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New In Coagulation

Monday, August 2, 2010

WHAT'S NEW IN COAGULATION: AUGUST 2010

Bristol-Myers Squibb Voluntarily Recalls Coumadin Samples.

Bristol-Myers Squibb has voluntarily recalled a number of blister packs of its anticoagulant warfarin, Coumadin, 1 mg, provided as samples to physicians and hospitals. The recall is a precautionary measure, based upon the possibility that some of the tablets included may not contain the correct amount of isopropanol, an additive required to maintain the active ingredient in a crystalline state. Our medical assessment indicates that there does not appear to be a clinically important risk related to Coumadin 1-mg tablets in regard to isopropanol level. Use of tablets with low isopropanol could lead to patient-to-patient variation in bioavailability, it notes, but "there have been no reports of adverse events related to this issue."

The affected lots include physician samples labeled 9A48931A, 9A48931B, and 9A48931C, with an expiration date of January 2012, and hospital unit dose (HUD) blister packs 8F34006B, 8k44272A, 8K46168A, 9F44437A, and 9K58012B, with expiration dates between June 2011 and November 2012. The recall affects only the US market and is being conducted with the knowledge of the FDA.

Clinical Trials To Continue For Potential Hemophilia Drug.

Biogen Idec Inc. and Swedish Orphan Biovitrum will continue clinical testing of a potential hemophilia drug based on promising results from an early trial." The companies "are testing a form of a protein called factor VIII," which "is involved in the formation of blood clots, and people with hemophilia A have little or none of it." Biogen and Biovitrum also "said that in an early study on 16 patients, their drug was safe and had 'a prolonged half-life' compared an older drug, Advate."

Improper Administration Of Hemostatic Agents Using Pressurized Sprayers May Lead To Air Or Gas Embolisms.

Clinicians administering hemostatic drugs or biological products, such as fibrin sealants with sprayers pressurized by air or gas, should adhere to recommendations for using these agents and sprayers to avoid life-threatening air or gas embolisms, the US Food and Drug Administration (FDA) announced. The agency is "not attributing the problem to the sprayers or agents in themselves." Instead, FDA officials "stated that the adverse events apparently stem from clinicians using sprayers in a manner inconsistent with approved product labeling and instructions. Altogether, "at least seven types of fibrin sealant sprayers were associated with air or gas embolisms, which appear to have occurred when pressure settings were too high or the sprayer tip was too close to the bleeding site. In addition to following the listed recommendations for pressure settings and proper distances for application, clinicians should be sure to monitor patients' blood pressure, pulse, oxygen saturation, and end-tidal CO2 levels for signs of embolism," officials explained. "The sprayers should also be maintained and tested regularly."

The sprayers in question, which come with dual syringes, simultaneously blend and apply 2 nonhomogenous liquids within a single spray head. They are connected to a pressure regulator and a source of compressed air or gas. The FDA listed a number of sprayers potentially subject to misuse in its announcement:

EasySpray and spray set used with Duploject system (Baxter Healthcare)
Tissomat and spray set used with Duploject system (Baxter Healthcare)
Evicel application device (Omrix Medical)
FibriJet aerosol applicator (MicroMedics)
HemaMyst surgical applicator system (Haemacure)
MicroMyst applicator and air pump models 20-5000 and AP-A-6063 (Confluent Surgical)
Vitagel hemostat spray set (Orthovita)

In addition to following recommendations on pressure settings and the distance between spray head and tissue surface, clinicians should monitor blood pressure, pulse, oxygen saturation, and end-tidal CO₂ for signs of an air or gas embolism. They also should ensure that regulators are properly maintained and regularly checked for safe performance, according to the FDA.

FDA Approves Generic Version Of Lovenox.

US Food and Drug Administration approved its generic version of Sanofi-Aventis SA's Lovenox [enoxaparin], an injected drug for preventing life-threatening blood clots.

The FDA also rejected an argument by Lovenox's maker, Sanofi-Aventis, that its drug, which is made from sugar molecules found in heparin, a substance derived from pig intestines, is too complex to be copied with precision by makers of generic versions of the medication."

House Lawmakers Say China Failed To Investigate Contaminated Heparin.

Chinese authorities did not investigate the tainted heparin which was sold in the US in 2007 and 2008, and has been connected to the deaths of about 81 Americans. Rep. Joe Barton (R-TX) said, "It is shocking to find out two years after Chinese-made heparin was killing Americans, the Chinese government still has done no investigating to find out why." Barton urged FDA Commissioner Margaret Hamburg, who is about to visit China, to discuss the matter with Chinese officials, who have stated that the charges are untrue.

Therapeutic Window Identified for Clopidogrel?

The first evidence of a "therapeutic window" for P2Y12-inhibitor antiplatelet agents such as clopidogrel has been reported, with the suggestion that hyperresponders and hyporesponders to these agents are not achieving the optimal levels of platelet inhibition There seems to be an optimal level of platelet aggregation, and there are problems at both ends of the spectrum.

Stent Thrombosis vs Bleeding Risks

Using the Multiplate analyzer test, levels above 468 aggregation units signal a high level of platelet aggregation--so a low responder to clopidogrel who is at increased risk of cardiac events. In contrast, levels below 188 aggregation units signal a low level of platelet aggregation--so an enhanced responder who will be at increased risk of bleeding. Normal responders--those with values between 188 and 468 aggregation units--have a very low risk of either cardiac events or bleeding. This is the first time this has been shown, and it suggests there is a therapeutic window for thienopyridine P2Y12-inhibitor agents. For the study, the researchers measured platelet aggregation in 2533 patients in the cath lab just before PCI. Using the cutoff values of 188 and 468 aggregation units, patients were classified as enhanced responders, low responders, or normal responders. Results showed that stent thrombosis was highest (2.8%) in low responders, and the incidence of bleeding was highest in enhanced responders (2.2%). Normal responders did not show increased risks of either stent thrombosis or major bleeding; the risk of these events was reduced by 60% in this group responders, compared with low or enhanced responders (odds ratio, 0.40; 95% CI, 0.22 to 0.75; p<0.003).

Sibbing noted that "people used to say the higher the platelet inhibition the better, but actually we have shown that the highest rates of inhibition are associated with increased bleeding. This makes perfect sense." They found that 38% of patients fit into this category of enhanced responders. Fewer patients (around 17%) were found to be low

Standardization of Tests Needed

This therapeutic window for thienopyridines is difficult to deal with because of many variables. There is a therapeutic window with coumarin but there are highly standardized tests to deal with this. This is not the case with platelet-function testing. There are a lot of devices and no standardization. And you are measuring something that is subject to change. There is lots of work to be done in this regard. The stability of these hypo- and hyperresponder phenotypes has not been shown over time. We have to monitor patients more often to assess this.

Extended Stroke Treatment Window Appears To Be A Safe Option For Saving Lives.

Extending the time window to treat stroke patients with the clot-dissolving drug tPA from three hours to up to 4.5 hours after the onset of stroke doesn't result in any significant delays in treatment and appears to be a safe option for saving lives. The "three-hour post-stroke time limit was set because of fears that use of the clot-dissolving drug beyond that period might cause dangerous bleeding or other complications," but after the "publication of two landmark studies, the American Heart Association, the American Stroke Association and the European Stroke Association revised their guidelines in October 2008 to recommend that tPA be used up to 4.5 hours after the onset of an ischemic stroke.

So, researchers at the Karolinska Institute "analyzed data from 23,942 patients with ischemic stroke who were included in SITS-ISTR [the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry] between December 2002 and February 2010 reported. "Although the rate of symptomatic hemorrhage and death was higher among those treated beyond three hours -- and the rate of functional independence was lower -- the benefits of treatment in that window outweighed the risks," the researchers explained. In fact, "safety and functional outcomes are less favorable after three hours, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier

FDA Panel To Review AstraZeneca's Experimental Blood Thinner.

Food and Drug Administration "regulators say" Brilinta (ticagrelor), "an experimental blood thinner from AstraZeneca PLC appears effective, though study results in the US did not match those seen abroad." AstraZeneca has asked the agency to approve the drug "to prevent blood clots in patients at risk for heart problems," but "FDA regulators have questions about the" drug's effectiveness, "according to a review posted online Monday afternoon," particularly since US patients taking it were "more likely to report heart problems.It requires two doses a day, the cardiology community is excited about the drug because it may offer an alternative for the roughly 30% of acute coronary syndrome patients who don't respond to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and because ticagrelor's antiplatelet effects quickly dissipate after dosing is stopped, making it suitable for patients who may need surgery on short notice."

FDA Advisors to Contemplate PLATO at July 28 Meeting on Ticagrelor

The cardiology community is excited about the drug because it may offer an alternative for the roughly 30% of acute coronary syndrome patients who don't respond to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and because ticagrelor's antiplatelet effects quickly dissipate after dosing is stopped, making it suitable for patients who may need surgery on short notice. Also, ticagrelor is not a thienopyridine like clopidogrel or prasugrel (Effient, Lilly/Daiichi), which has been linked to higher rates of bleeding than either ticagrelor or clopidogrel.

Ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with clopidogrel in the phase 3 Platelet Inhibition and Patient Outcomes (PLATO) trial, first reported at the 2009 European Society of Cardiology Congok ress. In the study, ticagrelor saved 14 lives per 1000 treated, according to the PLATO investigators.

Some cardiologists have warned that, due to its twice-daily dosing, ticagrelor may not be suitable for some patients. Also, 14.2% of patients on ticagrelor experienced dyspnea, compared with only 9.2% of the clopidogrel patients (p<0.001), although a new retrospective analysis shows that this common side effect resolves quickly and does not appear to cause any lasting problems. The FDA’s expert panel will likely weigh both of these concerns and what kind of labeling these issues might require, if the drug is ultimately approved.

The FDA panel may also discuss why PLATO showed a statistically insignificant trend toward worse outcomes with ticagrelor vs clopidogrel among the North American patients in the study, who made up 1800 of the total 18 000 patients. Most of the documentation on PLATO relates to the whole study population, so if the committee believes that the several different patient types should be considered separately, it will need to separately consider how this geographic disparity might affect each indication.

FDA Approves First Generic Enoxaparin Injection

The US Food and Drug Administration (FDA) has approved the first generic formulation of enoxaparin sodium injection (Sandoz, Inc; brand name, Lovenox; Sanofi-Aventis US, LLC), a low-molecular-weight heparin product used for multiple indications, including the prevention of deep vein thrombosis (DVT). The agency had previously received a citizen petition questioning the approval criteria for generic enoxaparin injection. Although generic approvals are typically based on manufacturer data demonstrating therapeutic equivalence with the brand-name product, the process can be more complex for a naturally derived product such as enoxaparin.

As with the brand-name formulation, generic enoxaparin injection will be available in prefilled syringes containing 30 mg/0.3 mL, 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL, 120 mg/0.8 mL, and 150 mg/mL.

Enoxaparin injection is indicated for DVT prophylaxis in patients undergoing abdominal and hip/knee replacement surgery and those with severely restricted mobility during acute illness. It also is approved for the treatment of acute DVT with or without pulmonary embolism, the treatment of acute ST-segment elevation myocardial infarction, and the prevention of ischemic complications from unstable angina and non-Q-wave myocardial infarction.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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