in Elderly Patients With Renal Insufficiency http://www.medscape.com/viewarticle/586211
Celgene, the manufacturer of tinzaparin sodium injection (Innohep) issued a Dear Healthcare Professional Letter in regard to an increased risk for death in renal-impaired elderly patients receiving tinzaparin vs unfractionated heparin. The letter advises of a change in labeling to apply the warning to all renal-impaired elderly, not just those older than 90 years of age. Findings from a controlled clinical study suggest that compared with unfractionated heparin, tinzaparin may increase the risk for death when used to treat elderly patients with renal insufficiency and clinicians should consider alternatives to tinzaparin.
On the basis of analysis reported in Celgene's letter, overall mortality was 6.3% in patients receiving UFH (n = 268) and 11.2% in patients receiving tinzaparin (n = 269).
Prasugrel FDA Hearing http://www.medscape.com/viewarticle/586187
The FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) will review the investigational antiplatelet agent prasugrel for the treatment of ACS patients who are managed with PCI. Prasugrel is widely considered the most important drug in Lilly's pipeline; it will be sold under the brand name Effient if approved and is expected to be the first real competitor to clopidogrel (Plavix, Bristol-Myers Squibb).
As widely reported by heartwire, the pivotal trial for prasugrel, TRITON-TIMI 38, showed significantly reduced ischemic events with the new drug compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI. Although prasugrel was granted priority review by the FDA, there is apparently discord between members of the CRDAC about the new drug.
Inadequate Warfarin Usually Seen in Atrial Fibrillation Patients With Stroke
http://www.medscape.com/viewarticle/586591
In high-risk atrial fibrillation patients who are candidates for anticoagulation, stroke usually occurs if warfarin is not used or drug levels are subtherapeutic. Many patients in the study were receiving no antithrombotic therapy.
Included in the study were 597 patients with atrial fibrillation and a first ischemic stroke and 323 with a prior stroke or transient ischemic attack, according to the report.In the first-time stroke group, 60% of strokes were disabling and 20% were fatal, the authors note. Just 10% of patients had therapeutic levels of warfarin at the time of stroke. Twenty-nine percent of patients had warfarin at subtherapeutic levels. Single antiplatelet therapy was used in 29% of patients, dual antiplatelet therapy in 2%, and no antithrombotics in 29%.
In the prior stroke group, 18% of patients had therapeutic warfarin levels at the time of their current stroke and 39% had subtherapeutic warfarin. Single antiplatelet therapy was used in 25% of patients, dual antiplatelet therapy in 3%, and no antithrombotics in 15%.
Stroke 2009;40:235-240.
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Effect of Atorvastatin on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Subjectshttp://www.medscape.com/viewarticle/584422
Abstract and Introduction
Abstract
Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.
Design. Open-label, randomized, crossover, two-arm, parallel-group study.
Setting. Single clinical research center in the United Kingdom.
Participants. Sixty-nine healthy men aged 18 to 60 years.
Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens.
Measurements and Main Results. Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 μM and vasodilator-stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose.
Conclusion. Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.
http://www.fda.gov/medwatch/safety/2009/safety09.htm#plavix
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FDA Continuing to Study Effectiveness of Clopidogrelhttp://www.medscape.com/viewarticle/587356
The Food and Administration (FDA) announced today that it is continuing to study the effectiveness of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients taking other medications, particularly proton-pump inhibitors (PPIs), and in those with genetic variants linked with clopidogrel resistance and a subsequent increased risk of cardiovascular outcomes [1].
Two studies published last month showed strong associations between a CYP2C19 variant and recurrent thrombotic coronary events in clopidogrel-treated patients. The genetic variant is extremely common, occurring in 30% of individuals of European ancestry, 40% of individuals of African ancestry, and more than 50% of individuals of Asian ancestry, suggesting that a large number of patients are at a considerably higher risk of stent thrombosis despite treatment with clopidogrel.
The FDA early communication also states that published reports suggest that PPIs might interfere with the effectiveness of clopidogrel by inhibiting the enzyme that converts clopidogrel into its biologically active form. Not all studies have suggested this effect, the agency notes, but the drugs are commonly prescribed to patients treated with clopidogrel, as the antiplatelet can cause irritation of the stomach.
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Study Weighs Warfarin Testing Benefitshttp://www.clpmag.com/clprime/2009-01-28_04.asp
New analyses by the University of Cincinnati show that genetic testing used to guide initial dosing of the blood-thinner warfarin may not be cost-effective for typical patients with atrial fibrillation but may be for patients at higher risk for major bleeding.
Warfarin is commonly prescribed to prevent blood clotting, particularly for patients with atrial fibrillation—a type of abnormal heart rhythm.
study, says the FDA changed the labeling for warfarin in 2007, suggesting that clinicians consider genetic testing before initiating therapy.There are certain genes that are known to contribute to an increased sensitivity to warfarin. Pharmacogenetic-guided dosing is to help guide the initial, and possibly lower, dose of warfarin for patients found to possess certain variants of the genes cytochrome P450 CYP2C9 and vitamin K epoxide reductase, or VKORC1. The hope is that more accurate dosing will translate into decreased major bleeds during the initiation phase of warfarin dosing. Genotype-guided dosing resulted in better outcomes, at a relatively high cost-over $170,000 per quality-adjusted life year gained.
Researchers also looked at the impact of other variables on the cost-effectiveness of genotype-guided dosing might be worth the costs: If it is used for patients at high risk for hemorrhage , prevents more than 32% of major bleeding events and is available within 24 hours and costs less than $200
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Recommendations for Prevention of Recurrent Stroke Reviewed
http://www.medscape.com/viewarticle/587443
Recommendations for prevention of recurrent stroke are reviewed in the January issue of Mayo Clinic Proceedings. In addition to control of modifiable risk factors, virtually all patients who have had ischemic stroke should be prescribed antiplatelet agents.
The leading cause of ischemic stroke is atherosclerotic vascular disease, which gives rise to occlusion or severe stenosis of major intracranial or extracranial arteries, as well as narrowing of small penetrating arteries of the brain.Coronary artery disease, or atherosclerosis of the coronary arteries, may result in myocardial infarction, which in turn is an indirect cause of cardioembolic stroke. Atrial fibrillation and cardioembolic stroke may also complicate ischemic heart disease.
For patients with symptomatic ischemic cerebrovascular disease, a crucial aspect of treatment is prevention of recurrent stroke, myocardial infarction, and other ischemic events. This requires optimal control of modifiable risk factors that accelerate development of atherosclerosis, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking..
Specific recommendations of the American Heart Association/American Stroke Association for antithrombotic therapy in patients with ischemic stroke of noncardioembolic origin (secondary prevention), and their accompanying levels of evidence, are as follows:
- Antiplatelet agents are recommended vs oral anticoagulants (level of evidence, I, A).
- Preferred options for initial treatment are aspirin (50 - 325 mg/day), a combination of aspirin and extended-release dipyridamole, or clopidogrel (level of evidence, I, A).
- The combination of aspirin and extended-release dipyridamole may be preferred vs aspirin alone (level of evidence, I, B).
- Instead of aspirin alone, clopidogrel may be considered (level of evidence, IIb, B).
- Clopidogrel is a reasonable option for patients who are hypersensitive to aspirin (level of evidence, IIa, B).
- Addition of aspirin to clopidogrel increases the risk for hemorrhage (level of evidence, III, A).
Mayo Clin Proc. 2009;84:3-4, 43-51.
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FDA Approves Human Fibrinogen Concentrate for Treatment of Bleeding in Congenital Fibrinogen Deficiencyhttp://www.medscape.com/viewarticle/587479
On January 16, the US Food and Drug Administration (FDA) granted accelerated approval to human fibrinogen concentrate (RiaSTAP, CSL Behring). This orphan drug is intended for use in the treatment of bleeding in patients with congenital fibrinogen deficiency.
Untreated patients who have this rare genetic defect are at risk for potentially life-threatening hemorrhage because they are unable to make sufficient amounts of fibrinogen. This coagulation factor normally is manufactured in the liver and is present in plasma at a concentration of 250 to 400 mg/dL.
Human fibrinogen concentrate, an intravenous fibrinogen concentrate made from the plasma of healthy human blood donors, is indicated for patients with afibrinogenemia (no detectable fibrinogen) or hypofibrinogememia (fibrinogen levels < 50 mg/dL). However, it is not indicated for patients with dysfibrinogenemia, who have normal fibrinogen levels but defective fibrinogen function and who are at risk for both hemorrhagic and thrombotic complications.
Data leading to the licensing of the concentrate came from a study of 15 patients with afibrinogenemia who achieved the target level of fibrinogen expected to prevent bleeding after they were given human fibrinogen concentrate at a dose of 70 mg/kg. A secondary endpoint of maximum clot firmness, a surrogate marker thought to predict clinical benefit, was present in plasma from 14 of the 15 patients. The most frequently reported adverse reactions were fever and headache.
US prevalence of fibrinogen deficiency is only 150 to 300 people. Bleeding from the umbilical cord site usually leads to diagnosis at birth. Parents of children diagnosed with fibrinogen deficiency are counseled to keep them from sports or other activities that could cause minor trauma and lead to bleeding.
A postmarketing study of both afibrinogenemic and hypofibrinogenemic patients will further assess clinical benefit of human fibrinogen concentrate.
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Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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