What's New: AUGUST 2008
What’s new: AUGUST 2008
Update on Heparin
Serious injuries and deaths have been associated with the use of heparin, a blood-thinning drug that contained active pharmaceutical ingredient (API) from China. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain
Questions and Answers
• Updated Questions and Answers on Heparin Sodium Injection (Baxter) (6/18/2008)
• Questions and Answers on Heparin, Medical Devices and In-vitro Diagnostic Assays (6/3/2008)
Screening Methods
** New Information ** (7/7/2008)
The United States Pharmacopeia (USP) has recently published updated compendial test methods for heparin sodium USP to include the two screening tests previously posted on FDA’s website. Effective immediately, in accord with section 501(b) of the FD&C Act, all heparin sodium USP must meet compendial requirements as specified at the following link http://www.usp.org/hottopics/heparin.html.
All other measures used to prevent contaminated heparin products from entering the US should remain in place, and we request that all heparin suppliers and manufacturers continue reporting results to FDA as outlined in the section "Heparin Test Results" until further notice.
http://www.medscape.com/viewarticle/575056
Reproducibility of Pretest Assessment in Suspected Pulmonary Embolism
Lori-Ann Linkins, MD, MSc(Epid), FRCPC
Lab Med. 2008;39(6):361-364. ©2008 American Society for Clinical Pathology
Role of Clinical Assessment in Suspected Pulmonary Embolism
Pulmonary embolism (PE) is a leading cause of mortality in North America. Prompt recognition and treatment of PE with anticoagulant therapy reduces the risk of mortality from 30% to 1.5%. Unfortunately, timely diagnosis of PE can be difficult because the clinical features of PE, such as chest pain and rapid heart rate, are not unique to PE. Although clinical assessment alone cannot confirm or exclude PE, it can be used to stratify patients according to their likelihood of having PE before diagnostic tests are performed (ie, pretest probability). This paper will review the role of clinical assessment in the diagnosis of PE, provide an overview of validated clinical prediction rules for PE, and discuss the reproducibility of clinical pretest probability assessment in suspected PE.
Role of Clinical Assessment in Suspected Pulmonary Embolism
Signs and symptoms considered "typical" for pulmonary embolism (PE) include dyspnea, pleuritic chest pain, hemoptysis, and tachycardia; however, this exact combination of features is uncommon, and each individual feature is associated with a number of other diseases (eg, myocardial infarction, pneumonia). Treating all patients who present with these features with anticoagulant therapy reduces the risk of missing a potentially fatal PE; however, this approach also increases the risk of serious bleeding complications, including fatal hemorrhage, in patients who do not have PE. Accurate identification of patients who have PE therefore depends on the performance of at least 1 objective test.
Although clinical assessment alone cannot confirm or exclude PE, it can be used to guide the performance and interpretation of objective tests. Bayes' theorem predicts that the posttest probability of a patient having a target disorder is determined by 1) the pretest probability of the target disorder, and 2) the sensitivity and specificity of the diagnostic test.[1] If the diagnostic test is positive and the pretest probability of the disorder is high, the posttest probability of the disorder will also be high (ie, true positive result). In contrast, if the diagnostic test is positive, but the pretest probability is low, the posttest probability of the disorder will decrease (ie, more likely a false positive result). Clinical assessment is therefore used to estimate a patient's pretest probability of PE, which is then combined with the result of an objective diagnostic test to determine whether or not the patient has PE.
Under the current standard of care, a diagnosis of PE is considered confirmed if the patient has any of the following: 1) an intraluminal defect on a pulmonary angiogram; 2) main or lobar intraluminal filling defect on contrast-enhanced helical computed tomographic (CT) scan; 3) segmental intraluminal filling defect on helical CT scan and moderate or high clinical suspicion of PE; 4) high-probability ventilation-perfusion lung scan and moderate or high clinical suspicion of PE; or 5) non-diagnostic CT or lung scan combined with ultrasound or venogram evidence of deep-vein thrombosis (DVT). Although pulmonary angiography is considered the reference standard test for PE, it is performed infrequently because it is invasive and expensive and requires technical expertise. Helical CT has largely replaced ventilation-perfusion lung scanning as a first-line diagnostic test because it is less likely to be non-diagnostic and may provide an alternative explanation for the patient's symptoms (eg, lung tumor, pneumonia); however, lung scanning is still prefered in young women (due to risk of breast cancer from contrast exposure during CT) and patients with a contraindication to contrast dye.
Clinical Prediction Rules for Diagnosing PE
Investigators have attempted to standardize the determination of clinical pretest probability for PE by developing clinical prediction rules. In general, clinical prediction rules for PE assign a score (and associated pretest probability) to a patient based on the presence or absence of signs, symptoms, risk factors, and the results of routine diagnostic tests, such as chest X-rays and electrocardiograms. The most commonly cited clinical prediction rules for PE in the literature, which have undergone external validation, are outlined below.
Wells and colleagues used criteria from the literature and expert opinion to create a clinical prediction rule, which they then tested in over 1,200 patients (both inpatients and outpatients) with suspected PE in 1998.[3] Patients were considered positive for PE if they had a positive pulmonary angiogram, an ultrasound or venogram positive for DVT, or a high- probability lung scan plus moderate or high clinical probability, or venous thromboembolism (VTE) confirmed within 3 months of follow-up. Their model successfully stratified patients into low pretest probability (59% of patients), moderate pretest probability (33% of patients), and high pretest probability (8% of patients) groups in which the incidence of PE was 3%, 28%, and 78%, respectively; however, the model was complex. In 2000, they simplified the model by using logistic regression analysis to select 7 variables which were significantly related to PE
Wicki and colleagues have also developed a clinical prediction rule for PE (Geneva score).[5] The Geneva score was derived from data collected from 2 prospective cohorts of patients who presented to an emergency center with suspected PE. As with the Wells score, the clinical predictors in the final model were distilled from a much longer list of variables using logistic regression analysis In contrast to the Wells score, the Geneva score does not require physicians to determine if PE is as likely or more likely than an alternative diagnosis; however, the Wells score does not require arterial blood gas sampling on room air whereas the Geneva score does. .
Kline and colleagues developed a decision rule (pulmonary embolism rule-out criteria [PERC], or Charlotte rule) to stratify patients presenting to emergency rooms with suspected PE into low-risk and high-risk pretest probability groups.[6] The primary objective of their decision rule was to determine which patients were too high risk (>40% prevalence of PE) to have PE ruled out using testing with D-dimer assays. Data for the decision rule was collected on patients who had an imaging study ordered by an emergency room (ER) physician to assess for PE (ie, CT or lung scan). Patients were considered positive for PE if they had a high-probability lung scan, an ultrasound positive for DVT with an abnormal lung scan, a positive CT or leg venogram, a positive pulmonary angiogram, or VTE confirmed within 3 months of follow-up. In contrast to other investigators, Kline and colleagues did not find that malignancy or previous history of PE or DVT were significantly associated with PE.
More recently, Le Gal and colleagues revisited the Geneva score with the objective of modifying it so that it was entirely based on clinical variables while remaining independent of the physician's judgment regarding potential alternative diagnoses.[7] The data they used to modify the score was derived from a multicenter outcome study of patients presenting to emergency rooms with suspected PE. The new Geneva score added symptoms such as unilateral lower-limb pain and hemoptysis while removing the requirement for arterial blood gas and chest X-ray interpretation. Points were assigned for the score according to the regression coefficients. Patients were considered positive for PE if they had an ultrasound positive for DVT, a positive CT, a positive pulmonary angiogram in a patient with high clinical suspicion, or a high-probability lung scan with inconclusive results on CT. When applied retrospectively to an independent cohort of patients with suspected PE, the prevalence of PE in the low pretest probability group, intermediate pretest probability group, and high pretest probability group was 8%, 29%, and 74%, respectively.
Investigators have also recently revisited the Wells score with the goal of simplifying the scoring system.[8] The Wells score was calculated prospectively for 3,306 patients with suspected PE enrolled in a diagnostic management study. The data was used to determine if the individual components of the Wells score could all be assigned unit weights (point value of 1) rather than as 3 sets of points: 1, 1.5, and 3 points. They determined that the Wells score and simplified Wells score had similar accuracy and diagnostic utility for PE but cautioned that the simplified Wells score requires prospective validation.
Comparison of the Properties of Externally Validated Clinical Prediction Rules for Pulmonary Embolism
Two Preemies Die in NICU After Heparin 'Mixing Error' in Pharmacy
By Todd Neale, Staff Writer, MedPage Today
Published: July 10, 2008.
CORPUS CHRISTI, Tex., July 10 -- Twin premature babies, a brother and sister, have died in the wake of a heparin overdose at a Level III neonatal intensive care unit here. As many as 17 infants in the NICU at CHRISTUS Spohn Hospital Corpus Christi-South were exposed to heparin concentrations as high as 100 times the normal dose. Sherry Carr-Deer, a spokesperson for the hospital, could not confirm the actual dose administered, but the typical solution used for infants is 10 units/mL.
The hospital confirmed that 14 infants were exposed to the dangerous levels of heparin. Three babies were discharged at the approximate time of exposure and may have received the elevated concentrations. Yet follow-up determined that they had no ill effects. All 12 infants remaining in the NICU are in stable condition. Carr-Deer said that all of the infants initially exposed had been in critical condition before the heparin was administered.
An ongoing internal investigation that is expected to last about a week initially determined that the overdoses were the result of a "mixing error" in the hospital's pharmacy on July 3. The hospital has "initiated an immediate review for pharmacy staff regarding procedures and processes assciated with mixing medications," according to a statement .No hospital staffers have been suspended, but two pharmacy workers requested two weeks of voluntary leave.
http://www.medpagetoday.com/PublicHealthPolicy/PublicHealth/tb/10081
Pediatric Stroke Guidelines Emphasize Differences from Adult Care
By Crystal Phend, Staff Writer, MedPage Today
Published: July 17, 2008
Children who have a stroke require a substantially different treatment approach than adults, according to the first comprehensive pediatric stroke guidelines. Even the mainstay of adult ischemic stroke treatment -- tissue plasminogen activator (tPA) -- was not generally recommended in younger children, particularly newborns, outside of a clinical trial, wrote E. Steve Roach, M.D., of Ohio State University and Nationwide Children's Hospital, and colleagues in a scientific statement from the American Heart Association.
A uniform treatment approach is impossible because of the range of presentations of pediatric stroke, which are remarkably different from those of adult stroke, they reported online in Stroke: Journal of the American Heart Association.Whereas 80% to 85% of strokes among adults are ischemic, in children only about 55% are.
Atherosclerosis is almost never a cause of stroke in children; congenital heart disease and sickle cell disease are the two most common, Dr. Roach noted. The frequency of stroke in childhood has grown substantially with better imaging technology, but primarily because physicians are aware of the possibility, Dr. Roach said. Stroke occurs in 10.7 per 100,000 children age 18 and younger every year, with a much higher 1 per 4,000 rate in neonates. Neonatal strokes often present as seizures, typically involving only an arm or leg, and account for an estimated 10% of seizures in neonates born at term.
Recommendations for treating neonatal stroke included:
• Correction of markedly low platelet counts, replacement of deficient coagulation factors, and vitamin K for dependent coagulation disorders
• Ventricular drainage and, later, shunting if needed for patients who develop hydrocephalus after an intracerebral hemorrhage
• Rehabilitation and ongoing physical therapy after perinatal stroke
• Anticoagulation with low molecular weight or unfractionated heparin should be considered but only for selected neonates
Whereas prevention focuses on risk of a first stroke for adults, secondary prevention is often the only option for children. This makes promptly recognizing and diagnosing pediatric stroke important, Dr. Roach said.
Recommendations for prevention in children who have had a stroke included:
• Evaluating children with ischemic stroke and migraines for other stroke risks
• Counseling on the benefits of a healthy diet, exercise, and avoiding tobacco
• Suggesting an alternative to oral contraceptives
• Thorough risk factor evaluation -- including cerebral angiography when noninvasive tests cannot establish a cause -- for children with nontraumatic brain hemorrhage
Primary source: Stroke: Journal of the American Heart Association
Source reference:
Roach SE, et al "Management of stroke in infants and children" Stroke 2008.
Low-Molecular-Weight Heparin May Be Preferred to Compression Stockings After Knee Arthroscopy CME
News Author: Laurie Barclay, MD
In patients undergoing knee arthroscopy, low-molecular-weight heparin (LMWH) for 1 week was more effective in reducing the occurrence of deep venous thrombosis and other vascular complications vs graduated compression stockings, according to the results of an assessor-blinded, randomized controlled trial reported in the July 15 issue of the Annals of Internal Medicine.
Study Highlights
• Consecutive patients presenting for knee arthroscopy to 1 center in Italy were eligible for study participation. Patients younger than 18 years or who had preexisting risk factors for thrombosis were excluded from study participation.
• Surgeries were performed by a team of 6 orthopaedic surgeons who used a standard 2-portal technique. Patients who underwent cartilage shaving could not bear weight on the treated leg for the first 3 weeks after the operation. All other patients were instructed to bear weight on the treated leg as tolerated while using crutches.
• Study participants were randomized to receive full-length graduated compression stockings (inflated to a pressure of 30 to 40 mm Hg at the ankle) for 7 days after the surgery or nadroparin 3800 IU daily for 7 or 14 days after surgery.
• At the end of prophylaxis, all participants underwent bilateral, whole-leg Doppler ultrasonography examinations to identify deep venous thrombosis. Patients also reported any symptoms of deep venous thrombosis or pulmonary embolism. Suspected pulmonary embolism was investigated with ventilation-perfusion scanning.
• The primary efficacy endpoint was the 3-month cumulative incidence of asymptomatic deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality. The primary safety endpoint was the rate of clinically relevant bleeding events.
• 1761 patients underwent randomization. The mean age of subjects was 42 years, and all participants received locoregional anesthesia.
• Approximately 40% of participants underwent meniscectomy, and one third underwent anterior cruciate ligament reconstruction.
• 7% of subjects underwent cartilage shaving.
• The safety committee overseeing the study protocol recommended discontinuing the 14-day treatment with LMWH after concerns regarding safety issues with this regimen. Nonetheless, 444 patients were analyzed in the 14-day treatment group vs 657 in the 7-day LMWH group and 660 receiving compression stockings.
• Approximately 90% of subjects in the 3 randomized groups completed their assigned treatment.
• The 3-month incidence of the composite efficacy endpoint was 3.2%, 0.9%, and 0.9% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. LMWH was statistically superior to compression stockings in this outcome.
• The most common outcome in the composite was symptomatic distal deep venous thrombosis.
• Asymptomatic distal deep venous thrombosis was also more common among subjects receiving compression stockings vs heparin.
• Half of all participants had symptoms of deep venous thrombosis, but deep venous thrombosis was confirmed in only 16 cases. There were 6 cases of confirmed pulmonary embolism.
• The incidence of clinically relevant bleeding events, including major bleeding events, was 0.3%, 0.9% and 0.5% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. There was no statistical difference between the LMWH and compression stocking groups in this outcome.
• The multivariate risk for venous thromboembolism in comparison of 7 days of LMWH with compression stockings was 0.27.
• Meniscectomy increased the risk for the composite primary endpoint.
• Heparin-induced thrombocytopenia did not develop in any of the participants receiving LMWH.
http://www.medscape.com/viewarticle/577719
Enoxaparin, Heparin Linked to High Bleeding Risk in Cardioembolic Stroke
Caroline Cassels July 18, 2008 — Using enoxaparin or heparin to bridge long-term anticoagulation therapy with warfarin for secondary stroke prevention has been associated with a high risk for serious bleeding in patients with cardioembolic stroke (CES). A retrospective study of 204 CES patients showed that only those who received bridging with enoxaparin went on to have symptomatic intracranial bleeding. Similarly, all CES cases with systemic bleeding were treated with intravenous heparin.
Clinical Dilemma
While it is widely acknowledged that CES patients require long-term anticoagulation, the issue of when and how to initiate it remains a clinical dilemma. Patients were categorized into one of 5 possible treatment groups. These included no treatment, aspirin only, aspirin followed by warfarin, intravenous heparin in the acute phase followed by warfarin, and full-dose enoxaparin combined with warfarin.
The study's primary outcomes included serious bleeding (defined as a parenchymal hematoma, grade 2, or systemic bleeding) and stroke recurrence during hospital stay.
All Intracranial Hemorrhage Occurred in a Single Group
Of the total study group, 8 subjects received no anticoagulation, 88 received aspirin alone, 35 were treated with aspirin followed by warfarin, 44 received intravenous heparin followed by warfarin, and 29 received full-dose enoxaparin combined with warfarin.
Hemorrhagic transformation occurred in 23 (11%) patients. Of these cases, 3 were symptomatic. Systemic bleeding occurred in 2 patients, who were both taking heparin.
Stroke progression occurred in 11 (5%) of patients and was significantly associated with poor outcome. All except 1 of these cases occurred in the aspirin-only group. In fact, the analysis revealed that patients receiving aspirin alone were 12.5 times more likely to experience progressive stroke compared with individuals on other types of anticoagulation. This finding, suggests aspirin may not be as potent as other forms of anticoagulation therapie
Arch Neurol. Published online July 14, 2008. Abstract
Growth Hormone Linked to Male Thrombosis Risk
By Michael Smith, North American Correspondent, MedPage Today
Published: July 11, 2008
- The well-known increased thrombosis risk among men compared with women may be related to differences in the way they secrete growth hormone and its effects on liver gene expression, researchers said here. Men secrete the hormone in pulses and women secrete it continuously.Because the production of coagulation proteins by the liver is controlled by growth hormone, the differences in secretion may be related to differences in clotting time and therefore to thrombosis. Male sex is known to be an independent risk factor for several thrombin-dependent processes, including myocardial infarction, venous thromboembolism (VTE), and thrombotic stroke, the researchers noted. For instance, men are on average 50% more likely to suffer recurrent VTE than females, they said. But while the difference in risk is known, the causes are not, they said.
In wild-type mice, they found, clotting times were significantly shorter (P=0.0001) in males than in females -- 50.57 versus 55.76 seconds on average. When the researchers used thromboplastin to induce pulmonary embolism, female animals were protected to a significantly greater degree (P=0.01) than males. On average, males survived 210 seconds versus 480 and male survival percentages were 12.5% versus 41%.
But in mice genetically altered to have a deficiency in growth hormone, both males and females had significantly longer clotting times (P<0.001) than male mice with normal growth hormone secretion.
The researchers also found that inducing a male secretion pattern in both male and female hormone-deficient mice (by periodic injection) restored their clotting times to those seen in male controls.
In-vitro analysis of liver tissue showed that expression of coagulation
inhibitors (Proc, Serpinc1, Serpind1, and Serpina5) were "strongly modulated" by sex-specific growth hormone patterns, the researchers said.
And growth hormone modulated resistance to activated protein C, which degrades Factor Va and Factor VIIIa.
The results "reveal what we believe to be a novel mechanism" of thrombosis involving growth hormone and a suite of changes in expression of coagulation inhibitor genes in the liver, the researchers said.
"We believe this is an important step in understanding the biological mechanism underlying important sex differences in disease susceptibility," Dr. Weiss and colleagues said.
"There is great value in understanding the mechanisms underlying such differences, as they may lead to novel paradigms of diagnosis or management of thrombotic disorders," they added.
http://www.medpagetoday.com/Cardiology/VenousThrombosis/tb/10091
Warfarin Anticoagulation Safe After Cardioembolic Stroke
By Michael Smith, North American Correspondent, MedPage Today
Published: July 14, 2008 HOUSTON, July 14 -- Warfarin (Coumadin) can be used safely as an anticoagulant in patients with cardioembolic stroke who have not been treated with tissue plasminogen activator, researchers here found.
Among the 204 patients, eight patients got no anticoagulant therapy, 88 were treated with aspirin alone, 35 got warfarin alone, 44 were given "heparin bridging" (intravenous heparin in the acute phase followed by warfarin), and 29 got "enoxaparin bridging" (enoxaparin combined with warfarin). Overall, the analysis found, patients given anticoagulant therapy were more than twice as likely to have a favorable outcome as those treated with aspirin or given no treatment.
The study also found that the most common adverse event was progressive stroke, with 10 of 11 cases seen in the aspirin group. Indeed, compared with patients getting any form of anticoagulation, those getting aspirin were nearly 13 times as likely to have stroke progression. Hemorrhagic transformation -- leaking of blood into the damaged area -- was seen in 23 cases (11% of the total) distributed across the treatment groups.
I
The researchers said the study should be viewed as hypothesis generating, since it is retrospective and may need prospective validation. "Until such validation occurs, our conclusions should be interpreted with caution," they said. The study also lacks long-term follow-up and stroke severity was not equally distributed among treatment groups, probably because of selection bias of the treating physician, the researchers added.
On the other hand, they said, the data "may provide guidance" on how to start long-term anti-coagulation. Specifically, warfarin treatment "appears to be safe and can be started at any point during the hospital stay along with deep vein thrombosis prophylaxis."
Primary source: Archives of Neurology
Source reference:
Hallevi H, et al "Anticoagulation after cardioembolic Stroke: To bridge or not to bridge?" Arch Neurol 2008; DOI: 10.1001/archneur.65.9.noc70105.
Additional Strokes Coverage
http://www.medpagetoday.com/Neurology/Strokes/tb/10112
HEALTHBEAT: Trio of experimental blood thinners has doctors hopeful for easier care
By LAURAN NEERGAARD | AP Medical Writer
8:06 PM CDT, July 14, 2008 WASHINGTON (AP) _ A trio of experimental drugs has doctors hopeful that for the first time in decades, millions of people at risk of lethal blood clots may soon get easier treatment.
The first goal is a pill option for people who now need daily blood-thinning shots for weeks after knee or hip replacement surgery.
But the ultimate goal is an alternative to that old standby warfarin, also called Coumadin, the nation's most troublesome lifesaver because of side effects and restrictions its 2 million users face.
Now in late-stage testing in thousands of Americans are three pills that work to prevent blood clots in ways that promise to be less burdensome. One of the trio, Boehringer Ingelheim's Pradaxa, just began selling in Europe.
The drug research comes as Medicare is considering withholding payment from hospitals when at-risk patients develop clots in their veins, usually the legs — a common preventable cause of hospital deaths. The National Quality Forum has estimated that only about a third of patients who need protective blood thinners while hospitalized get them.
Known medically as a "deep vein thrombosis" or DVT, such a clot can kill quickly if it moves up to the lungs. There aren't good counts, but recent estimates suggest that about 900,000 people a year suffer a vein clot, and nearly 300,000 die. Being immobile for long periods, such as during hospitalizations or even long airplane flights, can trigger a clot. Vice President Cheney suffered one after a long trip last year. NBC correspondent David Bloom died of one in 2003 after spending days in a cramped military vehicle while covering the invasion of Iraq.
But there are a variety of risks, including increasing age, smoking, birth control pills, obesity — and especially, big surgeries like knee or hip replacements.
Doctors use faster-acting shots of the blood thinner enoxaparin to protect orthopedic surgery patients. But warfarin is a top treatment once a vein clot strikes — and the leading protection for other types of clots, such as strokes caused by the irregular heartbeat atrial fibrillation. But too many of those patients go unprotected, too, because warfarin is so hard to use. Dangerous bleeding is the worst side effect, but it requires monthly blood checks because diet and other factors can throw off the dose.
"The need is substantial" for an easier alternative, says Dr. Richard Becker, a hematology and cardiovascular specialist at Duke University Medical Center who is monitoring the pipeline. "I don't know of a drug that has the inherent complexities and potential for harm that Coumadin does."
Hopes have been dashed before. Just a few years ago, the highly anticipated blood thinner Exantra was pulled off Europe's market, and rejected here, because of surprising liver damage. So while trial results have U.S. specialists optimistic about the three new attempts, they're watching closely for any hints of problems.
"There are some huge benefits to these drugs, all three of them — if they play out," says pharmacist John Fanikos of Boston's Brigham and Women's Hospital and the North American Thrombosis Forum.
In the pipeline:
—Rivaroxaban tamps down action of a key player in blood clotting, called Factor Xa. Last month, the New England Journal of Medicine published two studies of more than 7,000 knee and hip replacement recipients who received either a daily rivaroxaban pill or today's standard injections. Pill users were less likely to suffer fatal and nonfatal vein clots. Bleeding and other side effects were similar with both drugs.
Johnson
&
Johnson, which is developing rivaroxaban with Bayer Healthcare AG, plans to seek Food and Drug Administration approval later this summer.
—Pradaxa, or dabigatran, interferes with another blood clotting agent, called thrombin. European regulators cited research showing Pradaxa was as effective as standard shots in protecting orthopedic patients. Duke's Becker cautions that one U.S. study didn't show as big an effect; other research is continuing. This drug works similarly to the ill-fated Exantra, but Becker says there are no signs of liver toxicity so far.
—Bristol-Myers Squibb's apixaban works against the same clotting factor as rivaroxaban; its key studies are under way.
Orthopedic surgery is an easier hurdle — because vein clots are quick and common — than proving if these pills will work as well as warfarin for people who need longer-term care. Stay tuned: Large studies comparing warfarin to each have begun at hospitals nationwide.
If they work, their targeted action promises fewer side effects, dietary restrictions or dose problems than warfarin, Fanikos notes. But warfarin still will play an important role, he cautions — since the generic form sells for as little as $40 for a three-month supply.
http://www.chicagotribune.com/features/lifestyle/health/sns-ap-med-healthbeat-blood-thinners,0,7913002.story
Update on Heparin
Serious injuries and deaths have been associated with the use of heparin, a blood-thinning drug that contained active pharmaceutical ingredient (API) from China. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain
Questions and Answers
• Updated Questions and Answers on Heparin Sodium Injection (Baxter) (6/18/2008)
• Questions and Answers on Heparin, Medical Devices and In-vitro Diagnostic Assays (6/3/2008)
Screening Methods
** New Information ** (7/7/2008)
The United States Pharmacopeia (USP) has recently published updated compendial test methods for heparin sodium USP to include the two screening tests previously posted on FDA’s website. Effective immediately, in accord with section 501(b) of the FD&C Act, all heparin sodium USP must meet compendial requirements as specified at the following link http://www.usp.org/hottopics/heparin.html.
All other measures used to prevent contaminated heparin products from entering the US should remain in place, and we request that all heparin suppliers and manufacturers continue reporting results to FDA as outlined in the section "Heparin Test Results" until further notice.
http://www.medscape.com/viewarticle/575056
Reproducibility of Pretest Assessment in Suspected Pulmonary Embolism
Lori-Ann Linkins, MD, MSc(Epid), FRCPC
Lab Med. 2008;39(6):361-364. ©2008 American Society for Clinical Pathology
Role of Clinical Assessment in Suspected Pulmonary Embolism
Pulmonary embolism (PE) is a leading cause of mortality in North America. Prompt recognition and treatment of PE with anticoagulant therapy reduces the risk of mortality from 30% to 1.5%. Unfortunately, timely diagnosis of PE can be difficult because the clinical features of PE, such as chest pain and rapid heart rate, are not unique to PE. Although clinical assessment alone cannot confirm or exclude PE, it can be used to stratify patients according to their likelihood of having PE before diagnostic tests are performed (ie, pretest probability). This paper will review the role of clinical assessment in the diagnosis of PE, provide an overview of validated clinical prediction rules for PE, and discuss the reproducibility of clinical pretest probability assessment in suspected PE.
Role of Clinical Assessment in Suspected Pulmonary Embolism
Signs and symptoms considered "typical" for pulmonary embolism (PE) include dyspnea, pleuritic chest pain, hemoptysis, and tachycardia; however, this exact combination of features is uncommon, and each individual feature is associated with a number of other diseases (eg, myocardial infarction, pneumonia). Treating all patients who present with these features with anticoagulant therapy reduces the risk of missing a potentially fatal PE; however, this approach also increases the risk of serious bleeding complications, including fatal hemorrhage, in patients who do not have PE. Accurate identification of patients who have PE therefore depends on the performance of at least 1 objective test.
Although clinical assessment alone cannot confirm or exclude PE, it can be used to guide the performance and interpretation of objective tests. Bayes' theorem predicts that the posttest probability of a patient having a target disorder is determined by 1) the pretest probability of the target disorder, and 2) the sensitivity and specificity of the diagnostic test.[1] If the diagnostic test is positive and the pretest probability of the disorder is high, the posttest probability of the disorder will also be high (ie, true positive result). In contrast, if the diagnostic test is positive, but the pretest probability is low, the posttest probability of the disorder will decrease (ie, more likely a false positive result). Clinical assessment is therefore used to estimate a patient's pretest probability of PE, which is then combined with the result of an objective diagnostic test to determine whether or not the patient has PE.
Under the current standard of care, a diagnosis of PE is considered confirmed if the patient has any of the following: 1) an intraluminal defect on a pulmonary angiogram; 2) main or lobar intraluminal filling defect on contrast-enhanced helical computed tomographic (CT) scan; 3) segmental intraluminal filling defect on helical CT scan and moderate or high clinical suspicion of PE; 4) high-probability ventilation-perfusion lung scan and moderate or high clinical suspicion of PE; or 5) non-diagnostic CT or lung scan combined with ultrasound or venogram evidence of deep-vein thrombosis (DVT). Although pulmonary angiography is considered the reference standard test for PE, it is performed infrequently because it is invasive and expensive and requires technical expertise. Helical CT has largely replaced ventilation-perfusion lung scanning as a first-line diagnostic test because it is less likely to be non-diagnostic and may provide an alternative explanation for the patient's symptoms (eg, lung tumor, pneumonia); however, lung scanning is still prefered in young women (due to risk of breast cancer from contrast exposure during CT) and patients with a contraindication to contrast dye.
Clinical Prediction Rules for Diagnosing PE
Investigators have attempted to standardize the determination of clinical pretest probability for PE by developing clinical prediction rules. In general, clinical prediction rules for PE assign a score (and associated pretest probability) to a patient based on the presence or absence of signs, symptoms, risk factors, and the results of routine diagnostic tests, such as chest X-rays and electrocardiograms. The most commonly cited clinical prediction rules for PE in the literature, which have undergone external validation, are outlined below.
Wells and colleagues used criteria from the literature and expert opinion to create a clinical prediction rule, which they then tested in over 1,200 patients (both inpatients and outpatients) with suspected PE in 1998.[3] Patients were considered positive for PE if they had a positive pulmonary angiogram, an ultrasound or venogram positive for DVT, or a high- probability lung scan plus moderate or high clinical probability, or venous thromboembolism (VTE) confirmed within 3 months of follow-up. Their model successfully stratified patients into low pretest probability (59% of patients), moderate pretest probability (33% of patients), and high pretest probability (8% of patients) groups in which the incidence of PE was 3%, 28%, and 78%, respectively; however, the model was complex. In 2000, they simplified the model by using logistic regression analysis to select 7 variables which were significantly related to PE
Wicki and colleagues have also developed a clinical prediction rule for PE (Geneva score).[5] The Geneva score was derived from data collected from 2 prospective cohorts of patients who presented to an emergency center with suspected PE. As with the Wells score, the clinical predictors in the final model were distilled from a much longer list of variables using logistic regression analysis In contrast to the Wells score, the Geneva score does not require physicians to determine if PE is as likely or more likely than an alternative diagnosis; however, the Wells score does not require arterial blood gas sampling on room air whereas the Geneva score does. .
Kline and colleagues developed a decision rule (pulmonary embolism rule-out criteria [PERC], or Charlotte rule) to stratify patients presenting to emergency rooms with suspected PE into low-risk and high-risk pretest probability groups.[6] The primary objective of their decision rule was to determine which patients were too high risk (>40% prevalence of PE) to have PE ruled out using testing with D-dimer assays. Data for the decision rule was collected on patients who had an imaging study ordered by an emergency room (ER) physician to assess for PE (ie, CT or lung scan). Patients were considered positive for PE if they had a high-probability lung scan, an ultrasound positive for DVT with an abnormal lung scan, a positive CT or leg venogram, a positive pulmonary angiogram, or VTE confirmed within 3 months of follow-up. In contrast to other investigators, Kline and colleagues did not find that malignancy or previous history of PE or DVT were significantly associated with PE.
More recently, Le Gal and colleagues revisited the Geneva score with the objective of modifying it so that it was entirely based on clinical variables while remaining independent of the physician's judgment regarding potential alternative diagnoses.[7] The data they used to modify the score was derived from a multicenter outcome study of patients presenting to emergency rooms with suspected PE. The new Geneva score added symptoms such as unilateral lower-limb pain and hemoptysis while removing the requirement for arterial blood gas and chest X-ray interpretation. Points were assigned for the score according to the regression coefficients. Patients were considered positive for PE if they had an ultrasound positive for DVT, a positive CT, a positive pulmonary angiogram in a patient with high clinical suspicion, or a high-probability lung scan with inconclusive results on CT. When applied retrospectively to an independent cohort of patients with suspected PE, the prevalence of PE in the low pretest probability group, intermediate pretest probability group, and high pretest probability group was 8%, 29%, and 74%, respectively.
Investigators have also recently revisited the Wells score with the goal of simplifying the scoring system.[8] The Wells score was calculated prospectively for 3,306 patients with suspected PE enrolled in a diagnostic management study. The data was used to determine if the individual components of the Wells score could all be assigned unit weights (point value of 1) rather than as 3 sets of points: 1, 1.5, and 3 points. They determined that the Wells score and simplified Wells score had similar accuracy and diagnostic utility for PE but cautioned that the simplified Wells score requires prospective validation.
Comparison of the Properties of Externally Validated Clinical Prediction Rules for Pulmonary Embolism
Two Preemies Die in NICU After Heparin 'Mixing Error' in Pharmacy
By Todd Neale, Staff Writer, MedPage Today
Published: July 10, 2008.
CORPUS CHRISTI, Tex., July 10 -- Twin premature babies, a brother and sister, have died in the wake of a heparin overdose at a Level III neonatal intensive care unit here. As many as 17 infants in the NICU at CHRISTUS Spohn Hospital Corpus Christi-South were exposed to heparin concentrations as high as 100 times the normal dose. Sherry Carr-Deer, a spokesperson for the hospital, could not confirm the actual dose administered, but the typical solution used for infants is 10 units/mL.
The hospital confirmed that 14 infants were exposed to the dangerous levels of heparin. Three babies were discharged at the approximate time of exposure and may have received the elevated concentrations. Yet follow-up determined that they had no ill effects. All 12 infants remaining in the NICU are in stable condition. Carr-Deer said that all of the infants initially exposed had been in critical condition before the heparin was administered.
An ongoing internal investigation that is expected to last about a week initially determined that the overdoses were the result of a "mixing error" in the hospital's pharmacy on July 3. The hospital has "initiated an immediate review for pharmacy staff regarding procedures and processes assciated with mixing medications," according to a statement .No hospital staffers have been suspended, but two pharmacy workers requested two weeks of voluntary leave.
http://www.medpagetoday.com/PublicHealthPolicy/PublicHealth/tb/10081
Pediatric Stroke Guidelines Emphasize Differences from Adult Care
By Crystal Phend, Staff Writer, MedPage Today
Published: July 17, 2008
Children who have a stroke require a substantially different treatment approach than adults, according to the first comprehensive pediatric stroke guidelines. Even the mainstay of adult ischemic stroke treatment -- tissue plasminogen activator (tPA) -- was not generally recommended in younger children, particularly newborns, outside of a clinical trial, wrote E. Steve Roach, M.D., of Ohio State University and Nationwide Children's Hospital, and colleagues in a scientific statement from the American Heart Association.
A uniform treatment approach is impossible because of the range of presentations of pediatric stroke, which are remarkably different from those of adult stroke, they reported online in Stroke: Journal of the American Heart Association.Whereas 80% to 85% of strokes among adults are ischemic, in children only about 55% are.
Atherosclerosis is almost never a cause of stroke in children; congenital heart disease and sickle cell disease are the two most common, Dr. Roach noted. The frequency of stroke in childhood has grown substantially with better imaging technology, but primarily because physicians are aware of the possibility, Dr. Roach said. Stroke occurs in 10.7 per 100,000 children age 18 and younger every year, with a much higher 1 per 4,000 rate in neonates. Neonatal strokes often present as seizures, typically involving only an arm or leg, and account for an estimated 10% of seizures in neonates born at term.
Recommendations for treating neonatal stroke included:
• Correction of markedly low platelet counts, replacement of deficient coagulation factors, and vitamin K for dependent coagulation disorders
• Ventricular drainage and, later, shunting if needed for patients who develop hydrocephalus after an intracerebral hemorrhage
• Rehabilitation and ongoing physical therapy after perinatal stroke
• Anticoagulation with low molecular weight or unfractionated heparin should be considered but only for selected neonates
Whereas prevention focuses on risk of a first stroke for adults, secondary prevention is often the only option for children. This makes promptly recognizing and diagnosing pediatric stroke important, Dr. Roach said.
Recommendations for prevention in children who have had a stroke included:
• Evaluating children with ischemic stroke and migraines for other stroke risks
• Counseling on the benefits of a healthy diet, exercise, and avoiding tobacco
• Suggesting an alternative to oral contraceptives
• Thorough risk factor evaluation -- including cerebral angiography when noninvasive tests cannot establish a cause -- for children with nontraumatic brain hemorrhage
Primary source: Stroke: Journal of the American Heart Association
Source reference:
Roach SE, et al "Management of stroke in infants and children" Stroke 2008.
Low-Molecular-Weight Heparin May Be Preferred to Compression Stockings After Knee Arthroscopy CME
News Author: Laurie Barclay, MD
In patients undergoing knee arthroscopy, low-molecular-weight heparin (LMWH) for 1 week was more effective in reducing the occurrence of deep venous thrombosis and other vascular complications vs graduated compression stockings, according to the results of an assessor-blinded, randomized controlled trial reported in the July 15 issue of the Annals of Internal Medicine.
Study Highlights
• Consecutive patients presenting for knee arthroscopy to 1 center in Italy were eligible for study participation. Patients younger than 18 years or who had preexisting risk factors for thrombosis were excluded from study participation.
• Surgeries were performed by a team of 6 orthopaedic surgeons who used a standard 2-portal technique. Patients who underwent cartilage shaving could not bear weight on the treated leg for the first 3 weeks after the operation. All other patients were instructed to bear weight on the treated leg as tolerated while using crutches.
• Study participants were randomized to receive full-length graduated compression stockings (inflated to a pressure of 30 to 40 mm Hg at the ankle) for 7 days after the surgery or nadroparin 3800 IU daily for 7 or 14 days after surgery.
• At the end of prophylaxis, all participants underwent bilateral, whole-leg Doppler ultrasonography examinations to identify deep venous thrombosis. Patients also reported any symptoms of deep venous thrombosis or pulmonary embolism. Suspected pulmonary embolism was investigated with ventilation-perfusion scanning.
• The primary efficacy endpoint was the 3-month cumulative incidence of asymptomatic deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality. The primary safety endpoint was the rate of clinically relevant bleeding events.
• 1761 patients underwent randomization. The mean age of subjects was 42 years, and all participants received locoregional anesthesia.
• Approximately 40% of participants underwent meniscectomy, and one third underwent anterior cruciate ligament reconstruction.
• 7% of subjects underwent cartilage shaving.
• The safety committee overseeing the study protocol recommended discontinuing the 14-day treatment with LMWH after concerns regarding safety issues with this regimen. Nonetheless, 444 patients were analyzed in the 14-day treatment group vs 657 in the 7-day LMWH group and 660 receiving compression stockings.
• Approximately 90% of subjects in the 3 randomized groups completed their assigned treatment.
• The 3-month incidence of the composite efficacy endpoint was 3.2%, 0.9%, and 0.9% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. LMWH was statistically superior to compression stockings in this outcome.
• The most common outcome in the composite was symptomatic distal deep venous thrombosis.
• Asymptomatic distal deep venous thrombosis was also more common among subjects receiving compression stockings vs heparin.
• Half of all participants had symptoms of deep venous thrombosis, but deep venous thrombosis was confirmed in only 16 cases. There were 6 cases of confirmed pulmonary embolism.
• The incidence of clinically relevant bleeding events, including major bleeding events, was 0.3%, 0.9% and 0.5% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. There was no statistical difference between the LMWH and compression stocking groups in this outcome.
• The multivariate risk for venous thromboembolism in comparison of 7 days of LMWH with compression stockings was 0.27.
• Meniscectomy increased the risk for the composite primary endpoint.
• Heparin-induced thrombocytopenia did not develop in any of the participants receiving LMWH.
http://www.medscape.com/viewarticle/577719
Enoxaparin, Heparin Linked to High Bleeding Risk in Cardioembolic Stroke
Caroline Cassels July 18, 2008 — Using enoxaparin or heparin to bridge long-term anticoagulation therapy with warfarin for secondary stroke prevention has been associated with a high risk for serious bleeding in patients with cardioembolic stroke (CES). A retrospective study of 204 CES patients showed that only those who received bridging with enoxaparin went on to have symptomatic intracranial bleeding. Similarly, all CES cases with systemic bleeding were treated with intravenous heparin.
Clinical Dilemma
While it is widely acknowledged that CES patients require long-term anticoagulation, the issue of when and how to initiate it remains a clinical dilemma. Patients were categorized into one of 5 possible treatment groups. These included no treatment, aspirin only, aspirin followed by warfarin, intravenous heparin in the acute phase followed by warfarin, and full-dose enoxaparin combined with warfarin.
The study's primary outcomes included serious bleeding (defined as a parenchymal hematoma, grade 2, or systemic bleeding) and stroke recurrence during hospital stay.
All Intracranial Hemorrhage Occurred in a Single Group
Of the total study group, 8 subjects received no anticoagulation, 88 received aspirin alone, 35 were treated with aspirin followed by warfarin, 44 received intravenous heparin followed by warfarin, and 29 received full-dose enoxaparin combined with warfarin.
Hemorrhagic transformation occurred in 23 (11%) patients. Of these cases, 3 were symptomatic. Systemic bleeding occurred in 2 patients, who were both taking heparin.
Stroke progression occurred in 11 (5%) of patients and was significantly associated with poor outcome. All except 1 of these cases occurred in the aspirin-only group. In fact, the analysis revealed that patients receiving aspirin alone were 12.5 times more likely to experience progressive stroke compared with individuals on other types of anticoagulation. This finding, suggests aspirin may not be as potent as other forms of anticoagulation therapie
Arch Neurol. Published online July 14, 2008. Abstract
Growth Hormone Linked to Male Thrombosis Risk
By Michael Smith, North American Correspondent, MedPage Today
Published: July 11, 2008
- The well-known increased thrombosis risk among men compared with women may be related to differences in the way they secrete growth hormone and its effects on liver gene expression, researchers said here. Men secrete the hormone in pulses and women secrete it continuously.Because the production of coagulation proteins by the liver is controlled by growth hormone, the differences in secretion may be related to differences in clotting time and therefore to thrombosis. Male sex is known to be an independent risk factor for several thrombin-dependent processes, including myocardial infarction, venous thromboembolism (VTE), and thrombotic stroke, the researchers noted. For instance, men are on average 50% more likely to suffer recurrent VTE than females, they said. But while the difference in risk is known, the causes are not, they said.
In wild-type mice, they found, clotting times were significantly shorter (P=0.0001) in males than in females -- 50.57 versus 55.76 seconds on average. When the researchers used thromboplastin to induce pulmonary embolism, female animals were protected to a significantly greater degree (P=0.01) than males. On average, males survived 210 seconds versus 480 and male survival percentages were 12.5% versus 41%.
But in mice genetically altered to have a deficiency in growth hormone, both males and females had significantly longer clotting times (P<0.001) than male mice with normal growth hormone secretion.
The researchers also found that inducing a male secretion pattern in both male and female hormone-deficient mice (by periodic injection) restored their clotting times to those seen in male controls.
In-vitro analysis of liver tissue showed that expression of coagulation
inhibitors (Proc, Serpinc1, Serpind1, and Serpina5) were "strongly modulated" by sex-specific growth hormone patterns, the researchers said.
And growth hormone modulated resistance to activated protein C, which degrades Factor Va and Factor VIIIa.
The results "reveal what we believe to be a novel mechanism" of thrombosis involving growth hormone and a suite of changes in expression of coagulation inhibitor genes in the liver, the researchers said.
"We believe this is an important step in understanding the biological mechanism underlying important sex differences in disease susceptibility," Dr. Weiss and colleagues said.
"There is great value in understanding the mechanisms underlying such differences, as they may lead to novel paradigms of diagnosis or management of thrombotic disorders," they added.
http://www.medpagetoday.com/Cardiology/VenousThrombosis/tb/10091
Warfarin Anticoagulation Safe After Cardioembolic Stroke
By Michael Smith, North American Correspondent, MedPage Today
Published: July 14, 2008 HOUSTON, July 14 -- Warfarin (Coumadin) can be used safely as an anticoagulant in patients with cardioembolic stroke who have not been treated with tissue plasminogen activator, researchers here found.
Among the 204 patients, eight patients got no anticoagulant therapy, 88 were treated with aspirin alone, 35 got warfarin alone, 44 were given "heparin bridging" (intravenous heparin in the acute phase followed by warfarin), and 29 got "enoxaparin bridging" (enoxaparin combined with warfarin). Overall, the analysis found, patients given anticoagulant therapy were more than twice as likely to have a favorable outcome as those treated with aspirin or given no treatment.
The study also found that the most common adverse event was progressive stroke, with 10 of 11 cases seen in the aspirin group. Indeed, compared with patients getting any form of anticoagulation, those getting aspirin were nearly 13 times as likely to have stroke progression. Hemorrhagic transformation -- leaking of blood into the damaged area -- was seen in 23 cases (11% of the total) distributed across the treatment groups.
I
The researchers said the study should be viewed as hypothesis generating, since it is retrospective and may need prospective validation. "Until such validation occurs, our conclusions should be interpreted with caution," they said. The study also lacks long-term follow-up and stroke severity was not equally distributed among treatment groups, probably because of selection bias of the treating physician, the researchers added.
On the other hand, they said, the data "may provide guidance" on how to start long-term anti-coagulation. Specifically, warfarin treatment "appears to be safe and can be started at any point during the hospital stay along with deep vein thrombosis prophylaxis."
Primary source: Archives of Neurology
Source reference:
Hallevi H, et al "Anticoagulation after cardioembolic Stroke: To bridge or not to bridge?" Arch Neurol 2008; DOI: 10.1001/archneur.65.9.noc70105.
Additional Strokes Coverage
http://www.medpagetoday.com/Neurology/Strokes/tb/10112
HEALTHBEAT: Trio of experimental blood thinners has doctors hopeful for easier care
By LAURAN NEERGAARD | AP Medical Writer
8:06 PM CDT, July 14, 2008 WASHINGTON (AP) _ A trio of experimental drugs has doctors hopeful that for the first time in decades, millions of people at risk of lethal blood clots may soon get easier treatment.
The first goal is a pill option for people who now need daily blood-thinning shots for weeks after knee or hip replacement surgery.
But the ultimate goal is an alternative to that old standby warfarin, also called Coumadin, the nation's most troublesome lifesaver because of side effects and restrictions its 2 million users face.
Now in late-stage testing in thousands of Americans are three pills that work to prevent blood clots in ways that promise to be less burdensome. One of the trio, Boehringer Ingelheim's Pradaxa, just began selling in Europe.
The drug research comes as Medicare is considering withholding payment from hospitals when at-risk patients develop clots in their veins, usually the legs — a common preventable cause of hospital deaths. The National Quality Forum has estimated that only about a third of patients who need protective blood thinners while hospitalized get them.
Known medically as a "deep vein thrombosis" or DVT, such a clot can kill quickly if it moves up to the lungs. There aren't good counts, but recent estimates suggest that about 900,000 people a year suffer a vein clot, and nearly 300,000 die. Being immobile for long periods, such as during hospitalizations or even long airplane flights, can trigger a clot. Vice President Cheney suffered one after a long trip last year. NBC correspondent David Bloom died of one in 2003 after spending days in a cramped military vehicle while covering the invasion of Iraq.
But there are a variety of risks, including increasing age, smoking, birth control pills, obesity — and especially, big surgeries like knee or hip replacements.
Doctors use faster-acting shots of the blood thinner enoxaparin to protect orthopedic surgery patients. But warfarin is a top treatment once a vein clot strikes — and the leading protection for other types of clots, such as strokes caused by the irregular heartbeat atrial fibrillation. But too many of those patients go unprotected, too, because warfarin is so hard to use. Dangerous bleeding is the worst side effect, but it requires monthly blood checks because diet and other factors can throw off the dose.
"The need is substantial" for an easier alternative, says Dr. Richard Becker, a hematology and cardiovascular specialist at Duke University Medical Center who is monitoring the pipeline. "I don't know of a drug that has the inherent complexities and potential for harm that Coumadin does."
Hopes have been dashed before. Just a few years ago, the highly anticipated blood thinner Exantra was pulled off Europe's market, and rejected here, because of surprising liver damage. So while trial results have U.S. specialists optimistic about the three new attempts, they're watching closely for any hints of problems.
"There are some huge benefits to these drugs, all three of them — if they play out," says pharmacist John Fanikos of Boston's Brigham and Women's Hospital and the North American Thrombosis Forum.
In the pipeline:
—Rivaroxaban tamps down action of a key player in blood clotting, called Factor Xa. Last month, the New England Journal of Medicine published two studies of more than 7,000 knee and hip replacement recipients who received either a daily rivaroxaban pill or today's standard injections. Pill users were less likely to suffer fatal and nonfatal vein clots. Bleeding and other side effects were similar with both drugs.
Johnson
&
Johnson, which is developing rivaroxaban with Bayer Healthcare AG, plans to seek Food and Drug Administration approval later this summer.
—Pradaxa, or dabigatran, interferes with another blood clotting agent, called thrombin. European regulators cited research showing Pradaxa was as effective as standard shots in protecting orthopedic patients. Duke's Becker cautions that one U.S. study didn't show as big an effect; other research is continuing. This drug works similarly to the ill-fated Exantra, but Becker says there are no signs of liver toxicity so far.
—Bristol-Myers Squibb's apixaban works against the same clotting factor as rivaroxaban; its key studies are under way.
Orthopedic surgery is an easier hurdle — because vein clots are quick and common — than proving if these pills will work as well as warfarin for people who need longer-term care. Stay tuned: Large studies comparing warfarin to each have begun at hospitals nationwide.
If they work, their targeted action promises fewer side effects, dietary restrictions or dose problems than warfarin, Fanikos notes. But warfarin still will play an important role, he cautions — since the generic form sells for as little as $40 for a three-month supply.
http://www.chicagotribune.com/features/lifestyle/health/sns-ap-med-healthbeat-blood-thinners,0,7913002.story
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