Learning Center

New In Coagulation

November - News in Coagulation

Antithrombin III, Human (Thrombate III)
Misleading Safety Claims
Food and Drug Administration's Center for Biologics Evaluation and Research has reviewed sell sheet Thrombate III (Antithrombin III, Human) submitted by Talecris Biotherapies, Inc. (Talecris) . This sell sheet misbrands Thrombate III.
The FDA-approved professional labeling (PI) for Thrombate III states that it is indicated for the treatment of patients with hereditary antithrombin III (AT) deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. These are specific high risk situations for patients with clotting deficiencies. To underscore this limited indication, the Indications and Usage section describes how to determine accurately the existence of hereditary AT deficiency.
The sell sheet presents safety and efficacy superiority claims for Thrombate III versus fresh frozen plasma (FFP) based on comparison of Thrombate III's PI with anecdotal evidence. There are no adequate and well-controlled clinical trials or substantial clinical experience to support such superiority claims.
Specifically, the backside of the sell sheet includes a table comparing Thrombate III and FFP (fresh frozen plasma). The headings for the table read:
"Thrombate III ... the Necessary Therapy"
"Fresh frozen plasma (FFP) is contraindicated for a coagulopathy when the missing protein is available as a concentrate."
The table continues with the comparison of Thrombate III and FFP on efficacy, dosing, "safety processing," adverse events, side effects, storage, and "convenience." The overall presentation of the table misleadingly suggests that Thrombate III is safer and more effective than FFP when none of these characteristics have been compared in an adequately and well-controlled manner.
The sell sheet is misleading because it suggests that Thrombate III is safer than has been determined by substantial evidence or substantial clinical experience. There are significant safety risks involved with the use of Thrombate III for hemostasis, particularly involving the interaction of Thrombate III and heparin. Heparin is commonly used in high risk situations for which Thrombate III is indicated. The Warnings section of the PI states that the anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Concomitant use of heparin and Thrombate III requires careful monitoring. Therefore, the following statement, on page 2 of the sell sheet, is misleading: "Thrombate III reduces the risk of thrombotic events without increasing the risk of bleeding."

FDA Licenses Drug to Prevent Joint Damage in Children with Hemophilia A http://www.fda.gov/bbs/topics/NEWS/2008/NEW01900.html
The U.S. Food and Drug Administration today approved a new use for the blood product Kogenate FS to reduce the frequency of bleeding episodes and prevent joint damage in children with the most severe form of hemophilia.
Hemophilia A is a rare, hereditary, bleeding disorder in which a protein needed to form blood clots, factor VIII, is missing or its level is reduced. The disorder affects about 15,000 individuals in the United States, nearly all of whom are male.
"Administering Kogenate FS to children with hemophilia A on a daily basis before a bleeding event occurs will reduce bleeding into joints and help prevent joint damage, a major cause of disability in hemophiliacs," said Jesse Goodman, M.D., M.P.H., director, FDA's Center for Biologics Evaluation and Research.
When individuals with hemophilia are injured, they bleed longer than a person without hemophilia. As a result, these individuals may experience serious bleeding episodes, often in the joints and muscles. Repeated bleedings increase the chance of joint damage.
Kogenate FS is a genetically engineered version of factor VIII. It was first licensed in the United States in 1993 for use during surgery and to prevent or control other bleeding episodes.
In a clinical trial, 65 boys under 30 months of age with severe hemophilia A and normal joints were observed for five years. The patients received either one daily dose of the drug, or three doses at the time of a bleeding episode. Joint damage during a bleeding episode was 6-fold lower, and the rate of bleeding 8-fold lower, in those boys who received the drug on a daily basis compared to those who received the drug only when a bleeding episode occurred. Most patients received the drug intravenously through a catheter.
The most common adverse events were infection at the catheter site and fever.

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750

Clinical Context
Two-point ultrasonography is frequently used in the evaluation of patients with suspected DVT, but whole-leg color-coded Doppler ultrasonography has emerged as another diagnostic option as well. Two-point ultrasonography is relatively simple to perform and is associated with better access, particularly during weekends and nights. In addition, it does not require sophisticated ultrasound equipment and has a high rate of reproducibility.
However, the use of 2-point ultrasonography to diagnose DVT frequently requires repeated testing in 1 week to detect calf DVT, which can extend to the proximal veins. Whole-leg Doppler ultrasonography generally obviates this requirement, making 1-day testing possible. The current study examines the 3-month outcomes of patients tested for suspected DVT of the lower extremities with 2-point ultrasonography or whole-leg color-coded Doppler ultrasonography.
Study Highlights
14 centers in Italy participated in the study. Patients were eligible for study participation if they were 18 years or older and were presenting for evaluation of their first episode of suspected DVT of the lower extremities. Patients with a history of VTE were excluded from study participation.
Participants were randomly assigned to a diagnostic strategy of 2-point or whole-leg ultrasonography. Study subjects in the 2-point ultrasound group underwent an ultrasound examination focused on the common femoral and popliteal veins. Patients with normal results on 2-point ultrasound testing then underwent D-dimer testing, and, if the result of the D-dimer was negative, no additional testing was performed. Patients with abnormal D-dimer levels were scheduled to undergo another ultrasound test at 1 week.
Participants who received negative results on whole-leg testing did not receive any additional workup.
The main outcome of the study was the prevalence of objectively proven VTE during the 3 months after testing in patients with negative results on workup for DVT.
2098 patients underwent randomization. Baseline data were similar between diagnostic groups.
The mean age of the participants was 63 years, and 41% of subjects were men.
Many patients had significant risks for DVT, with 28% having a history of cancer and 25% having a history of leg trauma or fracture.
The rates of abnormal findings on initial ultrasonography were 22.1% in the 2-point ultrasound group and 26.4% of the whole-leg ultrasonography group.
In participants with abnormal results on D-dimer testing in the 2-point ultrasonography group, 5.5% had abnormal results on repeated ultrasonography at 1 week.
In participants with positive testing results on whole-leg ultrasonography, 76.6% had proximal DVT, 13% had isolated DVT of the posterior tibial or peroneal veins, and 10.4% had isolated muscular vein thrombosis.
Approximately one quarter of study participants had a clinical visit at 3 months after the initial evaluation, and the rest were contacted by telephone.
At 3 months, the mortality rates in the 2-point and whole-leg ultrasound groups were 1.1% and 0.9%, respectively.
16 participants had suspected DVT during follow-up in the 2-point ultrasound group, and DVT was confirmed in 7 of these patients. 21 participants had suspected DVT during follow-up in the whole-leg ultrasound group, and DVT was confirmed in 9 of these patients.
The overall rates of symptomatic VTE during follow-up were 0.9% and 1.2% in the 2-point and whole-leg ultrasound groups, respectively. The difference between groups was not significant.


Preliminary Data Suggest Spiriva Not Linked to Increased Stroke Risk
http://www.medscape.com/viewarticle/581756

October 8, 2008 - Preliminary data from a large, 4-year, company-sponsored study of about 6000 patients suggest that the inhaled, long-acting anticholinergic agent tiotropium bromide (Spiriva HandiHaler, Boehringer Ingelheim Pharmaceuticals, Inc) is not linked to an increased risk for stroke relative to placebo, the US Food and Drug Administration (FDA) announced yesterday in an updated early communication.
Complete results of the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study are expected to be available in November 2008, according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program. At that time, they will be subjected to an agency review that may take several months.
Thus far, however, the findings contradict those of 2 recent publications, which have reported an increased risk for mortality and/or cardiovascular events in patients receiving tiotropium and other inhaled anticholinergic agents for the treatment of chronic obstructive pulmonary disease (COPD).
One study was a systematic review and meta-analysis of 17 clinical trials involving inhaled anticholinergic agents (n = 14,783), and the other was a case-control study of inhaled medications that included an anticholinergic (n = 32,130 case patients and 320,501 control patients).
In March 2008, Boehringer Ingelheim had also reported findings from a meta-analysis of 28 placebo-controlled studies that suggested an annual excess risk for stroke of about 2 cases per 1000 patients. At that time, the FDA advised that these results be interpreted with caution.
Tiotropium is indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysima.

Societies Confront GI Risks of Antiplatelets, NSAIDS in Consensus Document
:http://www.medscape.com/viewarticle/581682

News Author: Steve StilesCME Author: Charles Vega, MD
Clinical Context
Upper gastrointestinal tract ulceration and bleeding are important complications of treatment with ASA and other NSAIDs. The annual incidence of ulceration related to NSAIDs is 2% to 4.5%. However, the rate of hospitalization from ulcerative events declined between 1992 and 2000, possibly because of the use of lower doses of NSAIDs and/or the increased use of antisecretory therapy. The use of NSAIDs in addition to regular ASA increases the risk for gastrointestinal tract adverse events to a greater degree than the risk associated with either medication alone.
The current Expert Consensus Document from the American College of Cardiology Foundation, American College of Gastroenterology, and American Heart Association describes the best practice to mitigate the risk for gastrointestinal tract adverse events associated with the use of ASA, NSAIDs, and antiplatelet agents.
Study Highlights
The use of low-dose ASA increases the risk for symptomatic or complicated upper gastrointestinal tract ulcers by 2- to 4-fold, to a level of 5 cases of ulceration for every 1000 ASA users per year. Enteric-coated ASA preparations do not reduce this risk, but higher doses of ASA promote an increased risk for ulceration. Therefore, ASA at doses higher than 81 mg daily should not be routinely prescribed for long-term therapy.
The combination of ASA with heparin or warfarin is synergistic in promoting upper gastrointestinal tract bleeding. When ASA is used with warfarin, the international normalized ratio should be maintained between 2 and 2.5.
The risk for gastrointestinal tract hemorrhage associated with clopidogrel is not significantly lower vs ASA, and a strategy of replacing ASA with clopidogrel only to reduce gastrointestinal tract risk is not recommended.
In patients with a history of ulcer complication or ulcer disease, patients should be tested for evidence of H pylori infection before initiation of antiplatelet therapy. If results of this testing are positive, patients should receive eradication therapy before antiplatelet therapy.
Patients with a history of previous ulcer, gastrointestinal tract bleeding, or who are to receive dual antiplatelet therapy or an antiplatelet medication plus an anticoagulant should receive gastrointestinal tract prophylaxis during treatment with an antiplatelet medication. In addition, patients with 2 or more of the following risk factors should receive gastrointestinal tract prophylaxis during antiplatelet therapy:
Age 60 years or older
Corticosteroid use
Dyspepsia or symptoms of gastroesophageal reflux disease
PPIs are the preferred medications for the therapy and prophylaxis of NSAID- and ASA-associated gastrointestinal tract injury. Misoprostol is associated with adverse effects, which often lead to treatment discontinuation. Sucralfate and H2 receptor antagonists are not adequately effective in the prevention of NSAID-related gastric ulcers.
The decision whether to discontinue ASA in the setting of acute ulcer bleeding must be made on an individual basis. One trial found that discontinuation of ASA after a bleeding ulcer was associated with a higher risk for mortality but no reduction in the risk for recurrent ulcer bleeding. It should be noted that patients received treatment with PPIs in this study.
ASA does not need to be discontinued before most endoscopic procedures, but each case should be evaluated individually.


Warfarin Warning: Shortfalls in Anticoagulation for AF Up Risks of ICH and Embolic Stroke
http://www.medscape.com/viewarticle/581882

News Author: Steve StilesCME Author: Charles Vega, MD
October 10, 2008 - Most patients with atrial fibrillation (AF) aren't getting prescriptions for warfarin, and of those who are on warfarin, most aren't being anticoagulated to the proper therapeutic extent; their international normalized ratios (INRs) are frequently outside the recommended range of 2.0 to 3.0, which puts them at significantly increased risk of intracranial hemorrhage or embolic stroke, suggest data gleaned retrospectively from prescription reimbursement claims, hospital records, and similar sources from the years 1999 to 2005 [1]. There was no record of a prescription for an antiplatelet agent for almost half the patients in the analysis.
Overall in the analysis:
Only 45% of the population was prescribed warfarin.
A total of 52% had insurance claims for an anticoagulant or antiplatelet agent.
Men were significantly more likely than women to be dispensed an anticoagulant (odds ratio [OR], 1.46; 95% CI, 1.40 - 1.52).
Patients aged 60 to 74 years were significantly more likely than those aged 40 to 59 years to be dispensed an anticoagulant (OR, 1.68 - 1.73; 95% CI lower limit ≥ 1.57, 95% CI upper limit ≤ 1.85, depending on age subgroup).
In a substudy of the 13,115 patients for whom INRs were recorded, the median during follow-up was within the therapeutic range (2.2 INR). However, about one third of the group was in the therapeutic range <> 3.0 were far less common.
Alarmingly, but not surprisingly, INR levels <>Clinical Context
Compared with normal sinus rhythm, nonrheumatic AF increases the risk for embolic stroke by 4- to 7-fold. This risk increases with age; AF accounts for nearly one quarter of strokes in persons between the ages of 80 and 89 years. In patients undergoing cardioversion for AF, nearly all thromboembolic events occur within 10 days of treatment. Other factors that promote embolic events in AF include female sex, hypertension, poor myocardial function, previous myocardial infarction, and a previous thromboembolic event.
Warfarin is indicated to prevent embolic stroke in patients with AF, particularly older adults with other cardiovascular risk factors. However, warfarin therapy can be difficult to manage for both patient and clinician alike. The current study uses a large patient database to examine the treatment of AF.
Study Highlights
Study data were drawn from a database of a large health plan in the United States. The database contains information on medical diagnoses used for billing, pharmacy claims, and laboratory work, with approximately 30% of outpatient laboratory values appearing in the database.
The current research focused on adults age 40 years or older who had at least 1 diagnostic code for AF between 1999 and 2005. Patients with diagnoses of mitral stenosis or heart valve replacement were excluded from study analysis.
The main outcome of the study was the prevalence of treatment of AF with warfarin. Researchers also examined INR levels within the study cohort and how these levels affected subsequent outcomes.
116,969 patients with AF were evaluated. 35% of cases appeared to be newly developed between 1999 and 2005, and the remainder were chronic AF.
59% of patients were men. The mean age of male subjects was 66 years, and the mean age of women was 70 years.
45% of subjects received a prescription for warfarin, and 48% had no claim for warfarin or an antiplatelet medication. 82% of participants had no INR recorded in the database.
Patients in the youngest age group, between 40 and 59 years, were the most likely to receive warfarin.
More than 30% of patients were hospitalized during the study period.
Risk factors for embolic stroke, such as age 75 years or older and hypertension, were far more common than risk factors for hemorrhage, such as coagulopathy.
Men were 46% more likely to receive warfarin vs women. In general, warfarin prescriptions were more common in patients at higher risk for embolic events. Older adults were more likely to receive warfarin, although subjects between ages 60 and 74 years were more likely to receive warfarin vs those age 75 years or older.
The median INR during follow-up was 2.2, but only 19% of subjects spent at least a large majority of the time in the therapeutic range of INR (between 2 and 3). Subtherapeutic INR results outnumbered supratherapeutic results.
There were 151 strokes, 62 intracranial bleeds, and 21 arterial thrombotic events during 13,200 person-years of INR monitoring. INR levels less than 2 were associated with an unadjusted relative risk of 2.39 for stroke and 5.68 for arterial thromboembolism vs therapeutic INR levels.
INR levels greater than 3 were associated with an unadjusted relative risk of 2.11 for intracranial hemorrhage vs therapeutic INR levels.
Current warfarin use was not a statistically significant risk factor for stroke, intracranial bleed, or arterial thromboembolism after accounting for INR level.

Black Patients May Be at Higher Risk for Microbleeds
http://www.medscape.com/viewarticle/582159
Allison Gandey
October 16, 2008 - African Americans have 32% more microbleeds after primary intracerebral hemorrhage than whites, a new study shows. The results are published in the October 7 issue of Neurology.
"Our study suggests that black patients with primary intracerebral hemorrhage have a far greater frequency of microbleeds compared with whites and that this may have important implications for diagnosis and treatment of risk factors," senior author Chelsea Kidwell, MD, from the Georgetown University Medical Center, in Washington, DC, told Medscape Neurology & Neurosurgery.
"However, we still need to better understand the contributions of various underlying risk factors in these populations," she said.
In this retrospective study, the researchers looked at patients diagnosed with primary intracerebral hemorrhage at 2 metropolitan stroke centers. Clinical and neuroimaging data were available for each patient. The investigators compared baseline characteristics and imaging findings by race.
The researchers report that age and hypertension were not significantly associated with microbleeds. However, race and heavy alcohol consumption were.
.Neurology. 2008;71:1176-1182. Abstract

Coffee and Tea May Protect Against Stroke
News Author: Pauline Anderson
http://www.medscape.com/viewarticle/576548
June 24, 2008 - High consumption of coffee or tea every day appears to protect male smokers against at least 1 type of stroke, a new study suggests.
This large, prospective, observational study showed that Finnish smokers who consumed 8 or more cups of coffee per day had a 23% lowered risk for cerebral infarction, whereas those who drank 2 or more cups of black tea daily had a 21% lowered risk for this type of stroke vs those who drank little or none of these beverages. The associations were independent of risk factors such as a history of coronary heart disease.
Their report is published in the June 2008 issue of Stroke.

Antioxidant Health Benefits
Both coffee and tea are widely consumed caffeinated beverages, the study authors write, and both are known to have antioxidant health benefits. For example, observational research suggests that coffee drinking is inversely associated with inflammation and endothelial dysfunction and that it may improve insulin sensitivity and reduce the risk for type 2 diabetes. As for tea, it contains high amounts of polyphenols, which prevent oxidation of low-density lipoprotein cholesterol and may reduce platelet activation and plasma C-reactive protein levels, a marker of inflammation.
Some of these health benefits may extend to prevention of cerebral infarction, said the study authors. "Beneficial effects of consumption of coffee and tea with regard to risk of cerebral infarction are biologically plausible because coffee and tea contain phenolic compounds with antioxidant properties that may prevent atherosclerosis," they write.
However, although the relationship between consuming caffeinated beverages and the risk for coronary heart disease has been studied extensively, this current study is among the few to examine the association with stroke risk.
Subjects for this study were participants of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial originally designed to determine whether alpha-tocopherol, beta-carotene, or both could reduce cancer incidence in male smokers. The cohort consisted of 29,133 Finnish men aged 50 to 69 years who smoked at least 5 cigarettes per day and had no history of stroke. From 1985 to 1988, these men were recruited into the trial, which ended in 1993.At baseline, participants completed questionnaires gathering general background characteristics, including medical, smoking, and physical activity histories. Investigators measured height, weight, and blood pressure, calculated body mass index, and obtained levels of serum total cholesterol and high-density lipoprotein cholesterol.Also at baseline, the researchers used validated food frequency questionnaires to assess consumption of coffee and black tea for the previous year. This information was provided by 26,556 of the randomized participants. At 2 to 5 years after randomization, the researchers asked the men how they usually prepared their coffee: filtered, boiled, or instant. This information was available for 20,427 of the participants. Most used the filter (14,513 [71.1%]) or boiling (4232 [20.7%]) method.
Approximately 2.5% of the study sample reported never drinking coffee, and approximately 64% did not drink tea. The mean daily coffee consumption among drinkers was 5.7 cups. Men with higher coffee consumption were slightly younger, smoked more, had lower systolic and diastolic blood pressures, were less likely to have a history of diabetes or coronary heart disease, were more likely to be physically active, and consumed less alcohol and tea than men with low coffee consumption. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein, a marker of inflammation linked with an increased risk for ischemic stroke.
In their analysis, the researchers included strokes occurring from the time of randomization to December 31, 2004. During a mean follow-up of 13.6 years, there were 2702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes.
The association was similar regardless of whether the coffee preparation method was boiling or filtered. Results also were much the same whether subjects were observed for less than 10 years or for 10 years or more. For tea, the association between consumption and cerebral infarction also did not vary significantly by age or cardiovascular risk factors. Because the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study includes only male smokers, the study authors write, their results may not be generalizable to women or to nonsmokers. "These findings warrant confirmation in other populations, particularly women and nonsmokers," they conclude.
Stroke. 2008;39:1681-1687.


U.S. Lawmakers Expand Probe to Aspirin-Combo Ads
http://www.medscape.com/viewarticle/582049
By Susan Heavey
WASHINGTON (Reuters) Oct 14 - U.S. Democratic lawmakers are expanding their probe into direct-to-consumer drug advertisements to include Bayer AG's combination aspirin product, according to letters released on Tuesday.
Bayer's marketing of its Aspirin with Heart Advantage, a combination product that includes a dietary supplement, appears to go against a U.S. Food and Drug Administration's request not to advertise such products, said House of Representatives Energy and Commerce Chairman John Dingell.In the letter to Bayer HealthCare President Gary Balkema, the Michigan Democrats asked whether the company planned to seek FDA approval for the combination product. They also called on the company to provide lawmakers with all related records within two weeks.
In a separate letter to U.S. Health and Human Services Michael Leavitt, the lawmakers asked whether the FDA or its lawyers were aware of the aspirin marketing or advertisements for any other combination products that include dietary supplements.
Dingell and Stupak have been investigating whether drug companies have misled the public through consumer-targeted advertisements. Other companies with ads under review include Pfizer Inc, Johnson & Johnson, Merck & Co Inc and Schering Plough.


New Rofecoxib Data Will Help Inform Treatment Decisions With Other Coxibs, NSAIDs
http://www.medscape.com/viewarticle/581985

News Author: Lisa NainggolanOctober 14, 2008 - New results from the extended follow-up of the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial provide a more complete assessment of the cardiovascular toxicity of the cyclooxygenase 2 (COX-2) inhibitor rofecoxib (Vioxx, Merck), than previously reported, say Dr John A Baron (Dartmouth Medical School, Hanover, NH) and colleagues in a report published online October 13, 2008, in the Lancet
Clinical Context
COX-2 inhibitors have been associated with cardiovascular toxicity. Rofecoxib was withdrawn from the worldwide market because of this effect, demonstrated in the APPROVE trial, which examined the protective effect of rofecoxib on adenomatous polyps but was terminated early because of cardiovascular toxicity.
This is an analysis of adverse cardiovascular effects of rofecoxib during and 1 year after the APPROVE trial, which was conducted at 108 centers worldwide with recruitment in 2000 and 2001.
Study Highlights
Included were men and women 40 years or older with 1 or more histologically confirmed large-bowel adenomas removed within 12 weeks, with no remaining polyps after colonoscopy.
Excluded were those receiving NSAID treatment and those with hypertension, heart failure, cardiovascular surgery within 1 year, or a history of transient ischemic attack or stroke within 2 years.
Patients were randomly assigned to 25-mg rofecoxib (n = 1287) or placebo (n = 1300) once daily for 3 years.
The protocol was amended to include those who used aspirin after the trial began.
A single-blind run-in period of 6 weeks assessed adherence.
Those who were at least 80% adherent were included in analysis.
The primary outcome was the combined incidence of nonfatal MI, nonfatal stroke, and death from cardiovascular, hemorrhagic, and other causes.
The trial was terminated 2 months before the planned completion rate because of adverse cardiovascular effects.
Posttreatment extended follow-up was completed on 84% of those receiving rofecoxib and 83% of those receiving placebo.
Median posttreatment follow-up times were 537.5 days for rofecoxib and 550 days for placebo.
Mean age of the participants was 59.4 years, mean weight was 81.3 kg, 62% were men, and 84% were white.
High baseline cardiovascular risk was more common in those without extended follow-up (34%) vs those with extended follow-up (27%; P = .04).
The relative risk for thrombotic cardiovascular events during treatment or within 14 days of stopping medication was 1.89 for combined events.
The HR did not differ significantly with time.
After adjustment for baseline age, sex, aspirin use, and cardiovascular risk, the HR for MI was 1.94 and for stroke, 2.17.
In total, 59 participants in the rofecoxib group and 34 in the placebo group had a combined event (unadjusted HR, 1.79; P = .006).
The increase in risk was seen early, in the first 6 weeks of treatment.
The difference in cumulative risks for a combined event between the 2 groups grew with time, reaching 1.74% at 36 months.
Relative risks were higher in those with cardiovascular risk factors, especially diabetes.
After discontinuation of treatment, 52 participants in the rofecoxib group and 32 in the placebo group had a cardiovascular event.
The adjusted HR for the posttreatment period was 1.41 for the rofecoxib group and persisted to 1 year.
The authors concluded that rofecoxib use was associated with increased cardiovascular risk, which persisted

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750
News Author: Steve StilesOctober 8, 2008 - Two ultrasound-based evaluations, both with their advantages and disadvantages, are about equally effective at guiding the management of patients with suspected lower-extremity deep-vein thrombosis (DVT), conclude the authors of a randomized trial reported in the October 8, 2008, issue of Journal of the American Medical Association [1]. But the writer of an accompanying editorial [2] gives the edge to one of the techniques, the one that's been around longer and is simpler and probably more widely available, and notes that a clinical prediction rule not evaluated in the study can also play a role in the initial evaluation of DVT.
The study of more than 2000 patients with suspected DVT found comparably low three-month rates of confirmed venous thromboembolism (VTE) among those who were spared the burdens of anticoagulation therapy based on the results of either two-point compression ultrasonography with provisional D-dimer testing or whole-leg color-coded Doppler ultrasonography.
Compression ultrasonography, typically performed on proximal leg veins, plus D-dimer testing "is simple, convenient, and widely available but requires repeat testing in one-fourth of the patients," according to the authors, led by Dr Enrico Bernardi (Civic Hospital, Conegliano, Italy).
The Doppler method "offers a one-day answer [and is] desirable for patients with severe calf complaints, for travelers, and for those living far from the diagnostic service but is cumbersome, possibly more expensive, and may expose patients to the risk of (unnecessary) anticoagulation," they write. Whole-leg color-coded Doppler ultrasonography, unlike the other method, will disclose DVT of the calf, they explain; its clinical importance, and therefore the value of anticoagulation directed at it, has been questioned.
Still, both methods are "reliable diagnostic options," Bernardi et al conclude. "Either strategy may be chosen based on the clinical context, on the patients' needs, and on the available resources."
The trial's patients had been referred to one of 14 ultrasound laboratories in Italy with a first episode of suspected symptomatic DVT. Of the 1045 randomized to the two-point ultrasonography strategy, 217 had abnormal findings at the initial workup and were classified as having proximal DVT; 828 had normal findings and underwent D-dimer testing. That test was abnormal in 256, who were scheduled for repeat ultrasonography a week later. Repeat ultrasound yielded abnormal findings in 14 patients.
So, 814 patients were spared anticoagulation therapy and were followed for the prespecified three months; they included the 572 with normal findings at ultrasonography and D-dimer testing plus 242 with repeatedly normal ultrasonography despite a positive D-dimer result.
Whole-leg color-Doppler ultrasonography yielded abnormal findings in 278 of the 1053 assigned to it. Those patients received anticoagulation therapy while the 775 with a negative test were followed.
Venous thromboembolism was confirmed in seven of the 801 patients in the two-point ultrasonography group (0.9%) and in nine of the 763 in the whole-leg ultrasonography group (1.2%) who hadn't been anticoagulated and were available for the three-month follow-up. The difference met the trial's criteria for equivalence, the authors write.
In his editorial, Landefeld recommends that patients with a suspected first instance of DVT be initially evaluated using two of three methods: the clinical prediction rule, two-point ultrasonography, and D-dimer testing. "If both tests are negative, DVT is effectively ruled out, and anticoagulation can be withheld safely," he said.
"If the clinical evaluation using the Wells criteria [3] suggests low [DVT] probability, and if the [two-point] ultrasound or the D-dimer test is negative, you've essentially ruled out DVT," Landefeld explained to heartwire. "If the compression ultrasound is positive for proximal DVT, you've made the diagnosis. If the clinical evaluation suggests intermediate or high [DVT probability] and the compression ultrasound is negative, then you have to do something more. And that could be to do another test in a week or a more definitive one right then, which would be venography or color-coded Doppler."http://www.medscape.com/viewarticle/581682




Aspirin: Should It Be Used for Primary Prevention in Diabetics?
http://www.medscape.com/viewarticle/582320.
Study Highlights
Patients eligible for study participation were aged 40 years or older and had type 1 or 2 diabetes. All participants had evidence of PAD, as suggested by an ankle brachial pressure index of 0.99 or less.
Patients with a history of symptomatic cardiovascular disease were excluded from study participation, as were those who regularly used aspirin or antioxidants.
Participants were randomly assigned in a 2 x 2-factorial design to receive aspirin 100 mg daily plus an antioxidant tablet daily, either active treatment alone plus placebo, or double placebo. Each antioxidant capsule contained alpha-tocopherol 200 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulphate 10 mg, nicotinamide 10 mg, lecithin 9.4 mg, and sodium selenite 0.8 mg.
Participants received standard disease therapy as well, which was left to the discretion of the study investigator and other responsible clinicians.
Participants were followed up every 6 months during a median of 6.7 years.
The main outcome of the study was the composite of death from CHD or stroke, nonfatal MI or stroke, or above-ankle amputation for critical limb ischemia. Secondary outcomes included the individual components of the composite outcome.
1276 patients underwent randomization. Baseline characteristics were similar between randomly assigned groups. The mean age was 60 years, and slightly more than half of the study cohort were women. Nearly one third of patients were current smokers, and the median ankle brachial pressure index was 0.90.
233 participants experienced 1 of the primary composite endpoints, and a total of 638 primary events were reported. There was no significant interaction between aspirin and antioxidants for the primary endpoint.
Aspirin was not effective in reducing the rate of composite vascular events (HR, 0.98). Moreover, aspirin did not significantly reduce the risk for death from CHD or stroke (HR, 1.23). Rates of significant adverse events were also not different between aspirin and placebo.
In a similar fashion, antioxidants were not effective in the prevention of the composite endpoint (HR, 1.03), and they also did not reduce the risk for death from vascular events. More participants not receiving antioxidants experienced gastrointestinal tract symptoms vs participants receiving antioxidants.
Secondary endpoints related to vascular outcomes were not significantly affected by study therapy. The overall risk for mortality was higher in the antioxidant group vs the placebo group (HR, 1.49), whereas aspirin had no effect on the risk for mortality.
Subgroup analysis on the basis of age, sex, and ankle brachial pressure index values did not alter the study's main findings.

Warfarin Does Not Significantly Reduce Stroke Risk in Blacks With AF
http://www.medscape.com/viewarticle/582298NEW YORK (Reuters Health) Oct 20 - Analysis of a cohort of patients hospitalized for atrial fibrillation (AF) shows that warfarin is statistically effective in preventing ischemic stroke among whites, but not among nonwhites, particularly not in black patients.To see if this benefit extends to other racial groups, a cohort of 18,867 patients hospitalized between 1995 and 2000 with AF. The population was 78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian. Over a median of 3.3 years, or 63,204 person-years, of follow-up, there were 1226 ischemic strokes.
All patients were on warfarin for essentially the same amount of time. The overall percentage of time the international normalized ratio was between 2 and 3 was 54.5%, but it was lower in blacks at 47.8%.The rate ratios of ischemic stroke with on warfarin treatment versus no warfarin treatment was0.79 for whites, 0.92 for blacks, 0.71 for Hispanics and 0.65 for Asians, Dr. Shen and colleagues report in the October issue of Stroke.
In this cohort, we did not observe a statistically significant lower rate of stroke with warfarin therapy among nonwhites (in particular blacks) with previous AF hospitalizations,However, a protective effect of warfarin in nonwhites can not be completely ruled out due to the "relatively small number of events among nonwhites." In addition, the number of nonwhites in the cohort was fairly small, so the estimates should be "interrupted with caution," the researchers add.
Stroke 2008;39:2736-2743.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
View Complete Profile

Links

• Coagulation Corner
• Hemostasis Happenings
• New In Coagulation
• Coagulation Case Studies

Previous Posts

Archives