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New In Coagulation

Friday, September 3, 2010

WHAT'S NEW IN COAGULATION: SEPTEMBER 2010

Prescribe Aspirin Early in Pregnancy to Cut Preeclampsia Risk: Meta-Analysis

Low-dose aspirin treatment of pregnant women at risk for preeclampsia can more than halve the risk of preeclampsia, preterm birth and intrauterine growth retardation (IUGR), a meta-analysis shows. Preeclampsia and IUGR are related to defective placentation, he and his colleagues explain in the August issue of Obstetrics & Gynecology. It's believed that as a result, inadequate perfusion and placental ischemia lead to endothelial dysfunction, with platelet and clotting system activation. If that's so, then aspirin should prevent vasoconstriction and pathological blood coagulation in the placenta that causes preeclampsia and IUGR.The problem is that randomized trials of prenatal aspirin have had contradictory results. The research team theorized that starting aspirin too late in pregnancy and including low-risk women in the trials could account for the negative results.

Through a search of Embase, PubMed and the Cochrane database, they identified 34 randomized controlled trials published between 1985 and 2005. The trials included 11,348 women with risk factors for preeclampsia, e.g., nulliparity, multiple pregnancy, abnormal Doppler ultrasound of the uterine artery, or a history of preeclampsia, other hypertensive disorders, IUGR, or stillbirth.Treatment groups received aspirin 50-150 mg/day, either alone or with dipyridamole less than 300 mg daily; control groups received placebo or no treatment. The authors stratified the studies according to gestational age at randomization (through 16 weeks, 12 studies; after 16 weeks, 22 studies).

Only when treatment started before 16 weeks did the researchers see significant differences in rates of preeclampsia, preterm birth, and IUGR.In the early treatment group, compared with placebo, aspirin significantly lowered the risk of preeclampsia (relative risk 0.47), IUGR less than the 10th centile, (RR 0.47), and preterm birth (RR 0.22), with numbers needed to treat of 8 or 9.

Obstet Gynecol. 2010;116:402-414.

Vitamin B Supplements May Not Prevent Second Strokes Or Heart Attacks.

Stroke patients who take vitamin B supplements to lower their homocysteine levels may not be protected from second strokes or heart attacks." Previous research pinpointed "an association between homocysteine, an amino acid, in the blood, and an increased risk for stroke and heart attack. Vitamin B supplements lower homocysteine levels, but whether this really has an effect on stroke and heart attack risk has been unclear," researchers in Australia pointed out.

So, they conducted a clinical trial that included "more than 8,000 patients in 20 countries" who were randomized to either placebo or a supplement that "contained 2 mg of folic acid, 25 mg of vitamin B-6, and 0.5 mg of vitamin B-12. "Through a median follow-up of 3.4 years, there was no significant between-group difference in the primary composite endpoint of stroke, MI, or vascular death," according to the paper in The Lancet Neurology. The author of an accompanying editorial did point out, however, that "even though the trial failed to show a 15% relative risk reduction in the supplementation group...there was evidence of a weaker risk reduction," and "if that is the true effect of the intervention, then B vitamins could still be potentially worthwhile

Bayer Says Xarelto As Effective As Standard Therapy In Preventing Blood Clots In Lungs, Legs.

Bayer AG's Xarelto [rivaroxaban] drug was as effective as the standard therapy of Sanofi-Aventis SA's Lovenox [enoxaparin] plus warfarin in preventing potentially deadly blood clots in the lungs and legs, the company said." Study participants "taking the anti-clotting pill were as likely to develop serious and uncontrolled bleeding, a potential side effect of the medicine, as those on the standard therapy combination, Bayer said in a statement, citing results of a late-stage clinical trial. Xarelto beat the standard therapy on a measure that counted only clot prevention and the most serious bleeding." The drug is currently approved in the EU for the prevention of clots following knee and hip replacement. The drugmaker has to refile its US application for this indication because the FDA requested more data on the drug. The company has indicated that it intends to refile later this year.

EINSTEIN-DVT: Rivaroxaban Meets Primary End Point in VTE Trial

The use of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is noninferior to standard medical therapy for reducing the cumulative incidence of symptomatic recurrent venous thromboembolism (VTE) [1]. The trial began in 2007, enrolled approximately 3400 patients, and was expected to be completed in 2011. Of the patients enrolled in the study, half were randomized to rivaroxaban 20 mg and half to enoxaparin 1.0 mg/kg twice daily for a minimal duration of five days followed by treatment with a vitamin-K antagonist. The primary end point was the recurrence of symptomatic VTE. Secondary outcome measures included clinically relevant bleeding, including major bleeding, and deaths and vascular events. Ttreatment with rivaroxaban resulted in an improved net clinical benefit, a composite of the primary efficacy end point plus major bleeding.

Administering Clopidogrel In The Cath Lab After Coronary Angiography As Safe, Effective As Pretreatment.

Patients undergoing percutaneous coronary intervention who are loaded with a high dose of clopidogrel in the cath lab have outcomes similar to those who are preloaded with clopidogrel prior to undergoing coronary angiography," according to a paper in Journal of the American College of Cardiology. "Currently, the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions recommend 300 to 600 mg of clopidogrel as early as possible before PCI, whereas the European Society of Cardiology recommends a 300-mg loading dose at least six hours before PCI." Yet, researchers in Italy found that "overall, 8.8% of" study participants "who received clopidogrel in the lab had a MACE [major adverse cardiac events], compared with 10.3% of the preload patients."

Rituximab May Be Safe, Effective For Patients With Refractory SLE.

Rituximab (Rituxan) appears to be both effective and safe for patients with refractory systemic lupus erythematosus (SLE)," according to a study published in the August issue of the journal Arthritis & Rheumatism. In a study of 136 SLE patients, researchers saw an "overall clinical response...in 71%." But, an editorial accompanying the study "cautioned that 'it cannot be assumed that treatments such as rituximab, which have failed to meet their primary endpoints in placebo-controlled trials, are effective.' However, they noted the difficulty of abandoning treatments with anecdotal and observational trial efficacy as well as biologically plausible mechanisms of action."

FDA Warns Physicians About Problems Associated With IVC Filters.

Medical filters that stop blood clots from reaching the lungs can move or break and cause life-threatening problems for patients, the government and a medical journal report said Monday." The AP adds, "In an advisory to doctors and patients, the Food and Drug Administration said it has received more than 900 reports about problems with these filters since 2005." Notably, the "problems can arise when filters are left inside veins too long, retrievable filters stay in permanently because patients are lost to follow-up,' or doctors don't know problems can occur when the devices are left in long-term. These "filters are tiny, spider-like implants that are placed into the inferior vena cava, which returns blood from the lower half of the body to the heart. They have thin metal legs that hold them in position in the vein and others that filter out blood clots before they can reach the heart." IVC filters "are primarily used to treat venous thromboembolism, or the formation of blood clots in the veins. About 200,000 Americans develop this problem each year."

The FDA recommended that physicians consider removing the IVC filter as soon as the pulmonary embolism risk subsides -- since the risk of device migration and fracture appears related to the length of time the filter remains in the body." Meanwhile, "a study of 80 patients treated at one Pennsylvania hospital who had an IVC filter remaining in place suggested a particularly high risk of fracture and embolization for two popular devices made by Bard. The study was released online the same day as the FDA warning."

FDA Clears All-in-One Reconstitution/Administration Syringe for Xyntha

The US Food and Drug Administration (FDA) has granted 510(k) clearance for a device (Prefilled Dual-Chamber Syringe; Pfizer, Inc) used to reconstitute and administer antihemophilic factor (recombinant) plasma/albumin-free intravenous infusion (Xyntha; Pfizer) in patients with hemophilia A. The all-in-one syringe is the first to supply freeze-dried albumin-free recombinant factor VIII and also the diluent (0.9% sodium chloride), thereby eliminating the reconstitution transfer step and improving patient convenience.The first ready-to-use syringe will be marketed in November 2010 and is designed to provide 3000 IU antihemophilic factor in a 4-mL volume. Lower doses are expected to be available in 2011.Albumin-free recombinant factor VIII uses a next-generation purification process designed to address the potential risk for murine and other viral contamination. Previously available in single-use vials containing 250, 500, 1000, or 2000 IU freeze-dried powder, the product is indicated for the control and prevention of bleeding episodes and for surgical prophylaxis in patients with hemophilia A.

Researchers Assess Dexamethasone, Postoperative Bleeding Risk In Pediatric Tonsillectomy Patients.

For pediatric tonsillectomy, postoperative bleeding risk doesn't rise with intravenous dexamethasone dose." In fact, "postoperative hemorrhage of any severity actually tended to be less common among children who got a 1.0-mg/kg dose than a 0.5-mg/kg dose (odds ratio 0.66, 95% confidence interval 0.42 to 1.05)," researchers at the Naval Medical Center San Diego found. "The same was true for bleeding that required operative intervention.

Concomitant Use Of PPI, Clopidogrel May Increase MI Risk, But Not Death.

Concomitant use of a proton pump inhibitor and clopidogrel (Plavix) significantly increased the risk of myocardial infarction but not death." In fact, after reviewing 25 studies that included nearly 160,000 patients, researchers discovered a "31% increase in the relative risk of MI (95% CI 1.12 to 1.53) among patients who took the two drugs together, compared with those who did not." Investigators also found that "treatment with a PPI reduced the risk of gastrointestinal (GI) bleeding by 50% in patients receiving clopidogrel alone or with a placebo."

Newer P2Y12 Inhibitors May Reduce All-Cause Mortality Compared With Clopidogrel.

Newer P2Y12 inhibitors reduce all-cause mortality compared with clopidogrel (Plavix), the older member of the class," according to a study published online in the Journal of the American College of Cardiology. Investigators reported that "pooled data from trials of prasugrel (Effient) and three investigational drugs showed that the newer medications significantly decreased death during follow-up by 17%." The researchers found that "the results were similar for patients undergoing percutaneous coronary intervention (PCI) for any reason (OR 0.85, 95% CI 0.75 to 0.96) and those undergoing PCI for ST-segment elevation MI. TIMI major bleeding was more common with the newer P2y12s in the all-PCI group...but there was no difference in major bleeding between patients on new p2y12s and clopidogrel in the PCI-for-STEMI patients."

Federal Judge Rejects Sanofi's Requests To Bar Generic Lovenox.

"Sanofi-Aventis SA's request to bar the US Food and Drug Administration from allowing sales of a lower-cost rival to its Lovenox [enoxaparin sodium injection] blood thinner were rejected by a federal judge yesterday." US District Judge Emmet Sullivan in Washington "denied the request, which would have forced the regulator to suspend its approval of the generic produced by Novartis AG's Sandoz unit with Momenta Pharmaceuticals Inc.'s technology."

Reduced Plavix Efficacy Associated With Specific Gene Variants Confirmed In Two New Analyses, But Not In A Third.

Patients with acute coronary syndrome, physicians often turn to Plavix (clopidogrel) to prevent clot-induced strokes and heart attacks. However, a significant number of patients carry genetic variations that impede the drug's effectiveness. While some believe a genetic test could help physicians make more accurate treatment decisions, others are wary. Now, two new studies are providing evidence that genetic testing may have limited value when considering a Plavix prescription. The trials are especially significant because of the recent arrivals of Plavix generics to the market. There are no clear winners yet, however, as a third trial indicates that Plavix may indeed benefit patients who were previously thought to imperfect candidates due to their genetic make-up. After analyzing "gene variations in more than 10,000 patients who participated in the PLATO study," an international team of researchers found that Brilinta (ticagrelor) "cut the risk of heart attacks, strokes, and death linked to heart disease more than Plavix, at a higher risk of spontaneous major bleeding, regardless of genetic variations." In the second study, "funded by Lilly and Daiichi Sankyo" and also published in The Lancet, Harvard "researchers analyzed patients from the 2007 Triton trial to find that a genetic variation that diminished the effectiveness of Plavix didn't have the same effect on Effient's [prasugrel] potency. However, "in the CURE trial of patients with acute coronary syndromes without ST-segment elevation, clopidogrel significantly reduced the rate of cardiovascular death, MI, or stroke compared with placebo, regardless of CYP2C19 genotype (HR 0.71, 95% CI 0.60 to 0.84

Manufacturers Seeking Stroke-Preventing Treatments Meant To Best Warfarin.

Boehringer Ingelheim GmbH may be the first drugmaker to win US approval of a revolutionary alternative" to warfarin for preventing strokes, Pfizer Inc. and Bayer AG "will present data at a medical meeting tomorrow on pills racing to overtake Boehringer's Pradaxa [dabigatran etexilate]." Pfizer is working with Bristol-Myers on apixaban and Bayer is partnered with J&J on Xarelto (rivaroxaban). "For Pfizer and Bristol-Myers, getting apixaban to market is critical as they brace for generic competition to their top- selling pills."

Certain Octagam Lots Recalled After Reports of Blood Clots, Embolisms

Octapharma USA is voluntarily recalling 31 lots of immune globulin G (IgG) intravenous (human) 5% liquid preparation (Octagam) based on increased reports of thromboembolic events, the US Food and Drug Administration (FDA) announced yesterday. This intravenous preparation of IgG is FDA-approved to treat primary immunodeficiency diseases such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. A boxed warning on the label states that renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with intravenous Ig products in predisposed patients. The FDA reports that 9 thromboembolic events were possibly associated with 7 lots of IgG intravenous 5% liquid preparation being withdrawn from the market. In collaboration with the agency, Octapharma has developed a number of tests that may predict the potential for increased risk for thromboembolic events with intravenous Ig products. These tests have raised questions about an additional 24 lots of intravenous IgG, which also are being withdrawn as a precaution, according to the FDA.In a press release, the company stated that thromboembolic events such as stroke, myocardial infarction, and deep vein thrombosis "have been observed with all intravenous [Ig] products."

RE-LY INR Analysis Confirms Dabigatran Benefits Across Spectrum of Warfarin Dosing

A RE-LY trial analysis, showing that dabigatran etexilate (Boehringer Ingelheim) is noninferior in the lower dose and superior with the higher dose to warfarin for stroke prevention in patients with atrial fibrillation, regardless of the average international normalized ratio (INR) control achieved in the warfarin comparator group, is now published online August 29, 2010 in the Lancet [1].

The results of the post hoc analysis are published just weeks before dabigatran goes before the FDA's Cardiovascular and Renal Drugs Advisory Committee on September 20, 2010. ]. Those results showed that dabigatran prevented strokes and peripheral embolic events in patients with atrial fibrillation significantly better than warfarin at a higher dose and just as well at a lower dose in a huge randomized trial of more than 18 000 patients.

The current analysis looked specifically at the level of INR control at the 951 sites participating in the study, with average INR per site serving as an approximation for all patients treated at that center. Even in centers where INR control was excellent, dabigatran was noninferior at the 110-mg dose and superior at the 150-mg dose to warfarin for prevention of stroke or systemic embolism, the primary outcome of RE-LY. Rates of intracranial hemorrhage (ICH) were lower at both doses of dabigatran than in the warfarin group, and major bleeding was at least noninferior to warfarin, regardless of INR control across centers. For the 150-mg dose, there were fewer bleeding events in the dabigatran-treated patients than in the warfarin-treated patients in the lower time-in-treatment-range (TTR) groups, and no differences in the higher TTR ranges. For the 110-mg dabigatran dose, major bleeding was lower for the dabigatran patients irrespective of TTR.

These findings support the superiority of 150-mg dabigatran twice daily and the noninferiority of 110-mg dabigatran twice daily vs warfarin for protection against stroke in atrial fibrillation, irrespective of the quality of INR control that a center can achieve. However, there seemed to be lower rates of nonhemorrhagic stroke at higher . TTR quartiles in the warfarin group, which is in accordance with previous findings. Accordingly, 150 mg dabigatran was not superior to warfarin at reducing the risk of nonhemorrhagic stroke at higher . . . TTR quartiles.

The RE-LY INR analysis supports the notion that patients currently excluded from warfarin therapy might be eligible to take newer anticoagulants, such as dabigatran, although only time will tell. In the meantime, attention should turn to the problem of optimizing warfarin dosing, they suggest, noting that TTR in therapeutic range varied widely in the RE-LY study, from 40% to 70%.

Drugmakers Competing To Develop Medications To Prevent Blood-Clotting Problems.

The leading drugmakers are competing to reach the market with a new class of pills to prevent the kind of dangerous blood clots in the veins and lungs that can travel to the brain, causing strokes." Currently, the FDA is "reviewing an application for Johnson & Johnson for rivaroxaban to reduce the risk of dangerous blood clots in people undergoing knee or hip replacement surgery." The agency is also "reviewing an application from Boehringer Ingelheim for dabigatran as a stroke prevention drug in patients with atrial fibrillation, the company said in a statement Monday."

Eisai's Experimental Anti-Clotting Drug May Reduce Certain Heart Risks.

Eisai Co.'s experimental anti-clotting drug may cut the risk of heart attacks, death, stroke, and repeated blockage of blood vessels without increasing the potential for serious bleeding, two studies found." Researchers found that "patients taking Eisai's E5555 together with drugs currently used in standard treatment were no more likely to suffer the side effect than people taking placebos," according to "the studies released...at the European Society of Cardiology Congress in Stockholm."

Researchers Say Experimental Blood-Thinner May Work Quickly In Patients Who Have Surgery To Unblock An Artery.

Portola Pharmaceuticals Inc. said its partner Novartis AG will begin final-stage testing of the experimental blood thinner elinogrel after researchers found it worked quickly in patients who had surgery to unblock an artery." Researchers found that "elinogrel took effect within a half hour to keep the blood's platelets from sticking together and forming a clot." However, the research, presented at the European Society of Cardiology conference, indicated that "the drug left patients at a higher risk of bleeding requiring medical attention and liver complications than...Plavix [clopidogrel].

Low Dose Of Unfractionated Heparin Appears To Be Preferable In Elective PCI To Higher Doses.

A new study has established that a 100-U/kg dose of unfractionated heparin appears to be preferable in elective PCI to higher doses previously recommended." In fact, the "ISAR REACT 3A study," which is detailed in the European Heart Journal, revealed that the "100-U/kg dose shows a net clinical benefit over the previous dose of 140 U/kg, with the benefit driven by a reduction in bleeding." The "trial also suggested that the 100-U/kg heparin was dose 'noninferior' to bivalirudin in this setting of PCI in biomarker-negative patients.

New Class of Antiplatelet Agents in Clinical Trials

A new investigational antiplatelet agent, atopaxar (E5555; Eisai)--which acts via a different pathway from that of aspirin and drugs such as clopidogrel and ticagrelor--has shown promising results in a two-arm phase 2 trial in Japan, one part in ACS patients and the other in people with high-risk CAD

Atopaxar, a protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation, also looks to have a good safety profile--there was a dose-dependent trend to an increased risk of nuisance bleeding in the study but no sign of any increase in clinically significant bleeding. However, there were some concerning signals with regard to liver function and prolongation of the QTc interval; but "in my mind, this drug should be tested in phase 3 trials," Goto said. The company developing the drug has not yet decided whether to go ahead with these, he noted. Another larger phase 2 trial with atopaxar, this time in mostly white, older patients, will be presented at TCT 2010 next month..

Phase 3 Studies Should Use 100 mg or Possibly 75 mg of Atopaxar

In the J-LANCELOT trials, 241 patients with acute coronary syndrome (unstable angina and NSTEMI) were given atopaxar at a loading dose of 400 mg followed by placebo or atopaxar 50 mg per day, 100 mg per day, or 200 mg per day for 12 weeks. More than 95% of the ACS patients were also taking aspirin and clopidogrel. Meanwhile, 263 patients with coronary artery disease were randomized to placebo or the same doses of atopaxar, this time for 24 weeks. All CAD patients were on aspirin, and around 40% were also taking clopidogrel.

The primary safety end point of the trials was bleeding events; the secondary end points were MACE (cardiovascular death, MI, stroke, recurrent ischemia) and inhibition of platelet aggregation (IPA).

Although there was a numerical trend toward an increase in any bleeding incidence with increasing doses of atopaxar, this was not statistically significant. Clinically significant bleeding consisting of TIMI major and minor bleeding and minimal bleeding requiring medical attention was almost the same between the placebo and combined active groups, 1.5% vs 1.5% in those with CAD and 6.6% vs 5.0% in ACS patients, respectively. While not powered to establish efficacy in both patient groups, all active groups demonstrated a numerically lower incidence of MACE relative to placebo, although the overall number of events was very low. MACE in the active group compared with the placebo group in the CAD trial was 1.0% vs 4.5% (p=0.066), and in the ACS trial it was 5.0% vs 6.6% (p=0.73). The MACE seen in these trials were predominantly driven by recurrent ischemia in the CAD patients and by MI in the ACS patients..

And atopaxar produced strong inhibition of platelet aggregation--at trough levels, over 90% mean inhibition of platelet aggregation was achieved with doses of 100 mg and 200 mg, and 20% to 60% inhibition was achieved with a dose of 50 mg in both study groups..

Four-Year REACH Analysis Grasps a Variety of Clinical Factors That Flag Atherothrombosis Risk

The final follow-up data from the international Reduction of Atherothrombosis for Continued Health (REACH) registry shows that markers of future ischemic risk can be easily identified REACH is a worldwide registry run by a multidisciplinary group of investigators intended to illuminate cardiovascular risk factors in stable outpatients. The latest analysis covers four years of data from 45 227 outpatients with coronary artery disease, peripheral artery disease, cerebrovascular disease, or multiple known risk factors for atherothrombosis at 3647 centers in 29 countries. Multivariable analysis of the data turned up clearly demarcated subgroups of atherothrombotic patients with widely varying risks of subsequent ischemic events, ranging from 7% in nondiabetic patients with some risk factors for atherothrombosis to 25% for patients with polyvascular disease who had suffered previous ischemic events. The multivariable model also shows that the presence of diabetes (hazard ratio 1.44), an ischemic event in the previous year (HR 1.71), and polyvascular disease (HR 1.99) each predict a significantly higher risk of cardiovascular death, MI, or stroke.

Geographically, people in Eastern Europe and the Middle East were at the highest risk, while Japanese patients had lower-than-average risk.During the four years of follow-up, 5481 patients experienced at least one cardiovascular adverse event, including 2315 cardiovascular deaths. A total of 1228 patients had an MI, 1898 had a stroke, and 40 had both an MI and stroke on the same day. Among patients with atherothrombosis, the 21 890 patients with previous history of ischemic events at baseline had the highest rate of subsequent ischemic events (18.3%). The 15 264 patients with stable coronary, cerebrovascular, or peripheral artery disease had a lower risk (12.2%), and the 8073 patients with risk factors but no established atherothrombosis had only a 9.1% risk (p<.001 for all comparisons).

One of the potential drawbacks of the study is that it mixed together individuals who had only cardiovascular risk factors with patients with cardiovascular disease. "Theoretically, at least, the risk-factor-alone group that had at least three strong cardiovascular risk factors but had no symptoms may have undergone a degree of selection biases, whereby they may have something that protects them, despite the risk factors, from the development of symptoms," Andreotti said. She suggested that the only way to address this potential bias in these studies to include a parallel healthy control arm in these studies.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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