New In Coagulation

No platelet aggregation rebound seen with discontinuation of clopidogrel.
Bankhead reports that "no evidence of a platelet aggregation rebound occurs with abrupt discontinuation of clopidogrel (Plavix) in patients undergoing percutaneous coronary intervention (PCI)," according to a study published in the Journal of the American College of Cardiology. Researchers found that "values for adenosine diphosphate (ADP)-induced platelet aggregation did not differ significantly between patients whose clopidogrel therapy was withdrawn abruptly and those in whom clopidogrel was tapered before discontinuation." The investigators also found that "tapering of clopidogrel does not lead to lower platelet aggregation values after clopidogrel withdrawal."

FDA official cleared in heparin conflict-of-interest investigation.
The Los Angeles Times reports that the collaboration between the FDA's Dr. Janet Woodcock and scientists for Momenta Pharmaceuticals Inc. "on research during the 2008 heparin crisis -- a time when the firm had a drug application pending -- did not constitute a conflict of interest, FDA legal counsel Ralph Tyler said Thursday." Tyler said the HHS investigation had been dropped, although as an "act of good grace," Dr. Woodcock "has voluntarily removed herself from consideration of the application by the company...as well as of a competing application by Amphastar Pharmaceuticals Inc." In a conference call to the Times, FDA Principal Deputy Commissioner Joshua Sharfstein emphasized that the agency "needed to be able preserve its ability to respond to public health emergencies...while also assuring the safety of new drugs."

Risk for DVT Low After Single Negative Whole-Leg Compression Ultrasound Result

The risk for deep vein thrombosis (DVT) is low for 3 months after a single negative result on whole-leg compression ultrasound (CUS) examination, according to the results of a systematic review and meta-analysis reported in the February 3 issue of the Journal of the American Medical Association.
The goal of this study was to assess the risk for venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT after a single negative whole-leg CUS result. The reviewers searched MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases for relevant articles published from January 1970 through November 2009, as well as Internet resources and bibliographies of retrieved articles. Content experts were also contacted.
Inclusion criteria were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who were not treated with anticoagulants and who were followed up for at least 90 days for venous thromboembolism events. Data on a single positive or negative whole-leg CUS result, venous thromboembolism during follow-up, and study quality were independently extracted and reviewed by 2 authors.
Selection criteria were met by 7 studies, enrolling a total of 4731 patients, with negative whole-leg CUS results who did not receive anticoagulation. Among the participants, most of whom were identified from an ambulatory setting, up to 647 (13.7%) had active cancer, and up to 725 (15.3%) had recently undergone major surgery.
Of 34 patients (0.7%) with venous thromboembolism or suspected venous thromboembolism-related death, 11 (32.4%) had distal DVT; 7 (20.6%) had proximal DVT; 7 (20.6%) had nonfatal pulmonary emboli; and 9 (26.5%) died, possibly related to venous thromboembolism. At 3 months, the combined venous thromboembolism event rate was 0.57% (95% confidence interval, 0.25% - 0.89%), based on a random-effects model with inverse variance weighting.
"Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up," the review authors write. "Using a single negative whole-leg CUS result as the sole diagnostic modality in patients with high pretest probability of DVT requires further study."
Limitations of this review and meta-analysis include variability in whole-leg CUS techniques, clinical pretest probability with a standardized clinical prediction rule not assessed by most studies, generalizability limited by the populations enrolled, duration of follow-up limited to 3 months, and potential verification bias.
In an accompanying editorial, Robert A. McNutt, MD, PhD, from Rush University Medical Center in Chicago, Illinois, and Edward H. Livingston, MD, from University of Texas Southwestern Medical Center, Dallas, note that evidence-based medicine requires appropriate clinical context.
"For instance, based on the meta-analysis by Johnson et al, clinicians may infer that not initiating anticoagulation treatment after a negative CUS result in some surgical or ambulatory patients at low risk of having VTE [venous thromboembolism] may be appropriate; however, that inference may not be true for hospitalized patients or those with cancer," Drs. McNutt and Livingston write. "Evidence-based medicine must evolve to include clinically and contextually explicit estimates for outcomes as guides to care. Clinical trials and studies evaluating diagnostic tests should be designed and reported to enable clinicians to maximize the care of individual patients, so they can avoid doing the sometimes right things for the sometimes wrong patients."
JAMA. 2010;303:438-445, 454-455.



New Oral Anticoagulants on the Horizon
New Oral Anticoagulants to Revolutionize Venous Thromboembolism (VTE) Management
Autar R
J Orthop Nurs. 2009;13:165-171
Background
Warfarin, a vitamin K antagonist, has been the essential key in deep venous thromboembolism treatment for more than 60 years. Warfarin is a coumarin derivative and acts as a vitamin K antagonist to antagonize the effect of vitamin K required for the synthesis of active clotting factors II, VII, IX, and anticoagulant proteins C and S. Antagonism of vitamin K reduces the amount of these clotting factors, thereby producing anticoagulation. However, warfarin is a relatively dangerous drug, with serious and significant limitations in relation to titrating a safe and therapeutic anticoagulation level. It requires adjusted and variable doses dependent upon the prothrombin time, reported as the International Normalized Ratio. Its narrow therapeutic dose range is 2.0-2.5. To achieve the desired therapeutic level, warfarin requires frequent monitoring and takes about 5 days for a stable antithrombotic effect to be achieved. Warfarin is influenced by several factors such as age, genetic status, medications, diet, and some medical conditions that contribute to variability of patient response. Although the safe use of warfarin is a challenge, there has not been a market competitor for oral long-term anticoagulation in the management of venous thromboembolism (VTE) until recently, with the development of 2 new oral anticoagulants: dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor.
Article Summary
This article examines the potential of these new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy, specifically in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. This article reviews the mechanism of action, bioavailability, and safety profile of these new drugs.
An improved understanding of how the blood clotting cascade works has led to the evolution of new oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. The new class of oral anticoagulants has been developed to pinpoint a specific target for controlling the clotting cascade with maximum efficacy and minimum inconvenience. Oral direct thrombin inhibitor binds directly to thrombin, blocking interaction with its substrates, thereby preventing the conversion of fibrinogen to fibrin and forming a crosslinked blood clot or preventing thrombin generation, and thus producing a state of anticoagulation.
The authors summarized the results of 7 randomized clinical trials, in which dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, the United Kingdom's National Institute of Clinical Excellence (NICE) has now endorsed dabigatran's clinical efficacy as a serious alternative to low-molecular-weight heparin and fondaparinux. Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.
The results of clinical trials (RE-VOLUTION for dabigatran etexilate and RECORDS for rivaroxaban) substantiate, at this time, the clinical efficacy of these drugs, without harmful effects. In the near future these new oral anticoagulants look poised to replace warfarin to some extent. Two more ongoing clinical trials (RE-MEDY and RESONATE), in addition to the RE-VOLUTION program undertaken by the manufacturer, are comparing the efficacy and safety of dabigatran with that of warfarin in the secondary prevention of VTE. These new oral thrombin and factor Xa inhibitors have demonstrated rapid onset of action and predictable pharmacokinetics. They offer the advantages of fixed dosing and preclude the need for routine blood monitoring, making them very attractive alternatives to warfarin. These anticoagulants also have a low propensity to clinically relevant drug-drug interactions. They potentially eliminate the need to provide additional follow up services to those on extended prophylaxis who are either unable or reluctant to self inject their low molecular weight heparin prophylaxis. Evidence is overwhelmingly supportive of the efficacy and safety of rivaroxaban and clinicians are eagerly anticipating that NICE will endorse the clinical and cost effectiveness data and deliver similar recommendations for dabigatran etexilate. US Food and Drug Administration approval of dabigatran is also pending.
Viewpoint
The debate on whether to treat certain types of patients with anticoagulant drugs has raged for years and around many different clinical conditions. Part of the controversy has to do with whether anticoagulation is really effective in preventing complications, and part of the controversy has to do with the risk-benefit ratio to patients. The risk of causing more problems with the use of warfarin has always weighed heavily in the treatment decision. The new anticoagulants discussed here have demonstrated their potential to revolutionize VTE management. When available, these drugs may enable clinicians and patients alike to make better treatment decisions. Although there are no reported adverse hepatic effects of these drugs, sufficient long-term data are unavailable to rule out this potential problem, seen in another drug previously introduced in the market. However, adverse hepatic effects will continue to be the focus of scrutiny as clinicians gain experience with these drugs.


New point-of-care anticoagulation test enables more accurate enoxaparin dosing before cardiac catheterization.

A novel point-of-care anticoagulation test not yet available in the US allowed more accurate dosing of enoxaparin (Lovenox) prior to cardiac catheterization in a clinical trial," according to a paper in the Journal of the American College of Cardiology. Researchers found that "patients in whom anticoagulation was insufficient with standard enoxaparin doses were identified with the Hemochron Jr. Hemonox test at a sensitivity of 94.9% and specificity of 73.3%, allowing for needed dosage adjustments before undergoing catheterization and coronary revascularization.

Aspirin's US REACH: 25% of Secondary-Prevention Patients Not Treated

One out of four US patients with vascular disease is not taking aspirin for secondary prevention of cardiovascular events, and one in 10 is not taking any kind of antithrombotic drug, a new registry analysis suggests [1]. The study, which included more than 25 000 US patients enrolled in the REACH registry, offers some unique insights into the kinds of patients who are taking daily aspirin and in what dose and, perhaps more tellingly, the kinds of patients who are not. According to investigators, the REACH numbers should also provide a benchmark going forward, for understanding whether aspirin usage is appropriate or not, in both the primary- and secondary-prevention arenas, once results from the major ongoing aspirin trials are in.
Aspirin's REACH
The international REACH registry included more than 68 000 outpatients with established atherothrombosis and three or more additional risk factors, enrolled between December 2003 and June 2004. The current analysis looked only at US patients, out to July 2006. Of the US patients enrolled in the registry, just under 60% had established CAD, just over 20% had cerebrovascular disease, and 9% had peripheral artery disease, leaving 25% who were asymptomatic but with CVD risk factors--essentially a primary-prevention subset.
In all, 71% of enrolled American patients were taking aspirin, with usage much higher among symptomatic subjects than among those with risk factors only (75% vs 59%). A full 9% of patients in the symptomatic group were not taking any antithrombotic drug at all, a number that reached 15% for the whole REACH US cohort.
Part of that [aspirin underutilization] could just be patient nonadherence, and part of that could be the fault of the physician, although I'd like to think that's not a big [component]. Some of the reasons for a physician not prescribing aspirin may be legitimate, such as life-threatening bleeding, but in other cases, patients may stop taking aspirin for something more minor, like gingival bleeding, and whether their doctors supported these kinds of decisions can't be gleaned from the current study.
A Two-Way "Indication Creep"?
There is also the danger that confusion over aspirin's potential harms in the primary-prevention setting might also spill over into the secondary-prevention population, he speculated. "I'm not sure what you'd call it--negative indication creep, perhaps. But there have been some well-done studies that call into question wide use of aspirin in primary prevention, and perhaps the message that doctors or patients themselves are hearing is, 'Maybe aspirin isn't so good after all,' not realizing that there is a difference between those recent publications in primary prevention and the guidelines and older data that really very strongly support broad use of aspirin for secondary prevention. These REACH data provide a contemporary sense of what utilization is, both for secondary prevention and primary prevention.
Low-Dose Aspirin Use Common in US
The REACH analysis also suggested that among patients taking aspirin, two-thirds were taking a low dose (75 to 100 mg/day). These patients were more likely to be women, Asian, or Hispanic; older; have high blood pressure or diabetes; have had previous cardiovascular interventions; and be taking other antiplatelet or anticoagulants..
There are several major randomized trials of aspirin in primary prevention ongoing: Aspirin in Reducing Events in the Elderly (ASPREE), Aspirin and Simvastatin Combination for CV Events Prevention Trial in Diabetes (ACCEPT-D), and A Study of Cardiovascular Events in Diabetes (ASCEND).


Aspirin may boost survival, cut risk of recurrence in breast cancer survivors.

A new study says breast cancer survivors who take aspirin regularly may be less likely to die or have their cancer return. The researchers found that "women who had been diagnosed with early breast cancer and who just happen to be taking aspirin, somewhere between two and five days, had a 50% reduction in dying of the breast cancer." In women who took "aspirin just once a week, there was no benefit," but, those who took "aspirin two to five times a week" experienced "a 71 percent reduction in dying from a return of the cancer,
The Los Angeles Times reports that the study of 4,164 breast cancer patients, published in the Journal of Clinical Oncology, showed that those "who took aspirin two to five days per week were 60 percent less likely to have a recurrence and 71 percent less likely to die from the disease." The findings challenge "at least five large studies" that "have shown that taking aspirin regularly has no effect on the risk of developing breast cancer in the first place."
USA Today (2/17, Szabo) reports that the researchers said that "aspirin may help control cancer by fighting inflammation," as "breast cancers produce more inflammatory chemicals than normal breast cells." But, they "cautioned that more research is needed to confirm the findings before recommending that breast cancer patients take aspirin to increase their chances of surviving," the Washington Post (2/16, Stein) "The Checkup" blog reported.
According to the Boston Globe (2/17, Smith), "The study did not ask women what dose of aspirin they were taking, nor why they were taking it." The findings "also suggested other nonsteroidal anti-inflammatory drugs...may reduce breast cancer recurrence, although that effect was evident only in women who took those medicines 6 to 7 days a week." Notably, "no link could be established between acetaminophen...and reduced breast cancer mortality."

Frostbite Resolution With Tissue Plasminogen Activator

Case Records of the Massachusetts General Hospital. Case 41-2009. A 16-Year-Old Boy With Hypothermia and Frostbite.
Sheridan RL, Goldstein MA, Stoddard FJ Jr, Walker TG
N Engl J Med. 2009;361:2654-362
Case Summary
The authors of this case study report the saga of a intoxicated teenage patient who sustained severe frostbite of the upper and lower extremities but who had nearly full return of function after intra-arterial thrombolytic treatment. The patient, a 16-year-old boy, was found unconscious in a snow bank after consuming large quantities of alcohol. The blood alcohol level was 0.12%. Because both of his hands and his right foot were severely frostbitten, the patient received intra-arterial tissue plasminogen activator (tPA) to the upper extremities over a 24-hour period. Both the upper and lower extremities improved dramatically.
Viewpoint
As in this patient, alcohol is often an underlying causative factor leading to frostbite. Current treatment involves rapid rewarming, usually in a water bath. In this patient, thrombolytic therapy was used because of radiographic evidence of diminished or absent arterial flow. Dramatic improvement occurred in all extremities, even though the tPA had been administered only to the arms. Just the great toe of one foot eventually required amputation. Using tPA therapy for suitably selected cases may reduce the need for amputation in patients with severe frostbite.

Embolic Protection: Unmet Clinical Need or Unneeded Technology

While the debate continues about whether embolic protection devices are really necessary.Ten years ago, the first embolic protection devices were born, and they have since provided a fertile and lucrative field for start-ups, many of which have been acquired by the large cardiology companies. But for the large companies that now sell the first-generation devices, the field hasn't lived up to its promise, not even in carotid stenting, where the ability to prevent stroke makes the use of these devices most compelling.
Embolic protection devices (EPDs) designed to capture the debris that breaks off during percutaneous revascularization procedures didn't exist 10 years ago, and now they make up a crowded category, particularly for an area whose promise remains largely unfulfilled. All the major cardiovascular companies jumped into the game by acquiring first-generation start-ups offering distal filters and occlusion balloons ( see Exhibit 1), in an effort to capture portions of what was originally seen as a market in excess of half a billion dollars.
What made the original vision of embolic protection devices compelling was not just the size of the market but the potential to expand the use of a variety of existing and emerging percutaneous procedures. This continuing interest can perhaps best be explained by the fact that there is a compelling underlying logic to the notion of using devices to protect against the risk of debris floating upstream to the brain and causing a stroke

Misoprostol may help stop postpartum hemorrhage.

As an alternative to oxytocin, researchers are suggesting that misoprostol may help stop postpartum hemorrhage. Researchers found that "among women who received prophylactic oxytocin in the third stage of labor, misoprostol was noninferior to oxytocin in stopping postpartum bleeding within 20 minutes (89% versus 90% of women)." In a similar trial conducted abroad on "women who did not receive prophylactic oxytocin, both drugs were highly effective, but misoprostol did not benefit as many women (90% versus 96%), and fell short of establishing noninferiority," according to a paper in The Lancet. Still, investigators concluded that "800 µg sublingual misoprostol could be an effective first-line treatment alternative when oxytocin is not available."

Prasugrel "Economically Attractive" Treatment Based on Cost-Effectiveness Analysis

A new cost-effectiveness analysis suggests that prasugrel (Effient, Lilly/Daiichi Sankyo) is an "economically attractive treatment strategy" when compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients with acute coronary syndrome (ACS) undergoing planned PCI [1]. After 15 months of treatment with either drug, average total costs were $221-per-patient lower with prasugrel, largely because of a reduction in the rates of rehospitalization following PCI. Prasugrel was also associated with a life expectancy gain of 0.102 years, the result of a decreased rate of nonfatal MI, report investigators.

Antithrombotic Agents and Endoscopic Procedures

The risk of developing a gastrointestinal (GI) hemorrhage during or following a GI endoscopic procedure is rare albeit well recognized. Clearly some procedures have a higher risk potential for bleeding, for example, polypectomy or sphincterotomy. Given the risk potentials, it has been fairly standard practice to withhold antiplatelet agents for a time before the endoscopy and to continue holding these for a defined period following a therapeutic endoscopy.
The use of antiplatelet agents, however, has clear benefit in patients with cardiovascular or neurovascular disease. Withholding these agents for even a short time may have considerable risks -- in particular, for coronary stent thrombosis, myocardial infarct, stroke, and death. Cardiology guidelines recommend dual antiplatelet therapy (aspirin + clopidogrel) for a minimum of 1 month following a bare metal stent and ideally continuing for 12 months. For patients who have a drug-eluting stent, a minimum of 6 months of dual therapy is recommended with extended benefit of continued use for up to 3 years.
Accordingly, in these patients, the risk for a thrombotic event during interruption of therapy must be carefully balanced against the potential risk for GI bleeding. Two recent publications address this balance and make new recommendations for the management of these antithrombotic agents for patients undergoing elective endoscopy. The first article is a guideline from the American Society of Gastrointestinal Endoscopy.[1] The second article is a consensus "white paper" by a writing group appointed from the American College of Cardiology and the American College of Gastroenterology.[2] Although physicians who deal with these patients should carefully review both of these documents, I have highlighted some of the important changes for clinical practice:
1. Diagnostic endoscopy: No clinical trials have demonstrated an increased bleeding incidence for patients taking aspirin or clopidogrel who undergo diagnostic GI endoscopy of any type when no biopsy is performed.
2. In assessing the risk for temporary discontinuation of antiplatelet therapies, it is important to assess the inherent risk of bleeding related to the procedures. High-risk procedures associated with increased bleeding risk include endoscopic polypectomy or mucosal resection, therapeutic enteroscopy, and laser ablation. Furthermore, some procedures are associated with bleeding that may be inaccessible or uncontrollable by endoscopic means. This includes dilation of strictures, percutaneous gastrostomy, fine needle aspirations, or Tru-Cut biopsy.
3. Aspirin should not be stopped at any point if the patient is high risk and aspirin is clearly needed for cardiovascular or neurovascular indications. For high risk procedures, clinicians may elect to stop aspirin or nonsteroidal anti-inflammatory drugs for 5-7 days depending on the underlying indication for the antiplatelet therapy.
4. Clopidogrel can be stopped for a short duration (typically 7-10 days prior to the procedure) if 1 month has elapsed since a bare metal stent procedure. For drug-eluting stents, short-term discontinuance of clopidogrel within 3 months should be avoided, and, ideally, clopidogrel should not be interrupted for the first 6 months. Abrupt cardiac stent thrombosis (which can occur when clopidogrel is withheld or discontinued) is associated with a myocardial infarct rate of 50% and related death rate of approximately 20%. Aspirin should be continued when clopidogrel is held.
5. In patients whose antiplatelet therapy is temporarily interrupted, treatment should be resumed as soon as possible following elective GI endoscopy. Whether a loading dose (600 mg) of clopidogrel is used for the initial dose or the patient is started on a maintenance dose (300 mg) should be gauged by the individual patient level of risk (stent type, time from stenting).

Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosis
Clinical Context

Although many patients present to primary care practices with symptoms consistent with lower-extremity DVT, up to 90% of these patients referred to noninvasive testing do not have thrombosis. The authors of the current study previously examined the use of a clinical risk score as well as serum D-dimer testing to help rule out DVT more effectively in primary care. The simple clinical scale assigned 1 point of risk for each of the following factors: male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, and distension of collateral leg veins. A difference in calf circumference of 3 cm or more counted for 2 points, and a positive D-dimer qualitative test was worth 6 points.
Use of this clinical tool was previously demonstrated to effectively rule out over 99% of cases of suspected thrombosis among low-risk adults. The current study seeks to validate the clinical decision rule in primary care practices.
Study Highlights
- Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
- Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
- All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
- All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
- The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
- 1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
- 49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
- 49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
- Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.
Pearls for Practice
- Clinical risk factors for DVT in the current clinical rule include male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, distension of collateral leg veins, and a difference in calf circumference of 3 cm or more.
- A simple clinical tool to evaluate the risk for lower extremity DVT safely reduced the number of patients referred to ultrasound by nearly half in the current study.

COX-2 Inhibitor Potential Treatment for Extraabdominal Desmoid Tumors

Meloxicam (Mobic), a cyclooxygenase (COX)-2 inhibitor drug used for arthritis, has shown promise as a treatment for extraabdominal desmoid tumors, according to the results of a small pilot study. The study results, which were published online December 21 in the Journal of Clinical Oncology, showed that of 20 patients treated with meloxicam who were available for evaluation, 19 (95%) had a final status of stable disease or better.
Extraabdominal desmoid tumors are generally sporadic in nature and can occur in virtually any body site, note the authors. However, they are primarily found in the extremities, chest, abdominal wall, and neck. They can be locally aggressive and invasive to surrounding anatomic structures, leading to pain, functional impairment, and deformity.
Management usually involves a multidisciplinary approach that includes surgery and radiation, but these have potential associated morbidities. This has led to investigations of both cytotoxic and noncytotoxic chemotherapy, but because the tumors are rarely fatal, finding a pharmacologic treatment with fewer complications is desirable, according to the authors.
The authors hypothesized, on the basis of previous studies, that COX-2 might be a potential therapeutic target. Experimental in vitro and in vivo research demonstrated decreased cell proliferation in desmoid cell cultures and small tumors when COX-2 was blockaded with pharmacologic agents.
Among the 20 patients evaluated, the researchers observed 1 complete response, 7 partial responses, 11 patients with stable disease, and 1 patient who had progressive disease. Although the 2 patients who discontinued treatment were not included in the evaluation, they had stable disease at the time they stopped the therapy. Patient sex, tumor size, tumor site, follow-up interval, and period of medication were not significant prognostic factors of responsiveness. However, age appeared to play a role; good responders were significantly older than poor responders (P = .0091).
Meloxicam was well tolerated and none of the patients in the final analysis experienced any adverse effects. Of the 2 patients who discontinued treatment, 1 did so because of mild gastritis, and the other was elderly with had a history of cerebral infarction and suffered from intermittent pneumonia and diarrhea.
Baxter may face product-liability suits over tainted heparin.
Baxter International Inc., which recalled its blood thinner heparin amid reports of allergic reactions and deaths in 2008, faces at least 30 lawsuits in Chicago by injured people." Meanwhile, "as many as 300 product-liability complaints may be filed in the Illinois state court, plaintiffs' attorney Allen Schwartz of Kralovec, Jambois & Schwartz said." The manufacturer "began a voluntary recall after...an increase in reports of allergic reactions to injections of the drug, said Erin Gardiner, a company spokeswoman." But, Gardiner noted that "a large number of claims" may not "involve contaminated heparin or in some cases, even Baxter heparin."


New anti-clotting drug performs better than Plavix in study.

Among patients who underwent planned stenting for treatment of acute coronary syndromes, those treated with the investigational antiplatelet agent ticagrelor (Brilinta) had fewer cardiovascular events than patients who received clopidogrel (Plavix)." This "finding emerged from a prespecified subset analysis of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, published online by The Lancet." Researchers found that, "for every 1,000 patients admitted to the hospital with a planned invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths, 13 fewer MIs, and six fewer cases of stent thrombosis. For people with acute coronary syndrome, this very well may replace Plavix." FDA "approval for Brilinta could come late this year, although it's difficult to predict the timing of such decisions,

Statins may reduce stroke risk.

Statins may reduce the risk of stroke, according to a study published in the Journal of the American College of Cardiology. Investigators looked at "data from clinical trials including almost 267,000 participants." The research "showed an overall 12 percent reduction in stroke incidence among those taking statins, with each one percent reduction in total cholesterol predicting a 0.8 percent relative risk reduction of stroke."

FDA says Spiriva may not be linked to increased stroke risk.

Spiriva HandiHaler (inhaled tiotropium bromide), which is used to treat patients with COPD, may not be linked to an increased stroke risk. The "FDA began investigating" the product's "safety last March after" Spiriva's maker "Boehringer reported slightly higher rates of stroke and heart attack for patients using its device, compared with a placebo." However, the agency "now says a recent review of a company-sponsored, 6,000-patient study did not show evidence of increased risk.
Many patients stop taking secondary prevention drugs within two years of stroke.
Many patients stop taking secondary prevention drugs within just two years after suffering a stroke. To prevent new cardiovascular events after stroke, preventive drugs should be used continuously.
But, investigators eventually discovered that "as many as 50% of stroke survivors stop taking secondary-prevention drugs within two years of hospital discharge. About 25% of patients had stopped taking antihypertensives at two years, and almost half had discontinued statin therapy for secondary prevention." In addition, "more than half had quit prescribed warfarin, and more than a third had stopped taking antiplatelet medication.

Update of the Guidelines for Lupus Anticoagulant Detection: F1000 Ranking: "Changes Clinical Behavior"

Changes Clinical Practice: Screening for lupus anticoagulant (LA) should be limited to two tests that represent two different assay principles. The Dilute Russell Viper Venom Time (dRVVT) and Activated Partial Thromboplastin Time (aPTT) should be the tests of choice.
This manuscript updates the guidelines on lupus anticoagulant (LA) detection. Several aspects from patient selection to the test itself are discussed in an attempt to minimise inappropriate test requests for LA, establish some modalities for blood collection and guide physicians on which tests should be performed and how the results should be analysed and interpreted. This article highlights the importance of using laboratory markers in the context of the clinical manifestations/suspicions and not as part of indiscriminate screening.
The authors suggest that LA testing should be limited to those with a significant probability of having antiphospholipid syndrome. Appropriateness to test for LA is graded from low to high in an attempt to avoid the risk of obtaining false-positive results. The authors establish some recommendations for optimal laboratory detection of LA, from blood collection to establishment of the cut off point and interpretation of the results. It is well recognised that there is no single test sensitive for all LAs, although the authors acknowledge that using more than two screening tests increases the rate of false positivity. The recommendation is to perform two different tests, being the Dilute Russell Viper Venom Time (dRVVT) believed to be the most specific and the Activated Partial Thromboplastin Time (aPTT) sensitive enough for the detection of LA. Other tests are less reliable and/or non-standardised and their use is discouraged. These guidelines are relevant to anyone working in the field of autoimmune diseases, particularly lupus and antiphospholipid syndrome. Some evidence supports the fact that dRVVT is the most robust and specific test for detecting LA. Any aPTT test could be the second choice because of its sensitivity.

Pleuritic Chest Pain, Thrombophilia Predict Pulmonary Embolism

Now the rules leave out certain variables that could help raise or lower suspicion, according to the authors. In their analysis, two of the strongest predictors of PE were a history of non-cancer-related thrombophilia and pleuritic chest pain.
The goal of the study was to assess the predictive value of information that physicians commonly collect from patients with suspected PE, information that has not been formally validated, Dr. Jeffrey A. Kline from Carolinas Medical Center, Charlotte, North Carolina, told Reuters Health by email.
Dr. Kline and his colleagues examined 13 "implicit variables" that are commonly used to initiate, delay, or obviate testing for PE, yet have not been validated or incorporated into existing prediction rules. The implicit variables were compared with 12 "explicit variables" that are included in prediction rules.
In a paper published online January 4th in the Annals of Emergency Medicine, the researchers report that they used data from 7940 emergency room patients who had formal testing for pulmonary embolism, as ordered by 477 different clinicians. Eventually, 568 patients (7.2%) met standard criteria for pulmonary embolism or deep vein thrombosis.
Among the implicit variables, a history of non-cancer-related thrombophilia (OR, 1.99), pleuritic chest pain (OR, 1.53), and family history of venous thromboembolism (OR, 1.51) were positively associated with venous thromboembolism, while female gender (OR, 0.57), current smoking (OR, 0.59), and substernal chest pain (OR, 0.58) were negative predictors. The presence of tachypnea and patient perception of dyspnea were marginally associated with an increased risk of venous thromboembolism.
Four of the implicit variables commonly used to support formal PE testing proved to be statistically nonsignificant, including pregnancy or postpartum state, sudden onset of symptoms, obesity, and history of treated but currently inactive malignancy.
Among the 12 explicit variables, 3 (hemoptysis, trauma within 4 weeks, and shock index greater than 1.0) were not statistically associated with venous thromboembolism. Of the remaining 9 variables, the strongest predictors were patient history of venous thromboembolism (OR, 2.90) and unilateral leg swelling (OR, 2.60), surgery in the last 4 weeks (OR, 2.27), current estrogen use (OR, 2.31), and hypoxemia (OR. 2.10).

Amphastar alleges FDA conflict of interest in heparin investigation.

The Los Angeles Times (1/21, Zajac) reports on a "new appeal in a conflict-of-interest controversy involving the Food and Drug Administration's handling of the deadly heparin contamination crisis of 2008." In announcing it would "appeal the FDA's rejection of a complaint," Amphastar Pharmaceuticals Inc. "alleged that Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, had a conflict of interest." Amphastar questions the inclusion of scientists from Momenta Pharmaceuticals on a taskforce with Woodcock tasked with identifying the culprit of the heparin contamination. Momenta is a rival of Amphastar, also applying for FDA approval of a generic form of heparin. FDA spokeswoman Karen Riley defended the taskforce saying that the agency "pulled together the team of experts, including Woodcock, under emergency conditions. 'People were dying. We had to find an answer,' Riley said."

New Variant Linked to Platelet Response and Bleeding Events With Clopidogrel

A new analysis of genetic data has identified yet another polymorphic variant of the CYP2C19 gene that influences platelet aggregation and bleeding events among clopidogrel-treated patients who underwent PCI. Individuals with a copy of the CYP2C19*17 allelic variant had a significantly reduced platelet response and significantly greater risks of bleeding compared with individuals without the *17 polymorphism, although there was no difference in rates of stent thrombosis with the variant.The results of the study are published online January 18, 2010 in Circulation.
Conversion to Its Active Metabolite
Clopidogrel is a prodrug that requires metabolization and activation to its active metabolite by the hepatic cytochrome P450 system. The metabolization of clopidogrel is achieved with a number of different isoenzymes, including CYP2C19, which is believed to play a dominant role in the process. Previous studies, have shown that a common loss-of-function CYP2C19*2 variant is associated with a blunted response to clopidogrel and affects platelet aggregation. The purpose of this study, was to determine whether the CYP2C19*17 variant, which has been linked to increased transcriptional activity and extensive metabolization of CYP2C19 substrates, leads to an enhanced response to clopidogrel and differences in clinical outcomes.
In total, 1524 patients undergoing PCI after pretreatment with 600 mg of clopidogrel were studied. Following the procedure, patients were discharged with a dual antiplatelet treatment regimen of aspirin 100 mg twice daily and clopidogrel 75 mg once daily. Of the patients, 622 were carriers of at least one *17 allele, including 546 patients who were heterozygous (wt/*17) and 76 who were homozygous (*17/*17) for the polymorphism.
Testing showed that the lowest ADP-induced platelet-aggregation values were seen in patients carrying both mutant alleles. Of the 622 patients who had at least one copy of the *17 variant, platelet aggregation values were significantly lower than individuals who did not have any copies of the *17 polymorphism.
Carriers of the CYP2C19*17 variant were also at a significantly greater risk of bleeding than those without the polymorphism, with the highest risk observed among individuals homozygous for the *17 variant (p=0.01 for trend).There are 25 known polymorphic variants of the CYP2C19 gene, with the frequency varying among different ethnic groups

Very Low Birthweight Male Babies Have Higher Risk for Intraventricular Bleeding

Among very low birth weight (VLBW) infants, the risk of intraventricular hemorrhage (IVH) is higher in males, and male babies are also more likely to have severe IVH, new research shows. These conclusions are based on data from nearly 105,000 VLBW infants born in the U.S. between 1997 and 2004. All of the infants were free of major congenital abnormalities.
In general, male infants "are more susceptible to adverse outcomes of prematurity, including death, respiratory distress syndrome, and bronchopulmonary dysplasia. There is also evidence from a small cohort study that males are at greater risk for IVH than are females.According to a report in the February issue of Pediatrics, 15.9% of male infants had IVH compared with 13.6% of female infants (OR, 1.15, p < 0.001).
After controlling for significant confounding variables, the investigators found that in addition to having a higher incidence of IVH, boys were more likely to have severe IVH (38% vs. 32.7%, OR, 1.18, p < 0.004). Body weight appeared to influence the association between gender and IVH, the findings suggest. Specifically, the link between male gender and IVH was stronger in babies weighing 1000 to 1499 g than in those who weighed <1000 g (OR: 1.19 vs. 1.14, p = 0.006).
Pediatrics 2010;125:e333-e339.

WHAT'S NEW IN COAGULATION: January 2010



Thrombectomy Can Improve DVT, VTE Outcomes

Major changes in the most recent version of the American College of Chest Physicians (ACCP) guidelines could lead to improved outcomes for patients with extensive deep vein thrombosis (DVT). All physicians need to do is follow them, but widespread adoption of these changes will take time, venous thrombectomy is now recommended for extensive DVT [i.e., iliofemoral DVT]. Before 2008, anticoagulation was the standard of care. Thrombectomy was added to the ACCP guidelines for the treatment of extensive DVT on the basis of data from a randomized controlled trial showing that thrombectomy with arterio-venous fistula was superior to anticoagulation. Arterio-venous fistula added to thrombectomy increases the blood flow velocity after the clot is removed, reducing the likelihood of rethrombosis.
In addition, 2 randomized trials from Europe showed that catheter-directed thrombolysis of iliofemoral DVT improved patency, reflux, and length of hospital stay compared with anticoagulation.. The guidelines suggest pharmacomechanical prophylaxis instead of catheter-directed thrombolysis alone to shorten treatment time.

Smoking Interaction With Clopidogrel Seen in CHARISMA; Effects of Other Antiplatelets Unclear

More data suggesting that clopidogrel may have a greater effect in smokers than in nonsmokers have come from a new analysis of the CHARISMA study. Smoking causes increased platelet activation and that clopidogrel has been reported to result in greater inhibition of platelet aggregation in smokers than nonsmokers. In studies that assessed the variability of platelet response to clopidogrel, smokers were less likely than nonsmokers to be hyporesponders, but whether smoking affects clinical outcomes in patients receiving clopidogrel remains uncertain.
To look at this issue, they evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA trial who had established cardiovascular disease. CHARISMA compared clopidogrel 75 mg/day vs placebo long-term in patients at high risk for cardiovascular events. Results showed that after a median follow-up of 28 months, clopidogrel was not significantly more effective than placebo in reducing the rate of MI, stroke, or cardiovascular death.
Results of the present analysis showed that current smoking was associated with an increase in all-cause mortality, cardiovascular mortality, and cancer mortality compared with never smoking.
The risk of bleeding also appeared to differ according to smoking status, with clopidogrel associated with a significantly increased risk among current smokers but a smaller and nonsignificant increase among never-smokers.
Two possible reasons for the observation of an enhanced effect of clopidogrel in smokers:
- Smokers could just represent a higher-risk group. Their platelets may be more active, so they would be expected to benefit more from any antithrombotic intervention. A similar enhanced effect in smokers has also been reported with lytics and GP IIb/IIIa blockers, which gives weight to this explanation.
Smoking is known to induce the CYP1A2 enzyme that is involved in the conversion of clopidogrel to its active metabolite, and this would therefore be expected to result in increased concentrations of the active metabolite, which may translate into an increased effect on clinical events and
References
1. Berger JS, Bhatt DL, Steinhubl SR, et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120:2337-2344. Abstract


Small Trial Probes Risks, Benefits of Stopping Aspirin in CV Patients With Bleeding Ulcers

A new randomized trial--albeit a small one--suggests that continuing aspirin in patients with cardiovascular disease who develop peptic-ulcer bleeding will, not surprisingly, double their risk of bleeding but may also radically reduce their risk of all-cause mortality The increased bleeding was seen despite all patients receiving a 72-hour infusion of the proton-pump inhibitor (PPI) pantoprazole, followed by oral pantoprazole, after undergoing endoscopic therapy.
The study enrolled 156 patients already taking aspirin for secondary prevention of cardiovascular or cerebrovascular events who developed peptic-ulcer bleeding; after diagnosis and treatment (hemostasis achieved) of a bleeding ulcer, patients were randomized to receive low-dose aspirin or placebo for eight weeks. (Of note, patients taking clopidogrel were included in the study, but clopidogrel was stopped until the ulcer was completely healed.) Three patients withdrew during the course of the study.
In an intention-to-treat analysis, recurrent ulcer bleeding at 30 days--the study's primary end point--was nearly twice as high in the aspirin group as the placebo group. For the secondary end point of all-cause mortality, placebo-treated patients had a more than 10-fold increase in events, a statistically significant difference. Aspirin-treated patients also had lower rates of mortality due to cardiovascular, cerebrovascular, or gastrointestinal events.
Long-term effects of bleeding include future ischemic events and CV mortality, he added. What the study underscores is the need to evaluate patients on a case-by-case basis, he continued. Some patients on antiplatelet medication who develop bleeding may have good indications for continuing on aspirin.
"On the basis of all available data, international consensus recommendations (including the results from Sung and colleagues) concluded that patients with upper gastrointestinal bleeding who require secondary cardiovascular prophylaxis should resume low-dose aspirin therapy as soon as the cardiovascular risks outweigh the gastrointestinal risks (usually within seven days)," they note. "Until additional data become available to better guide management, clinicians will need to rely on limited evidence and appropriate use of common sense that considers the patient as a whole without focusing on a specific organ system to the detriment of another."
Author disclosures are listed in the paper.
References
1. Sung JJY, Lau JYW, Ching JYL, et al. Continuation of low-dose aspirin in peptic ulcer bleeding. Ann Intern Med 2009; available at: http://www.annals.org.
2. Barkun AN and Bardou M. Aspirin withdrawal in acute peptic ulcer bleeding: Are we harming patients? Ann Intern Med 2009; available at: http://www.annals.org.


SUBDURAL BLEEDING IN INFANTS

Nonaccidental head injury is the most common cause of subdural bleeding (SDB) in infants below 12 months of age, according to findings from an autopsy review by German investigators. 12% to 30% of infants with SDB will die as a result, and 60% to 70% of survivors will have significant neurologic deficits.
They emphasize that, "because every case of unexplained SDB in infants raises immediate concerns about the possibility of nonaccidental head injury, the differential diagnosis of SDB in infants is crucial." In recent years, however, a so-called "unified hypothesis" has "become the center of an ongoing debate" because it suggests that SDB in infants is not necessarily a result of abuse. Instead, it postulates that infants may develop SDB from a combination of severe hypoxia, brain swelling, and increased central venous pressure, which causes blood to leak into the subdural space.
In their review of autopsies performed at their hospital between 1956 and 2005, the authors found that 715 were in infants less than 1 year old, and 50 were in babies with SDB. Death was due to nonaccidental head injury in 17 cases and possibly related in two more. Fourteen had SDB.
Patients with nonaccidental head injury tended to be significantly older than patients with SDB caused by other events and patients with neither nonaccidental head injury nor SDB (mean ages 140 days vs 76 days vs 74 days, respectively).
SDB was present in 82.4% of babies with nonaccidental head injury but in only 5.2% of infants with other causes of death.
Two observations contradict the unified hypothesis -- the rarity of SDB and unexplained SDB, as well as the lack of correlation between brain weight (a marker of brain swelling) and the presence of SDB.
"If hypoxia and/or brain swelling has a possible role in the pathogenesis of infantile SDB, according to the unified hypothesis, then the incidence of SDB in infants' autopsies should be very high," the authors point out.
Pediatrics 2009;124:1587-1594.

Pradaxa may be as safe, effective as warfarin.

Bloomberg News (12/6, Kresge) reported that the "blood-thinning pill Pradaxa [dabigatran] may provide a more convenient alternative to" warfarin, "the standard therapy for potentially deadly clots," according to a study published in the New England Journal of Medicine and presented at the American Society of Hematology conference. Pradaxa "'is a far more convenient drug,' since levels in the body don't react with foods and other medicines the way warfarin does, researchers...wrote in the study." The investigators found that "Pradaxa reduced the risk of bleeding by 29 percent compared with warfarin."
MedPage Today (12/5, Gever) reported that "there were no significant differences in safety outcomes, including bleeding events, acute coronary syndrome, and abnormal liver function tests," according to the researchers.



Risk of Venous Thromboembolism Greater, Lasts Longer, Than Thought

New research in middle-aged women suggests that the risk of venous thromboembolism (VTE) after many different types of surgery is greater and lasts for longer than has previously been appreciated [1].
The findings are crucial because they show that the risk is greatest in the first six weeks following surgery, peaking around three weeks afterward. But most patients receive prophylaxis only for the duration of their hospital stay, which averages around six days. The risk of VTE also remains high for 12 months postoperatively.
National Health Service (NHS) hospital admission and death records for 947 454 middle-aged women recruited from 1996 to 2001. They excluded 207 302 women who had had surgery in the previous year or who had had a hospital admission for VTE before recruitment, history of a blood clot, or a previous cancer.During follow-up (average 6.2 years), there were 239 614 hospital admissions for surgery and 5419 admissions for VTE, and a further 270 women died from VTE. Compared with the risk without surgery, women were almost 70 times more likely (relative risk 69.1) to be admitted with VTE during the first six weeks after an inpatient operation--with the peak incidence being three weeks afterward--and almost 10 times more likely after a day case operation (RR 9.6).
The fact that day surgery was associated with an increased and prolonged risk of VTE--albeit a lesser one than that for inpatient surgery--is important because preventive treatment for thrombosis is not normally used in day surgery patients, the researchers say.
The risks were lower but still elevated seven to 12 weeks after surgery, with those women almost 20 times more likely to suffer VTE compared with those undergoing no surgery (RR 19.6). And in most cases, an increased risk remained for at least one year, the researchers note. Risk also varied considerably by type of surgery, being highest after inpatient surgery for hip or knee replacement (relative risk 220.6) and cancer (RR 91.6) within the first six weeks postoperatively. This confirms in clinical practice previous findings from clinical trials about the highest-risk surgical groups for VTE,

Dabigatran Can Replace Warfarin in Venous Thromboembolism: RECOVER
Results

The new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) could replace the older product, warfarin, say researchers presenting new data from a large clinical trial in patients with acute venous thromboembolism (the RECOVER study). The results show that dabigatran is as effective and as safe as, if not safer than, the older agent, but it also offers the advantage of a fixed dose and no need for blood monitoring, as opposed to the regular monitoring and dose adjustment needed with warfarin.
The lack of a need for monitoring would "be welcome news for both patients and their physicians.An oral agent that frees patients from these concerns about diet and drug interactions and that behaves in a predictable manner is a very positive development. These factors will simplify the use of anticoagulants, and he predicted that patient compliance and adherence to treatment will be greatly improved. Warfarin has a very narrow therapeutic index, with a small difference between the dose that is therapeutic and the dose that is toxic, there is no more dangerous drug on the market."
Third Major Indication
The use of dabigatran for venous thromboembolism, which was explored in the RECOVER study, represents a third major indication for the drug. A second similar trial, known as RECOVER-2, is underway..
Venous thromboembolism, which covers both deep vein thrombosis and pulmonary The initial indication for dabigatran, and the only one that is currently approved - but not in the United States - is for prophylaxis in orthopedic surgery patients. Dabigatran was approved for this use in Europe and Canada in 2008, on the basis of 2 large trials (the RE-MODEL study in patients undergoing total knee replacement and the RE-NOVATE study of total hip replacements), which showed that dabigatran was comparable to enoxaparin 40 mg once daily in preventing venous thromboembolism. However, a similar study conducted in North America in knee replacement (RE-MOBILIZE) used a higher dose of enoxaparin (30 mg twice daily) and showed dabigatran to be inferior, so the company did not file in the United States, Dr. Schulman explained. A new North American trial in hip replacement patients (RE-NOVATE 2) is now underway, and is using the enoxaparin 40 mg dose, he said.
The second potential indication for dabigatran is in atrial fibrillation, and highly positive results in this population were recently reported in the RE-LY study. A long-term safety follow-up study of these patients is currently underway (RELY-ABLE). The company has said that it plans to file for registration for this indication in 2010.
All of these studies have been funded by the manufacturer, Boehringer Ingelheim.
Details of RECOVER Study
The RECOVER study was conducted in 2539 patients with acute symptomatic venous thromboembolism who were randomized to 6 months of treatment with either dabigatran 150 mg twice daily or warfarin once daily, given in doses adjusted to an international normalized ratio (INR) of 2 to 3. All patients received initial treatment for 6 days with a parenteral anticoagulant (either intravenous heparin or a subcutaneous low-molecular-weight heparin derivative), to allow the dose of warfarin to be adjusted to achieve an INR of 2 to 3.
The final analysis was conducted on 1274 patients who received dabigatran and 1265 who received warfarin.
The primary end point was recurrent venous thromboembolism or fatal pulmonary embolism, which was confirmed in 2.4% of patients receiving dabigatran and 2.1% of patients receiving warfarin. There was 1 death in each treatment group. The hazard ratio was 1.1 (95% confidence interval [CI], 0.65 - 1.84), and this shows noninferiority, Dr. Schulman reported.
Major bleeding was seen in 1.6% of patients receiving dabigatran and in 1.9% of patients receiving warfarin, which is not significantly different, he said.
However, when major bleeding was combined with clinically relevant nonmajor bleeding events, there was a significant difference, with such events being confirmed in 5.6% of patients receiving dabigatran and in 8.8% patients receiving warfarin. The hazard ratio was 0.63 (95% CI, 0.47 - 0.84; P = .002).
The difference was also significant for any bleeding event, which was seen in 16.1% of patients receiving dabigatran and in 21.9% receiving warfarin. The hazard ratio for this was 0.71 (95% CI, 0.59 - 0.85; P < .001), which represents a 29% risk reduction, and this was highly significant.


Clopidogrel Resistance: Is It Just Noncompliance?

In a new paper that turns the notion of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) nonresponsiveness on its head, researchers propose that a high rate of noncompliance may explain the variability in platelet inhibition that has been associated with the drug [1].
To look at the issue of compliance in patients taking clopidogrel chronically, Serebruany et al retrospectively analyzed blood samples from 422 heart disease patients and 209 poststroke patients who had had their platelet activity tested before and after clopidogrel use in various trials. They measured levels of clopidogrel, the inactive carboxyl metabolite, and the active thiol metabolite. Clopidogrel noncompliance was defined as plasma concentration of inactive carboxyl metabolite <5000 ng/mL in any posttreatment evaluable sample after at least one month of clopidogrel maintenance therapy.
The nonactive metabolite of clopidogrel was used to evaluate compliance, as this is much more stable than the active metabolite. "We were dealing with samples from blood drawn seven or eight years ago. It is much more reliable under these conditions to test for the nonactive metabolite, as it will still be present, whereas the active metabolite is unstable and might have disappeared."
As expected, they found that of the three biomarkers assessed, only the inactive carboxyl metabolite of clopidogrel was consistently present in large quantities in the blood samples. The active thiol metabolite was mostly undetectable, whereas unchanged free clopidogrel was successfully recovered in about half of the patient samples.
Stroke Patients Had Worst Compliance
Based on the noncompliance definition, 138 patients (22%) were identified as noncompliant. There were more noncompliant subjects among poststroke victims (n=79, 38%) as compared with 59 patients with heart disease (14%).
There was a strong correlation between inhibition of platelet activity (IPA) and plasma levels of all three biomarkers indicative of clopidogrel metabolism. Low IPA in the range of −5% to 20% was consistently observed in noncompliant patients, with a strong predictive value (C statistic=0.911).
"We found that some of the patients whom we would classically describe as 'resistant' to clopidogrel, in that they showed low levels of platelet inhibition, in fact didn't actually have clopidogrel on board. Future antiplatelet trials should recognize noncompliance as a critical confounding factor, and every attempt should be made to minimize and strictly monitor prescribed antiplatelet regimens.
Once-daily dose of enoxaparin may be feasible for children at high risk of VTE.
MedPage Today (12/9, Susman) reported, "Researchers said it is feasible to provide once daily dosing of the low molecular weight heparin enoxaparin (Lovenox) to children at high risk of venous thromboembolism." The study presented at the American Society of Hematology meeting used "pharmacokinetic modeling and data from 126 children -- including neonates, infants and children -- who were administered enoxaparin off-label" to perform "pharmacokinetic analyses." The lead researcher said, "According to these results...a once-daily enoxaparin dosing regimen seems to be feasible for at least 50% of this population."
Nearly 20% of stroke survivors fail to take medications to prevent another episode.
University of California-Los Angeles researchers discovered that "about one-fifth of ischemic stroke survivors don't take medications that can reduce their risk of another stroke." According to the paper in the American Journal of Preventive Medicine, "men, older patients, and non-Hispanic patients were more likely to take blood thinners," whereas "19 percent" of the 4168 participants studied "didn't take blood thinners."





Different Antithrombotic Combinations up Risks for Bleeding and Recurrent MI

A nationwide survey of patients taking antithrombotic medications after an MI indicates that a combination of clopidogrel plus a vitamin-K antagonist (typically warfarin) or a combination of warfarin, clopidogrel, and aspirin carries a far higher risk of bleeding than aspirin alone.
Different Combinations, Different Risks
The study looked at prescription claims and bleeding events among all patients admitted for a first-time MI in Denmark between 2000 and 2005: a total of 40 813 patients. During a mean follow-up of approximately 15 months, 1852 patients (4.5% of the original group) were readmitted to the hospital with nonfatal bleeding, mostly gastrointestinal in nature; an additional 115 died from a bleeding event.
Compared with aspirin alone, rates of fatal and nonfatal bleeding were higher for clopidogrel and for any combination of antithrombotic drugs (use of a vitamin-K antagonist as monotherapy was not associated with a significant increase in bleeding, compared with aspirin). Strikingly, the risk of clopidogrel plus vitamin-K antagonist, which has in the past been recommended as a potentially safer combination than aspirin, clopidogrel, and vitamin-K antagonist, was only slightly lower than the combination of all three drugs. Risk of bleeding was amplified in older patients and in those who'd had a previous bleeding event.
The more antithrombotic treatments you receive, the greater the risk for being admitted for the bleeding diagnosis. Aspirin and clopidogrel, gave only a slightly increased risk of being admitted with a bleeding diagnosis. Other combinations such as a vitamin-K antagonist and clopidogrel, or all three drugs, carried a three to four times higher risk of being admitted to the hospital with bleeding.The study also illuminates an association of increasing concern to physicians: namely, the poorly understood link between increased risk of bleeding and higher MI rates. In their study, 37.9% of the 1852 patients with a nonfatal bleed had a subsequent MI or died over the follow-up period. That's compared with 18.4% of 38 960 patients who were not hospitalized for bleeding.



Defining the Link Between CYP2C19*2 and Clopidogrel Response
JAMA. 2009;302:849-857
Summary
The authors of this study had 3 aims: (1) to establish whether laboratory response to clopidogrel is an inherited trait; (2) to identify genetic variants that predict platelet inhibitory response to clopidogrel; and (3) to demonstrate the clinical importance of these variants by association with clinical outcomes.
First, by studying a large population of related Amish individuals, they demonstrated that laboratory response to clopidogrel is a highly heritable trait. Furthermore, the authors estimated that the genetic contribution far outweighs non genetic contributions such as age, body mass index, and lipids.
To meet their second objective, the authors used the same population to conduct a genome wide screen of more than 500,000 genetic variants and found that 1 variant, CYP2C19*2, was most closely associated with poor laboratory response to 7 days of clopidogrel dosed at 75 mg/day. Individuals carrying 2 copies of this genetic variant receive, on average, a 40% inhibition in platelet aggregation with clopidogrel. In contrast, those who do not carry this genetic variant have 65% inhibition with clopidogrel.
Finally, by genotyping a large group of patients undergoing elective percutaneous coronary intervention, the authors demonstrated that patients who carry the CYP2C19*2 variant experience a reduced platelet inhibitory response to clopidogrel and have a 3- to 4-fold increased risk for cardiovascular events in the subsequent year. Most important, the authors also demonstrated that patients were not at an increased risk for events when not treated with clopidogrel.
Celebrex may interfere with cardioprotective benefit of aspirin
The pain killer celecoxib (Celebrex) may interfere with the cardioprotective benefit of low-dose aspirin, researchers found." The researchers reported online in the Proceedings of the National Academy of Sciences that celecoxib "tightly binds to one form of Cox-1 that prevents aspirin from reaching its antiplatelet target." In addition, the researchers "confirmed that celecoxib and aspirin given together did not prevent clotting to the same degree as aspirin alone in an animal model."


Bleeding Patterns May Be Better Controlled With a 21 vs 24-Day Oral Contraceptive Pill

Cycle control may be better with a 21-day norgestimate/ethinyl estradiol 25-µg regimen vs a 24-day drospirenone/ethinyl estradiol 20-µg regimen of oral contraception, according to the results of a study by Andrew M. Kaunitz, MD, from the University of Florida College of Medicine in Jacksonville, and colleagues, reported in the December issue of Obstetrics & Gynecology.
Abnormal bleeding (breakthrough bleeding) on oral contraceptive pills (OCPs) is one of the leading reasons that women discontinue OCPs. The 24/4 design has generally (although not consistently) demonstrated better inhibition of follicular development (and endogenous estradiol production) compared to 21/7 formations. Based on this, 24/4 pills may be superior compared to 21/7 formulations in the treatment of premenstrual symptoms, acne, and dysmenorrhea.
The goal of this 3-cycle, open-label, multicenter study was to compare bleeding patterns with a 21/7-day triphasic norgestimate/ethinyl estradiol 25-µg OCP vs a 24/4-day drospirenone/ethinyl estradiol 20-µg OCP among healthy, sexually active women. To ensure balanced allocation distribution between regimens for "fresh starts" and "switchers," randomization was stratified. An interactive voice-response system allowed daily collection of bleeding data. Criteria endorsed by the 2007 US Food and Drug Administration's Reproductive Health Drug Advisory Committee were used to define bleeding.
Across the 3 cycles, there were fewer unscheduled bleeding days in the 21/7-day OCP group (n = 165) vs the 24/4-day OCP group (n = 167; mean, 4.6 vs 6.1 days; P = .003). There were significantly fewer episodes of unscheduled bleeding in women using the 21/7-day OCP vs those using the 24/4-day OCP (mean, 1.47 vs 2.01 days; P = .001), and women using the 21/7-day OCP had a significantly lower absence of scheduled bleeding at each cycle (P < .001). Tolerability was good for both regimens.
This study suggests that unscheduled bleeding is less common with 25 mcg OCs given in the 21/7 formulation compared to the 20 mcg EE/drospirenone in a 24/4 schedule, at least for the first 3 months. For women who are particularly prone to discontinuation of OCs due to any breakthrough bleeding, the 25 mcg EE/norgestimate selection may be a better first choice. An accounting of overall patient satisfaction scores between the two different formulations would be enlightening and helpful to the clinician. For instance, it is conceivable that some patients may be more willing to tolerate occasional unscheduled bleeding if premenstrual symptoms were improved with the 24/4 20 mcg EE/drospirenone pill compared to the 21/7 25 mcg EE/norgestimate brand.


ERASE-MI: Initial Results With Elinogrel--A New IV/Oral P2Y12 Antiplatel

Initial phase 2 results with a new antiplatelet agent that has both intravenous and oral formulations have been published The agent, elinogrel (Portola Pharmaceuticals), is a P2Y12 ADP-receptor antagonist similar to clopidogrel, but it is the first agent in this class to be developed in both intravenous and oral formulations, which will give it an advantage, particularly when being used acutely in the cath lab.The current phase 2 study, ERASE-MI, published in the December 2009 issue of the American Heart Journal, was conducted by a team led by Dr Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).
The second author of the paper, Dr Matthew Roe (Duke Clinical Research Institute), explained to heartwire that an intravenous agent would give immediate platelet inhibition. "This would be great for use acutely, particularly in urgent PCI," he noted. He added that the P2Y12 antagonists currently available come only as oral formulations and take a couple of hours to reach maximal platelet inhibition. The first intravenous agent to be developed, cangrelor, was tested in the CHAMPION trials, which were presented at last month's American Heart Association meeting, as reported by heartwire . In these trials, cangrelor did inhibit platelet activity more effectively than clopidogrel, but this was not translated into a reduction of the primary end point. Many possible reasons for this anomaly were suggested.
One of the reasons put forward was that there might have been some interaction between cangrelor and clopidogrel when transitioning patients from the intravenous drug to the oral drug. An agent that is available as both intravenous and oral formulations, such as elinogrel, would therefore alleviate any concerns about possible interactions between different agents when transitioning from the IV to oral products.
In the ERASE-MI trial, 70 STEMI patients were randomized to one of four doses of elinogrel or placebo before the start of the diagnostic angiogram preceding primary PCI. All patients also received a 600 mg clopidogrel loading dose, followed by a 300 mg clopidogrel loading dose four hours after PCI.
Results showed that the incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel and in those treated with placebo. No differences were demonstrated between elinogrel and placebo in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count, or ST resolution.
A second part of the trial was planned as a dose-confirmation study using the highest tolerated dose from the first part of the study. Although no safety issues emerged in the first part, the trial was prematurely terminated after its completion by the sponsor, so the dose-confirmation part was not conducted.
Roe told heartwire that the company had decided not to continue with the ERASE-MI study because it was instead going ahead with a different phase 2 study with a new design. ERASE-MI was evaluating the intravenous formulation of elinogrel only and the transitioning of patients onto oral clopidogrel, but the new trial, INNOVATE, will evaluate the use of both the intravenous and oral formulations of elinogrel.
The authors conclude: "Given the unique properties and dual formulations of elinogrel, this novel P2Y12 ADP-receptor antagonist may have broad applications for patients with acute myocardial infarction, those undergoing PCI, and other patient groups typically treated with P2Y12 inhibitors."
The ERASE-MI study was funded by Portola Pharmaceuticals.
References
1. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009; 158:998-1004.e1. Abstract

Low-Dose Aspirin During Pregnancy Has No Adverse Impact on Preterm Infants

Preterm infants whose mothers took low-dose aspirin (LDA) exhibit no negative long-term effects and may have fewer neurobehavioral difficulties as children, according to a study published online December 21 in Pediatrics.
Aspirin is well tolerated by the fetus and seems to produce a moderate reduction of several different risks (preeclampsia, delivery before 37 weeks of gestation, and fetal growth restriction) without increasing infant bleeding, To determine the effects of LDA on preterm children, researchers studied 656 children born in France in 1997 before 33 weeks' gestation. Newborn data were gathered from the Etude Epidemiologique des Petites Ages Gestationnels (EPIPAGE) cohort study, which primarily measured mortality and cerebral lesions. Obstetric records confirmed LDA intake. After 5 years, the investigators examined the children for incidence of cerebral palsy, behavioral issues, and cognitive ability.Researchers concluded there was no significant relationship between LDA and any long-term outcome. Furthermore, they reported an association of LDA with a decrease in behavioral difficulties.
The cerebral palsy rate at 5 years of age did not differ according to LDA treatment nor did the rate of low MPC [mental processing composite] or low sequential processing scores (<70). The rate of simultaneous processing scores of <70 was significantly lower in the LDA group than in the no-LDA group (7% vs 19%; P = .04), but not after adjustment for PS [propensity score], prognostic factors, and social class (adjusted odds ratio [aOR]: 0.59 [95% confidence interval (CI): 0.17-2.06]). Results showed a reduction at the limit of significance in total behavioral difficulties (aOR: 0.44 [95% CI: 0.19-1.02]) and hyperactivity (aOR: 0.43 [95% CI: 0.17-1.05]) associated with LDA treatment after adjustment for PS and prognostic factors.
The study authors acknowledged several limitations, including the fact that 25% of the children were not evaluated as 5-year-olds. They also stated that the rate of loss to follow-up was higher in the control group vs the LDA faction, which "may have resulted in an underestimation of neurodevelopmental impairments in the no-LDA group.
Pediatrics. Published online December 21, 2009.


Optimal Duration of Dual Antiplatelet Therapy After DES: 12 Months, But More Data Coming

A review paper published in the December 2009 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions tackles the issue of the optimal duration of dual antiplatelet therapy following drug-eluting stent (DES) implantation, and while the authors are reluctant to prescribe a one-size-fits-all approach, the currently recommended 12 months of therapy is the right option.
Clinical trials are lacking, more data are coming, with numerous ongoing studies addressing different durations of dual antiplatelet therapy. In the meantime, "the take-home message is that we need to comply with the guidelines; whether we agree or disagree with them.
The evidence examining the relationship between dual antiplatelet therapy and stent thrombosis, noting that the strongest predictor of stent thrombosis is stopping thienopyridine therapy within six months of stent implantation. Observational studies have also shown that extending dual antiplatelet therapy from six to 12 months was not associated with reductions in late or very late stent thrombosis. If treatment extends beyond 12 months, clinicians should realize they are treating systemic disease rather than issues related to the stent implantation.
The largest of the studies is the Dual Antiplatelet Therapy (DAPT) study, a 20 000-patient, $100-million, multisponsor randomized clinical trial testing optimal duration of dual antiplatelet therapy following stent implantation. DAPT is comparing 12 vs 30 months of dual antiplatelet therapy among 15 000 patients who have been treated with a drug-eluting stent, powered to assess the primary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety end point for DAPT is major bleeding. An additional 5000 patients treated with bare-metal stents will also be enrolled.
The ISAR-SAFE study, a 6000-patient study, is testing dual antiplatelet durations of six months vs 12 months in patients treated with a drug-eluting stent. The primary end point is death, MI, stroke, and TIMI major bleeding at 15 months.
References
1. Kandzari DE, Angiolillo DJ, Price MJ, Teirstein PS. Identifying the "optimal" duration of dual antiplatelet therapy after drug-eluting stent revascularization. J Am Coll Cardiol Cardiovasc Intervent 2009; 2:1279-1285.

Study finds Aranesp nearly doubles risk of stroke in certain patients.

An online published study by the New England Journal of Medicine "raises fresh safety concerns about widely used anemia medicines, finding that the drug Aranesp [darbepoetin alfa] nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis." The study of "4,038 people with type 2 diabetes, kidney problems, and moderate anemia" found that strokes "occurred in 101 patients given Aranesp and 53 patients given" a placebo shot. The study's authors concluded that for many patients, "this risk will outweigh its potential benefits." The researchers "also found that among patients with a history of cancer, 60 of 188 patients taking Aranesp died, compared with 37 of 160 on placebos." Amgen, the maker of Aranesp, said it will share the "information with drug regulators and expects the results of the study will lead to changes in the official prescribing information guiding Aranesp's use

Researcher says healthy people should not take aspirin to prevent heart attackThe use of aspirin to ward off heart attacks and strokes in those who do not have obvious cardiovascular disease should be abandoned. The UK's Telegraph reports that "after carrying out a review of studies, has found that the beneficial effects of aspirin are small in healthy people and are heavily outweighed by the risk of potentially deadly stomach bleeding.

Supreme Court rejects Plavix patent challenge.
The Wall Street Journal reports that the Supreme Court rejected Apotex Corp.'s appeal to invalidate a patent for the blood thinner Plavix [clopidogrel]. Sanofi-Aventis SA and Bristol-Myers Squibb Co. sued Apotex for patent infringement when the company applied for FDA approval to market a generic version of the drug before the original patent expired.
"An earlier Sanofi patent on the drug expired in 2003, and Apotex said the disputed second patent covered a variation that wasn't innovative enough to warrant legal protection," Bloomberg News (11/3, Stohr) reports. For their part, Bristol-Myers and Sanofi "argued in court papers that the disputed patent covered 'a new, breakthrough drug compound that took years and millions of dollars to develop.'"
Anticoagulants may improve biochemical control of localized prostate cancer.
Anticoagulants, including aspirin, warfarin, and clopidogrel, were associated with improved biochemical control of localized prostate cancer in men treated with radiation therapy, according to a new retrospective study of 662 men" conducted by researchers at the University of Chicago. In fact, "at four years, biochemical control, or the absence of biochemical relapse as measured by prostate-specific antigen testing, was statistically significantly better in the group of prostate cancer radiotherapy patients receiving anticoagulants than in the group not receiving the blood-thinning therapy (91 vs. 78 percent)." This "potential benefit is most pronounced in patients with high-risk localized disease," investigators pointed out. The authors speculated that the benefit "likely stems from an 'interaction' between the radiation and the drugs."
Plavix appears to work about as well in women as it does in men.
Unlike aspirin, clopidogrel (Plavix) appears to work about as well in women as it does in men," according to a meta-analysis appearing in the Journal of the American College of Cardiology. In fact, "clopidogrel reduced cardiovascular events by 7% in women and 16% in men compared with placebo, with only a 'weak' trend for a difference between genders." The researchers found that "major bleeding risk was elevated 43% in women and 22% in men compared with placebo, again without a significant difference.

Anti-clotting drugs may lower risk of prostate cancer recurrence in men undergoing radiation.The use of anti-clotting drugs, including aspirin, appears to lower the odds that cancer will recur in men undergoing radiation treatment for prostate cancer," according to research presented at the American Society for Radiation Oncology annual meeting. In a study of "662 men with prostate cancer undergoing radiation treatment," researchers found that "cancer recurred in only nine percent of men taking an anti-clotting medication, compared with 22 percent of those who weren't taking the drugs." Notably, "the benefit was most pronounced in men with high-risk aggressive cancers that had not yet spread (metastasized) at the time of radiation treatment." Data indicated that among this group, "cancer recurred in 18 percent of men on anticoagulants vs. 42 percent of men not taking the drugs."

ESAs may increase risk of venous thromboembolism.
Drugs that are used to stimulate red-blood-cell production in cancer patients made anemic by chemotherapy" may "increase the risk of venous thromboembolism," according to research published in the Journal of the National Cancer Institute. The FDA "required a strong warning on the label of the drugs, known collectively as erythropoiesis-stimulating agents, or ESAs," in 2007 "and suggested limiting their use to patients with unusually low red blood counts." In a study of "56,210 cancer patients treated with chemotherapy," researchers found "that 14.3 percent of patients receiving ESAs developed thromboembolism (deep vein thrombosis or pulmonary embolism) compared with 9.8 percent of those who did not receive an ESA." The drugs "are intended to reduce the number of blood transfusions needed during chemotherapy," but the study showed that "the rate of blood transfusions remained the same for both groups."

FDA approves tranexamic acid for heavy menstrual bleeding.
The FDA-approved Lysteda (tranexamic acid) has been approved as the first non-hormonal treatment for heavy menstrual bleeding." The agency said the drug can "reduce bleeding by acting on a protein that helps blood clot." But the FDA also "warns that taking Lysteda with hormonal contraceptive drugs can increase the risk of blood clots, stroke and heart attacks. Women should only use the products together if there is a strong medical need, the agency says.



Biomarkers of hypercoagulability may be reduced by treatment with rivaroxaban.
Biomarkers of hypercoagulability -- ominous signs in patients with heart failure -- appear to be reduced by treatment with the oral, direct Factor Xa inhibitor rivaroxaban," according to research presented at the American Heart Association conference. Researchers found that "over the course of a week, levels of prothrombin fragment 1.2 increased by 11.6 ng/ml among placebo patients with severe heart failure (New York Heart Association Class III/IV)." However, "among patients on rivaroxaban, prothrombin fragment 1.2 actually decreased 2.7 ng/ml, indicating a significant reversal of the level."
Experimental blood thinner may be safe, effective in heart patients.
Boehringer Ingelheim GmbH's Pradaxa [dabigatran etexilate] was safe and effective when added to aspirin and Plavix [clopidogrel] in reducing clots in patients with chest pains and minor heart attacks," according to a study presented at the American Heart Association meeting. Researchers "looked at four doses of Pradaxa in patients with acute coronary syndrome." The drug "didn't cause major bleeding during a six-month study," which included "more than 1,800 patients."

Distribution of Body Fat Important in VTE
A 10-year prospective study in Denmark illustrates that the distribution of body fat, as well as the amount, is important when it comes to the risk of venous thromboembolism (VTE) . All measures of obesity are predictors of VTE, including body weight, body-mass index (BMI), waist circumference, hip circumference, and total body-fat mass, and that these associations persist after adjustment for known cardiovascular risk factors. In the report published online October 26, 2009 in Circulation, they also found some differences between genders, with hip circumference being predictive of VTE in women but not in men, whereas waist circumference was linked with VTE in men but not women.
Study Highlights
- From 1993 to 1997, a total of 27,178 men and 29,876 women aged 50 to 64 years were recruited into a Danish prospective study (Diet, Cancer, and Health), and the incident VTE events were identified.
- During 10 years of follow-up, the outcome of VTE events was identified in the Danish National Patient Registry and verified by review of medical records.
- A VTE diagnosis was considered verified when typical clinical symptoms were combined with confirmatory diagnostic test results (ultrasound study, venography, echocardiography, ventilation-perfusion lung scan, or computed tomography scan).
- Body weight, BMI, waist circumference, hip circumference, and total body fat were measured at baseline.
- Cox proportional hazard models were used to assess the association between anthropometry and VTE.
- Age was used as a time axis, with further adjustment for smoking; physical activity; height; hypertension; diabetes mellitus; cholesterol; and, among women, use of hormone replacement therapy.
- Results of this study verified 641 incident VTE events and found monotonic dose-response relationships between VTE and all anthropometric measurements in both sexes.
- The incidence rate of VTE was 1.15 (95% confidence interval, 1.06 - 1.24) per 1000 person-years.
- The associations were the same according to the different types of VTE.
- Adjustment for potential confounding factors had no substantial implications.
- In mutually adjusted analyses of waist and hip circumference, it was found that hip circumference was positively associated with VTE in women but not in men, whereas waist circumference was positively associated with VTE in men but not in women.
Clinical Implications
- The distribution of fat predicts the risk for arterial thrombotic events in that central obesity is a better predictor of coronary heart disease than BMI, and peripheral obesity is not a predictor of coronary heart disease.
- All measurements of obesity are predictors of the risk for VTE; as such, positive associations were found between VTE and body weight, BMI, waist circumference, hip circumference, and total body fat mass in both sexes.

Low Factor V Levels Signal Poor Prognosis With Hepatitis B-Induced Acute Liver Failure
In patients with acute hepatic failure resulting from hepatitis B, factor V level on day 3 of diagnosis can help predict the risk for mortality, and thus can help triage patients for liver transplantation, according to a study from India reported here at the American Society for Clinical Pathology 2009 Annual Meeting.The study was performed at the All India Institute of Medical Sciences, New Delhi.
Levels of factor V lower than 10% vs those higher than 10% can distinguish which patients need transplant and which can recover with supportive therapy. Acute hepatic failure is mainly caused by viral hepatitis, toxic substances, acetaminophen overdose, and metabolic disorders such as Wilson's disease. It is frequently fatal, and liver transplantation is the only curative treatment.
The study was performed in a cohort of 40 patients with viral hepatitis-induced acute liver failure, 26 of whom died (65%), and 14 of whom survived (35%). Investigators examined variables that were hypothesized to predict survival, including age, interval between onset of jaundice and encephalopathy, coagulation factor level, and various metabolic parameters. They excluded patients with liver failure caused by paracetamol poisoning or Wilson's disease, drug overdose, history of recent (within 1 week) alcohol use, and possible infiltrating tumor.
Patients were evaluated on day 1 and day 3 of admission. Evaluations included factor V, arterial blood gases, and serum lactate estimation.
Serum lactate levels and average arterial blood glasses were largely similar between patients who died and those who survived. However, factor V level on day 1 of admission was significantly lower in patients who died - in the range of 0% to 5% - whereas one quarter of patients who survived had factor V levels higher than 5%. Factor V level on day 3 was even more highly associated with survival. The level ranged from 0% to 10% among those who died compared with 7% to 25% for those who survived (P < .034), Dr. Gupta reported.
Altogether, maximum factor V levels were 12% for patients who died and 25% for those who lived, he noted.
American Society for Clinical Pathology 2009 Annual Meeting: Abstract 83. Presented October 31, 2009.


Prehospital Triage "Immediately Successful" in Boosting Rates of Thrombolytic Therapy for Stroke
Toronto researchers report that a citywide prehospital protocol aimed at early triage of stroke patients and bypassing closer hospitals for dedicated stroke centers has raised their rates of thrombolytic treatment to the among the highest in North America. Implementation of the citywide protocol was associated with a 4-fold increase in the number of patients arriving within 2.5 hours of symptom onset, he told Medscape Neurology, "and that translated into many more patients being eligible for, and receiving, tissue plasminogen activator [tPA], with overall good results."
The protocol provided that stroke patients be transported directly to 1 of 3 regional stroke centers, even if it meant bypassing local hospitals. Aiding this coordinated effort was a paramedic screening tool comprising a standardized prompt card to help first responders identify a possible stroke, and an ambulance destination decision rule. Paramedics began to call ahead to the designated stroke centers so that stroke teams could be waiting, and possible stroke patients arriving through the emergency department were routed directly to the stroke team, in most cases skipping assessment by the emergency department physicians.
In this article, Dr. Gladstone and colleagues compared the use of thrombolytic therapy in patients with stroke arriving at their center during the first 4 months of the new protocol, from February 14 to June 14, 2005, with treatment rates for the same time period in 2004. A television advertising campaign undertaken by the Heart and Stroke Association of Ontario about the warning signs of stroke was in effect during both tested time periods, the authors note.
"The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset," they write. "We observed a 4-fold increase in patients who were eligible for and treated with [tPA]; 1 in 2 of patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (1 in 5 of patients with ischemic stroke overall)."
Although onset-to-arrival times were longer after the protocol was instituted, probably as a result of additional transfer time, median onset-to-needle times for tPA were significantly reduced.

Clopidogrel Effects in Men vs Women
A new meta-analysis of the major clopidogrel trials has suggested that the drug reduces cardiovascular events and increases bleeding in both men and women, without significant differences between the sexes. Preliminary data suggest that men and women respond differently to antiplatelet drugs. This has been seen with aspirin and with GP IIb/IIIa blockers. So we wanted to look at clopidogrel in this regard, because it is a commonly used medication and whether it has differential effects on men and women has not been studied to date." He added: "We saw small differences, but they were nonsignificant and could have easily occurred by the play of chance. Overall, we can say that, from 80 000 patients studied, clopidogrel is effective in reducing cardiovascular events and confers an increased risk of bleeding in both men and women."
The meta-analysis included the major placebo-controlled clopidogrel trials--CURE, CREDO, CLARITY TIMI 28, COMMIT, and CHARISMA--in a total of 79 613 patients, of whom 30% were women.
Results showed that in the overall population, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (cardiovascular death, MI, or stroke), with no significant differences in treatment effect between women and men. Among the 23 533 women enrolled, the risk reduction with clopidogrel seemed to be greatest for MI, with the effects on stroke or death not statistically significant. Among the 56 091 men enrolled, the risk reduction was significant for MI, stroke, and death individually. Clopidogrel increased the risk of major bleeding in both women and men.
Asked how these latest data on clopidogrel fit in with the differential effects seen with aspirin and GP IIb/IIIa blockers in the two sexes, Berger explained that the data on aspirin suggest that it is of benefit in both sexes but in men it tends to reduce cardiovascular events, while in women it tends to reduce stroke. Differences between the sexes have also been seen with GP IIb/IIIa blockers in ACS, with men benefiting more than women, but Berger said this was probably accounted for by the fact that men were higher risk in terms of testing positive for troponin, and this is the group that benefits from GP IIb/IIIa blockers.
1. J Am Coll Cardiol 2009; 54:1935-1945.


Sleep Apnea a Risk Factor for Venous Thromboembolism

Sleep-disordered breathing (SDB) is a condition rife with significant risk factors for blood clot events that should be identified in the clinical setting, according to the findings of a large retrospective study, presented here at CHEST 2009: American College of Chest Physicians Annual Meeting.Intermittent hypoxia and hypercapnia have been associated with adverse cardiovascular outcomes, but this study found an association with venous thromboembolism (VTE) - either pulmonary embolism (PE) or deep vein thrombosis (DVT).
They analyzed 2,434,123 patients hospitalized with SDB between 1979 and 2005; Dr. Alnas called them "a spectacular group of patients." The researchers found evidence of PE in 24,953 patients (1.03%), of DVT in 28,378 patients (1.7%), and of VTE in 47,160 patients (1.94%). Of the SBD patients, 1,464,485 were males (60%) and 969,638 were females (40%).
Among women with SDB, the incidence of PE was 1.53%, of DVT was 1.12%, and of VTE was 2.32%. Among males with SDB, the incidence of PE was 0.69 %, of DVT was 1.2 %, and of VTE was 1.68%. Among those 60 years and older with SDB, PE incidence was 1.09%, DVT incidence was 1.4%, and VTE incidence was 2.3%.
At the end of the study, researchers found that the relative risk for VTE in SDB patients, compared with those without SDB, was 1.72 (95% confidence interval [CI], 1.70 - 1.74). The relative risk for VTE in females with SDB, compared with those without, was 2.11 (95% CI, 2.08 - 2.14). This supports the hypothesis that inflammation is a risk factor for VTE. It's been known from other studies that sleep apnea and the resulting hypoxemia promotes inflammation.
CHEST 2009: American College of Chest Physicians Annual Meeting: Session 4280. Presented November 4, 2009

Pulmonary Embolism and Drug Reactions Top List of Diagnostic Errors
Pulmonary embolism and drug reactions or overdose are the most common diagnostic errors committed or observed by physicians, according to a survey of general practitioners and specialists, the results of which are published in the November 9 issue of the Archives of Internal Medicine.
This sample of diagnostic errors represents "the largest reported case series of diagnostic errors to date and affords valuable insights into the types of errors that physicians are committing and witnessing," write Gordon D. Schiff, MD, from the Division of General Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts, and colleagues.
Researchers asked physicians to recall 3 clinically significant diagnostic errors that they had seen or committed, to estimate how often they had seen those errors, and to rate the clinical impact or outcome of each error. A diagnostic error was defined as any mistake or failure in the diagnostic process leading to a misdiagnosis, missed diagnosis, or delayed diagnosis.
The survey analyzed 583 cases of diagnostic error reported anonymously by 283 physicians - 47% were primary care physicians - from 22 institutions in 6 states. Physicians reported an average of 2.2 errors each. These physician respondents had been in practice an average of 9 years.Of these 583 errors, 30% directly involved the reporting physician and 68% were witnessed by them. In all, 28% of these errors were rated as major in severity, 41% as moderate, and 31% as minor or insignificant.
Only 8% of the errors were considered common, with 35% rated as occasional, 26% as infrequent, and 27% as rare. After pulmonary embolism (4.5% of total) and drug reactions or overdose, including poisoning (also 4.5%), the next most common missed diagnoses were lung cancer (3.9%), colorectal cancer (3.3%), acute coronary syndrome, including acute myocardial infarction and breast cancer (each 3.1%), and stroke (2.6%). At 20.2%, all types of cancer together constituted the largest disease category.
Errors in the testing phase, including failing to order, report, or follow-up on laboratory results, occurred most frequently (44%), followed by clinician assessment errors, such as failure to consider and overweighing competing diagnoses (32%), history taking (10%), physical examination (also 10%), and referral or consultation errors and delays (3%).

Cardiologists Shocked by New FDA Alert on Clopidogrel-PPI Interaction
The FDA has issued a new public-health warning on the possible interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the proton-pump inhibitor (PPI) omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states: "New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."
The FDA alert says the new information on which its warning is based comes from new studies conducted by the sponsor that compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in people who took clopidogrel plus omeprazole vs those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart, the statement adds.
Based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of clopidogrel is conducting follow-up studies to explore this and other drug interactions.
The agency advises patients using clopidogrel to consult with their healthcare provider if they are currently taking or considering taking omeprazole. It adds that patients who use clopidogrel and need a medication to reduce stomach acid can use antacids or H2 antagonists such as ranitidine, famotidine, or nizatidine, because the FDA does not believe that these medicines will interfere with the anti-clotting activity of clopidogrel. However, cimetidine should not be used, it says.
The FDA adds that the manufacturers of clopidogrel have agreed to look at other possible drug interactions with clopidogrel.
It also says that other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. "Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel," it adds.

Oral Anticoagulants Redeemed? Daily Dabigatran "Safe" With Dual Antiplatelets After MI
The oral anticoagulant that seems more congenial than warfarin and a better protector against stroke in the setting of atrial fibrillation looks like it could have a future in high-risk patients with recent acute coronary syndromes.
The randomized REDEEM trial, reported here at the American Heart Association 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran etexilate (Boehringer Ingelheim) that strikes a good balance between clinical effectiveness and bleeding risk in daily use with aspirin and clopidogrel after acute STEMI or non-STEMI.
Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with six-month rates of "major and clinically relevant minor bleeds" that the investigators called "low and acceptable"--no higher than 2%--despite a significant dose-related rise in the risk of bleeding complications (p<0.001). The two highest dosages in the study, 110 mg twice daily and 150 mg twice daily, had been tested against warfarin in the randomized RE-LY trial, the higher dosage showing superiority and the lower showing noninferiority in preventing stroke and embolic complications in patients with atrial fibrillation, as recently reported by heartwire . Oldgren emphasized that the confidence he and his colleagues have in dabigatran's level of safety is based on both REDEEM and RE-LY.
"Given that the dual antiplatelets and dabigatran up to 150 mg [twice daily] caused not more than a 1% absolute increase in major bleeds [compared with placebo], it's a safe drug," Oldgren told heartwire . "We also have the RE-LY data, a different population, of course, but a large cohort with a lot of safety data and a good safety profile, an extremely low rate of intracranial bleeds, and a low rate of major bleeds. Given that, and the low increase in bleeding in this study, we think that it's okay to go forward with the 110-mg or 150-mg twice-daily dose. But you could argue that the 75-mg or 50-mg [twice-daily] dosages decreased anticoagulation activity and had a very safe profile concerning bleedings."
The trial entered 1861 patients with at least one cardiovascular risk factor aside from their acute event, which included prior MI in 29%, diabetes in 31%, and heart failure in 12%. They were randomized to placebo or to dabigatran at one of the four dosages starting within a few weeks (mean 7.4 days) of acute STEMI or non-STEMI and continuing for six months. Patients were already on aspirin and clopidogrel and about half had undergone PCI at the time of randomization.
Handheld Decision-Support System May Improve Diagnostic Workup for Pulmonary Embolism CME
To help clinicians safely and efficiently assess patients with suspected pulmonary embolism, extensive data and guidelines are widely available. Noninvasive testing for pulmonary embolism should be guided by clinical probability estimates.
Because clinician inconsistency in use of systematic diagnostic approaches increases overall risks for misdiagnosis and recurrent venous thromboembolism, there is a need for effective interventions to improve diagnostic decision making for pulmonary embolism. A point-of-care, handheld computer-based CDSS could help address this need, but studies to date have not examined the efficacy of such a handheld CDSS.
Study Highlights
- The hypothesis tested by this cluster randomized trial was that a handheld CDSS intended to guide diagnostic testing for pulmonary embolism could improve diagnostic decision making more than paper-based educational material.
- The goal was to determine the efficacy of a handheld CDSS to improve the diagnostic workup in the emergency department of patients with suspected pulmonary embolism.
- Clinicians at 20 emergency departments in France were permitted to become familiar with inputting clinical data into handheld devices for a total of 1103 consecutive outpatients with suspected pulmonary embolism.
- Investigators evaluated baseline testing during this preintervention period.
- With use of a random number table, the emergency departments were then assigned to activation of a CDSS on the devices (10 centers, 753 patients) or to use of posters and pocket cards showing validated diagnostic strategies (10 centers, 1015 patients).
- Providers were not blinded as to intervention assignment. Outcome evaluation was automated.
- Appropriateness of diagnostic workup (any sequence of tests yielding a posttest probability < 5% or > 85%) was the main endpoint of the study.
- Strict adherence to guideline recommendations and the number of tests performed per patient were secondary endpoints.
- The proportion of patients with appropriate diagnostic workups was greater during the trial vs the preintervention period in both groups.
- However, the computer-based guidelines group had a greater increase in this proportion during the trial vs the paper guidelines group (absolute change, 30.2% vs 10.9%).
- The adjusted mean difference in increase was 19.3 percentage points favoring the computer-based group (95% CI, 2.9 - 35.6 percentage points; P = .023).
- Patients in whom pulmonary embolism was ruled out accounted for most of this improvement.
- For those patients in whom diagnostic workups were appropriate, those in the computer-based guidelines group received slightly fewer tests vs patients in the paper guidelines group (mean tests per patient, 1.76 ± 0.98 vs 2.25 ± 1.04; P < .001).
- The computer-based guidelines group also had a greater increase in strict adherence to recommended diagnostic testing (adjusted mean between-group difference in the change, 17.1 percentage points; 95% CI, 1.9 - 32.4 percentage points; P = .030).
- Limitations of the study include insufficient power to detect differences in patients' clinical outcomes during follow-up, low frequency (approximately 40%) of handheld computer use in real time, and enrollment of more patients in the paper guidelines group vs the computer-based guidelines group.
- The investigators concluded that a handheld CDDS improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.
- They recommend more widespread use of this tool if their findings are confirmed by others and if the community agrees that such a tool should be widely used by clinicians.
Clinical Implications
- A program to guide diagnosis of pulmonary embolism when used on a mobile, handheld device allowed emergency department clinicians to test patients with suspected pulmonary embolism more appropriately vs use of paper guidelines alone, according to the results of a cluster randomized trial.
- For patients in whom diagnostic workups were appropriate, those in the computer-based guidelines group received slightly fewer tests vs patients in the paper guidelines group. The computer-based guidelines group also had a greater increase in strict adherence to recommended diagnostic testing.
Advertisements for Plavix may have cost US taxpayers hundreds of millions of dollars.
"Sanofi-Aventis SA and Bristol-Myers Squibb Co.'s best-selling blood thinner Plavix [clopidogrel] may have cost US taxpayers hundreds of millions of dollars because of ineffective advertising," according to a study published Nov. 23 in the Archives of Internal Medicine. The research "raises concerns that companies may shift the cost of advertising to public and private insurers if sales don't take off," according to the authors of the study. Reuters reports that in a four-year period between 2001 and 2005, ad spending in the United States for Plavix averaged around $70 million per year. At the same time, even though physicians treating Medicaid patients did not alter their prescribing habits, Medicaid expenditures on Plavix increased significantly.
Chest CT Angiograms to Diagnose Pulmonary Embolism Twice as Likely to Find Other Pathology
Chest computed tomography angiograms (CTAs) to evaluate patients for acute pulmonary embolism in the emergency department are more than twice as likely to find an incidental pulmonary nodule or adenopathy as they are to find a pulmonary embolism, according to the results of new research published in the November 23 issue of the Archives of Internal Medicine. The aim of this study was to determine the prevalence and management implications of such incidental findings.
The investigators reviewed the results of 589 pulmonary CTAs that were ordered in the emergency department of a large academic tertiary care hospital that had 50,000 visits annually.
The mean age of the patients was 53 years (range, 34 - 72 years), and 63% were women.
The investigators report that pulmonary embolism was found in 55 CTAs (9%) and that 195 patients (33%) had findings indicative of other diagnoses.
A total of 141 patients (24%) had a new incidental finding that required clinical or radiologic follow-up.
Pulmonary nodules were the most common incidental finding and were found in 127 patients (22%). Of these, 73 were a new finding.
"Using current clinical guidelines, follow-up [CT] or another procedure would be recommended for 96% of patients with new incidental pulmonary nodules," the authors note.
In addition, new adenopathy requiring follow-up was found in 51 patients (9%).
They conclude that systematic approaches to determining clinical risk and higher yield indications for CTA are recommended during assessments of acute pulmonary symptoms in the emergency department.
Arch Intern Med. 2009;169(21):1966-1968, 1961-1965.
Ultrasound-Assisted Thrombolysis Improves Outcomes in Chronic DVT

Aggressive intervention in chronic deep vein thrombosis (DVT) using ultrasound-assisted thrombolysis shows superior outcomes compared with non-ultrasound-assisted thrombolysis. Each year, about 600,000 patients will develop DVT, and about 100,000 will die. Approximately 30% of DVT patients will have recurrent DVT within 10 years, with the greatest risk occurring in the first 2 years. Many of these patients are unable to work or be productive members of society. Current treatment options include anticoagulation and compression stockings plus extremity elevation. There is no high-level evidence to support endovascular therapy in chronic DVT, he noted.
The DVT registry Dr. Garcia presented included 53 patients with chronic DVT involving 59 limbs (11 upper limbs and 48 lower limbs). Five patients were excluded from the analysis (incomplete data or death). Of 48 treated patients, only 1 failure occurred. Mean age was 52 years, and about 50% of the patients were men. Of 47 successful procedures, 17 were ultrasound-assisted and 30 were non-ultrasound-assisted.
Complete lysis was achieved in 67% of the ultrasound-assisted group vs 52% of the non-ultrasound-assisted group. Sixty percent of the ultrasound-assisted group said they were "much improved" or "somewhat improved" compared with 37% of the non-ultrasound-assisted group.Fifty percent of the ultrasound-assisted group had no symptoms after the procedure compared with 33% in the non-ultrasound-assisted group. Some pain was experienced by 17% vs 56%, respectively.
"This study showed that physicians should not sit back and let these patients suffer. We need to be proactive about treating chronic DVT. Some physicians say there is nothing you can do, but if you can traverse the chronic hard clot, you can make a difference. There are millions of patients out there with chronic DVT. This is a real opportunity to improve outcomes and quality of life for these patients," Dr. Garcia said.
36th Annual VEITH Symposium. Presented November 20, 2009.
High-Impact Exercise Reduces Stroke Risk

Regular workouts are protective against ischemic stroke, say researchers.
They suggest that the intensity of the activity is important and the effect is independent of the improvement exercise has on hypertension, diabetes, or dyslipidemia.
The research team looked at more than 3000 people from the Northern Manhattan Study. Only 20% reported that they regularly participated in moderate- to heavy-intensity activities.
The average age of the study sample was 69 years, and participants were followed up for approximately 9 years. During that time, there were 238 strokes.
The results appear in the November 24 issue of Neurology and point to the benefits of high-impact workouts.
"We were somewhat surprised that the total energy expended was not associated with risk of ischemic stroke, but the intensity itself was," Dr. Willey said. "This could represent difficulties with measuring total energy expended in the elderly, or it may be that the ability to perform more moderate- to heavy-intensity activity is indicative of overall good health."
These results are contrary to other studies that found that even light exercise reduced the risk of stroke. In the Nurses' Health Study and the Women's Health Initiative Observational Study, even mild-intensity activity, such as walking, was beneficial.
"Due to the number of events, we may not have been able to detect more subtle protective effects from light-intensity activity that others have found," Dr. Willey explained.
Surprisingly, the protective effect investigators observed occurred only in men and not in women. "This may not be an actual biological phenomenon," he said. "There may be factors that we had not measured in our study, such as hormone replacement therapy." Some have suggested that hormone replacement increases the risk for stroke and influences physical activity.
Dr. Willey also points out that the cohort included older people with a high prevalence of physical inactivity and other stroke risk factors. He emphasized that there are many benefits of regular workouts beyond reduction of ischemic stroke. "Our findings should not discourage women from exercising," he said.
This study was funded by the National Institutes of Health. Dr. Willey has disclosed no relevant financial relationships.
Neurology. 2009;73:1774-1779.