| |
Learning Center
New In Coagulation
Monday, May 4, 2009
WHAT'S NEW IN COAGULATION: MAY 2009
Aspirin May Lower Cancer Risk, but Jury Is Still Out
http://www.medscape.com/viewarticle/590335
A growing body evidence suggests that aspirin-related nonsteroidal anti-inflammatory drugs (NSAIDs) might exert a chemopreventive effect, particularly for colorectal cancers.However, because of ethical constraints, there are no long-term randomized placebo-controlled clinical trials on aspirin use and prevention of cancer, note the authors of a review paper published online March 26 in the Lancet. Although opportunistic trials of aspirin that were designed to test vascular protection provide some evidence of a reduction in cancer, more evidence from other sources is needed before the role for aspirin in chemoprevention can be better defined.
The benefits of aspirin in vascular disease have been well documented, but the most conclusive evidence for an association between aspirin and cancer would have to be demonstrated by randomized controlled trials. However, because the risks for both vascular events and cancer increase with age, the denial of vascular benefits to individuals in the control group of a chemoprevention trial would probably be judged unethical.
Data from 3 large randomized trials, designed to examine the effect of aspirin on vascular disease, showed varying results. In the Physicians' Health Study, which included 22,071 American men randomized to 325 mg aspirin or placebo every other day, the relative risk of developing colorectal cancer in the aspirin group, compared with the placebo group, at 5 years was 1.15 (95% confidence interval, 0.80-1.65), they noted. A British study of 5000 male doctors showed that after 6 years, cancer deaths were 18% lower in the aspirin-treated group (500 mg daily), but there was no effect on nonfatal cancer incidence. The Women's Health Study examined 40,000 American women randomized to 100 mg aspirin or placebo every other day. At 10 years, aspirin users did not show a reduction in total cancer, breast cancer, or colon cancer incidence. The researchers note, however, that deaths from lung cancer were reduced among aspirin users in all 3 trials (by 22%, 36%, and 18%, respectively).
The ongoing Nurses' Health Study, with a cohort of almost 80,000 American women, showed a 12% reduction in cancer deaths with aspirin use, which became statistically significant at 10 years and increased to 44% by 20 years. Although only a modest association with death from all cancers was observed (relative risk [RR], 0.88), it was statistically significant for death from colorectal cancer (RR, 0.72) (Arch Intern Med. 2007;167:562-572).
Aspirin use has also been associated with a reduced risk for other types of malignancies, but study results have been less consistent than in the colorectal studies, according to the authors. For example, the large Cancer Prevention Study II showed a significant reduction in overall cancer for men only, a reduction in colon and prostate cancer, and a nonsignificant reduction in breast cancer. In addition, 20 observational studies found that NSAIDs appear to offer a degree of protection against breast cancer and might be of benefit to women with cancer; some benefit has also been observed for both gastric and esophageal cancers.
Lancet. Published online before print March 27, 2009.
Stroke Patients May Develop Posttraumatic Stress Disorder
http://www.medscape.com/viewarticle/590336
A new study has shown that a surprising 37% of subarachnoid-hemorrhage patients met the diagnostic criteria for posttraumatic stress disorder (PTSD).Researchers suggest the results, published in the December 2008 issue of Neurosurgery, may help explain why some stroke patients continue to experience a reduced quality of life despite relatively good clinical outcomes.
Neurosurgery. 2008;63:1095-1105. Abstract
Clopidogrel and Aspirin Reduce CV Events in Atrial Fibrillation
http://www.medscape.com/viewarticle/590415
In patients with atrial fibrillation (AF) who cannot take warfarin, the combination of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and aspirin reduced major vascular events, particularly stroke, compared with placebo, although at the expense of an increase in major bleeding. Although warfarin and vitamin-K antagonists are the treatment of choice for AF patients at high risk for stroke, up to 50% are not treated with either because they are judged as unsuitable candidates by their physician, and for these patients who are treated only with aspirin, there is a major unmet medical need. "The results of ACTIVE-A, which is the largest trial ever performed of an antithrombotic therapy in atrial fibrillation, with more than 3 times as many strokes as any other trial, have clearly shown that clopidogrel reduces major vascular events, primarily due to a reduction in stroke.
Suppression of antiplatelet activity in AF with aspirin reduces stroke by about 22%; the addition of clopidogrel to aspirin reduces platelet activity further and has been shown to reduce vascular events in the setting of acute coronary syndromes with an acceptable bleeding risk.
In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial program, patients with atrial fibrillation and 1 or more additional risk factors for stroke were enrolled in 1 of 2 trials. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of a vitamin-K antagonist reduced the risk for stroke by 42% over clopidogrel and aspirin (ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;367:1903-1912).
Those considered unsuitable for warfarin therapy were enrolled in ACTIVE-A and randomized to receive clopidogrel (75 mg/day) or placebo on a background of aspirin therapy. The reasons patients were not considered suitable for vitamin-K-antagonist therapy and enrollment in ACTIVE-W included the presence of a specific risk factor for bleeding in 23%, a physician assessment that the patient was inappropriate in 50%, and in 26%, he said, "the only reason given for enrollment in ACTIVE-A was a patient preference not to receive a vitamin-K antagonist.The primary outcome was a composite of major vascular events, including stroke, MI, non-central-nervous-system (CNS) systemic embolism, or death from vascular causes. A total of 7554 patients were enrolled from 580 centers in 33 countries. Median follow-up was 3.6 years.
The primary outcome was reduced by 11% with the combination of clopidogrel and aspirin, a highly statistically significant reductionThere was a trend to a reduction in MI, but this was not statistically significant. There was no reduction in vascular death and no reduction in non-CNS systemic embolism.
N Engl J Med. Published online March 31, 2009.
.
Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosis
http://www.medscape.com/viewarticle/588448
A simple clinical decision rule and a point-of-care D-dimer assay assists in primary care management of clinically suspected deep vein thrombosis (DVT), according to the results of a prospective management study reported in the February 17 issue of Annals of Internal Medicine. The goal of this study was to examine the safety and efficacy of a clinical decision rule, including a point-of-care D-dimer assay, to exclude DVT at initial presentation in primary care. Features included in the rule were male sex (1 point), use of hormonal contraceptives (1 point), active cancer in the past 6 months (1 point), surgery in the previous month (1 point), absence of leg trauma (1 point), distention of collateral leg veins (1 point), difference in calf circumference of 3 cm or more (2 points), and abnormal D-dimer assay (6 points).
Ann Intern Med. 2009;150:229-235.
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.
Short Course of Steroids, Antihistamines, Can Keep Allergic Patients From Stopping Clopidogrel
http://www.medscape.com/viewarticle/590626
A small study addressing the problem of hypersensitivity reactions to clopidogrel suggests that a short-term combination of steroids and antihistamines can help patients stay on their antiplatelet therapy poststenting, potentially reducing their risk of thrombotic events. Clopidogrel hypersensitivity affects roughly 6% of patients and results in drug discontinuation in 1.5% of patients--a potentially lethal situation. Doctors typically respond to allergic clopidogrel reactions by using a "washout period," then trying to gradually reintroduce the drug to desensitize the patient and prevent an allergic response--typically in the form of pruritic rash or angioedema. But, as the authors point out, this approach can leave a patient without clopidogrel on board for several days, exposing them to stent thrombosis.
In a retrospective analysis, they found that 21 out of 24 patients who received either bare-metal or drug-eluting stents, treated with long- and/or short-acting antihistamines and/or methylprednisolone or prednisone, were successfully desensitized to clopidogrel, usually with a six-day course of treatment. All successfully desensitized patients were able to stay on clopidogrel for the entire recommended treatment duration (depending on type of stent received), with no deaths, MI, or stroke.
A six-day treatment regimen involving a corticosteroid taper, a long-acting, nonsedating antihistamine 180 mg daily, and a short-acting antihistamine (25-50 mg at bedtime). For symptom relapse, they propose a longer course of corticosteroids, a leukotriene inhibitor, and a referral to an allergy specialist.
,
Four Health Behaviors Combined Help Predict Stroke Incidence
http://www.medscape.com/viewarticle/588615
Four health behaviors combined predict more than a 2-fold difference in stroke incidence in men and women, according to the results of a population-based prospective study reported in the February 20 Online First issue of the BMJ. Behaviours such as smoking, physical activity, and diet influence the risk of cardiovascular disease, including stroke. Previously we looked at the combined impact of four health behaviors - smoking, physical activity, alcohol intake, and fruit and vegetable intake - on total and cause specific mortality in men and women living in the general community. As these health behaviours could beneficially affect the incidence of stroke we examined the potential magnitude of their combined impact on incidence of stroke in men and women aged 40-79.
In the European Prospective Investigation of Cancer-Norfolk study, adults living in the general community in Norfolk, United Kingdom, were followed up to 2007. The study cohort consisted of 20,040 men and women aged 40 to 79 years with no known stroke or myocardial infarction when surveyed at baseline from 1993 to 1997. Participants were scored from 0 to 4, receiving 1 point for each of the following health behaviors: current nonsmoking; physically not inactive; moderate alcohol intake (1 - 14 units a week); and fruit and vegetable intake of 5 or more servings daily, as reflected by plasma concentration of vitamin C of 50 µmol/L or more.
Average follow-up was 11.5 years. During 229,993 person-years of follow-up, there were 599 incident strokes. Compared with people with all 4 health behaviors, the relative risks for stroke for men and women were 1.15 (95% confidence interval [CI], 0.89 - 1.49) for 3 health behaviors, 1.58 (95% CI, 1.22 - 2.05) for 2 health behaviors, 2.18 (95% CI, 1.63 - 2.92) for 1 health behavior, and 2.31 (95% CI, 1.33 - 4.02) for no health behaviors (P < .001 for trend), after adjustment for age, sex, body mass index (BMI), systolic blood pressure, cholesterol concentration, history of diabetes and aspirin use, and social class. Subgroups based on sex, age, BMI, and social class all had similar findings. Exclusion of deaths within 2 years also did not affect the observed pattern of results. BMJ. Published online February 20, 2009. NeIncluded were 20,040 men and women aged 40 to 79 years at baseline recruited from an age-sex register of general practitioners with a population-based sampling frame. At baseline from 1993 to 1997, patients completed a detailed health and lifestyle questionnaire and listed medical conditions. The lifestyle behaviors examined were smoking, alcohol intake, intake of fruits and vegetables verified by vitamin C levels, and physical activity. 4 separate categories were used for alcohol intake. 1 unit of alcohol was defined as 8 g and equivalent to a half pint of beer or a glass of wine, or a unit of spirits (liquor) and total alcohol consumption were estimated as units consumed per week. A moderate drinker was defined as someone drinking 1 or more units per week but less than 14 units per week. Physical activity was assessed during the previous year and was validated against heart rate monitoring. A physically inactive person was defined as having a sedentary job with no recreational activity. A physically not inactive person was defined as a person with any activity above that of a physically inactive person. Trained nurses made anthropomorphic measurements, and a blood level for vitamin C was determined as a biomarker of fruit and vegetable intake. Participants scored 1 point for each positive behavior: currently not smoking, physically not inactive, moderate alcohol intake (1 - 14 units per week), and plasma vitamin C concentration of 50 µmol/L or higher indicating vegetable and fruit intake of at least 5 servings a day. The score range was 0 to 4 for combined health behaviors. Incident cases of stroke were ascertained by death certificate data and hospital record linkage, and trained nosologists coded death certificates. There were 599 strokes during 229,992 person-years of follow-up (average, 11.5 years). Of the stroke cases, 28% were fetal. Among participants, mean age was 58 years, almost half were men, BMI was 26.5 kg/m2, mean systolic blood pressure was 135 mm Hg, and total cholesterol concentration was 6.2 mmol/L. In the sample, men were older, had higher BMI and higher systolic blood pressure, and were more likely than women to be current or former smokers. The also consumed more alcohol weekly, were more physically active, and were less likely to consume 5 or more servings of fruits and vegetables daily. A significantly higher proportion of women scored 4 for combined health behaviors vs men, but the incidence of stroke was not significantly different for men vs women. The risk for stroke increased in a linear fashion for every 1-point decrease in combined health behavior score. Men and women who scored 0 for combined health behaviors had a 2.3 times increased risk for stroke (relative risk, 2.31) vs those who scored 4. The findings were consistent after adjustment for age, sex, BMI, and social class. The absolute risks for incident stroke were 1.7%, 2.4%, 4.0%, 6.1%, and 5.8% for health behavior scores of 4, 3, 2, 1, and 0, respectively. The relative risks for stroke vs those with a score of 4, after adjustment, were 1.15 for a score of 3 health behaviors, 1.58 for a score of 2 health behaviors, 2.18 for a score of 1 health behavior, and 2.31 for a health behavior score of 0. The authors concluded that the combined impact of 4 modifiable lifestyle behaviors resulted in a significant reduction in the risk for stroke for both men and women. Clopidogrel Benefit Greater in Smokers: New CLARITY-TIMI 28 Analysis
http://www.medscape.com/viewarticle/591033
Smoking has become the latest factor shown to affect responsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), with a new post hoc analysis of the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) trial illustrating that the benefits of the drug are greater in patients who smoked more than half a pack of cigarettes per day than in those who did not [1]. The study, by Dr Nihar R Desai (Brigham and Women's Hospital, Boston, MA) and colleagues, is published in the April 14, 2009, issue of the Journal of the American College of Cardiology.
Clopidogrel is an orally administered platelet aggregation inhibitor that has been shown to prevent death and adverse cardiovascular events in patients with acute coronary syndromes. The response to clopidogrel varies greatly among patients, and lowered response to clopidogrel is associated with an increased risk for ischemic events. Cigarette smoking induces cytochrome P450 1A2, which converts clopidogrel into its active metabolite. Previous studies suggest that in people who smoke 10 or more cigarettes per day, clopidogrel shows greater inhibition of platelet aggregation.
Study Highlights
The goal of this study was to evaluate the interaction between cigarette smoking and the clinical efficacy of clopidogrel in STEMI.
The study sample consisted of 3429 patients with STEMI who were enrolled in the CLARITY-TIMI 28 randomized trial.
Participants were stratified by smoking intensity: not current smokers (n = 1732), smokers of 1 to 9 cigarettes per day (n = 206), 10 to 19 cigarettes per day (n = 354), 20 to 29 cigarettes per day (n = 715), and 30 or more cigarettes per day (n = 422).
The investigators compared the effect of clopidogrel vs placebo on angiographic and clinical outcomes in this study sample, using logistic regression to adjust for other baseline characteristics and interaction terms to test for effect modification.
Clopidogrel was associated with reduced overall rate of the primary endpoint of a closed infarct–related artery or death/MI before angiography in the CLARITY-TIMI 28 trial.
However, this benefit was strongest among those who smoked 10 or more cigarettes per day (adjusted OR, 0.49; 95% confidence interval [CI], 0.37 - 0.66; P < .0001) vs those who did not (adjusted OR, 0.72; 95% CI, 0.57 - 0.91; P = .006; Pinteraction = .04). The benefit of clopidogrel vs placebo at reducing the rate of cardiovascular death, MI, or urgent revascularization through 30 days was also more apparent in those who smoked 10 or more cigarettes per day (adjusted OR, 0.54; 95% CI, 0.38 - 0.76; P = .0004) vs those who did not (adjusted OR, 0.98; 95% CI, 0.75 - 1.28; P = .87; Pinteraction = .006). Rates of TIMI major or minor bleeding were less than 2%, and there was no statistically significant interaction between smoking and clopidogrel on the risk for TIMI major or minor bleeding. The investigators concluded that cigarette smoking appears to positively modify the benefit of clopidogrel on angiographic and clinical outcomes and that common clinical factors that affect the metabolism of clopidogrel may alter its clinical efficacy. Limitations of this study include post hoc analysis of a completed trial, lack of platelet aggregation studies, smoking status not randomized, inability to exclude residual confounding, and lack of adjustment for medications associated with altered clopidogrel pharmacology. Other limitations were inability to definitely exclude a dose-response effect for the interaction of clopidogrel with the number of cigarettes smoked and inability to determine mechanisms underlying the interaction. Reducing LDL Cholesterol With Statins Reduces Stroke Risk: Meta-Analysis
Reducing LDL-cholesterol levels with statins is effective in reducing initial and recurrent stroke, according to an updated meta-analysis [1]. Data from 24 randomized clinical trials showed that lipid lowering with statins cut the risk of stroke by one-fifth compared with controls, report investigators.The meta-analysis, published in the May 2009 issue of Lancet Neurology, includes more than 165 000 patients and shows that for every 39-mg/dL decrease in LDL-cholesterol levels, there was a 21% reduction in the relative risk of stroke. Statin therapy is an important treatment in stroke prevention, with studies showing that lowering cholesterol levels with statins reduces the risk of stroke in high-risk populations and patients with noncardioembolic stroke or transient ischemic attack (TIA).
Overall, the incidence of all strokes was reduced 18%, and there was also a statistically nonsignificant 13% reduction in the risk of fatal stroke. In secondary prevention, reducing LDL-cholesterol levels with statins significantly reduced the risk of recurrent stroke and major cardiovascular events. Overall, the incidence of hemorrhagic stroke did not increase, which is in contrast to SPARCL and HPS, two studies that suggested an increased risk of hemorrhagic stroke in secondary prevention.
Future areas of study involve testing intensive lipid-lowering strategies for stroke prevention, similar to the host of lower-is-better cholesterol trials in the past few years. Other drugs that raise HDL-cholesterol levels should also be tested, as epidemiological evidence suggests raising HDL cholesterol reduces the risk of stroke, while other studies have shown the LDL:HDL cholesterol ratio to be the best predictor of stroke and MI. Triglyceride-lowering therapies also need to be tested in randomized, controlled trials, they add.
Amarenco has received honorarium and speaker fees from Pfizer and is a steering committee member of the Pfizer-sponsored Stroke Prevention by Aggressive Reduction of Cholesterol Levels .
References
Amarenco P, Labreuche J. Lipid management in the prevention of stroke: Review and From Medscape Medical News
Antiplatelet Treatment Associated With Cerebral Microbleeds
http://www.medscape.com/viewarticle/591203?sssdmh=dm1.459214&src=nldne
A new analysis from the Rotterdam Scan Study shows that cerebral microbleeds on magnetic resonance imaging (MRI) are more prevalent in elderly subjects who use platelet-aggregation inhibitors than in nonusers. In particular, strictly lobar microbleeds - which may indicate the presence of cerebral amyloid angiopathy and possibly bleeding-prone microvessels - were more frequent among those who used aspirin vs users of carbasalate calcium, the researchers report. The association between anticoagulant use and microbleeds was not significant.
The researchers, with senior author Monique M. B. Breteler, MD, PhD, from Erasmus MC University Medical Center, in Rotterdam, the Netherlands, caution that the cross-sectional design of their study prevents determining whether these microbleeds increase the risk for symptomatic hemorrhage and point out that the benefits of antithrombotic therapy in patients with a history of myocardial infarction and cerebrovascular disease have been shown to outweigh the risks.
Cerebral microbleeds consist of deposits of hemosiderin in macrophages and can be seen on T2-weighted gradient recalled echo (GRE) MRI as small areas of hypointensity, the authors write. In the past decade, "these microbleeds have become acknowledged as new markers of small vessel disease in the brain."
Microbleeds are thought to occur in the setting of either cerebral amyloid angiopathy or arteriosclerotic microangiopathy, they note. Their location in the brain is thought to reflect their underlying origin: microbleeds in the deep or infratentorial locations, for example, are thought to relate to hypertensive or arteriosclerotic microangiopathy, while those in the strictly lobar brain sites result from cerebral amyloid angiopathy, a bleeding-prone state. Previous work has linked the use of platelet-aggregation inhibitors and anticoagulants to increased risk for symptomatic hemorrhage in patients with cerebral amyloid angiopathy, raising the question of whether asymptomatic microbleeds might also be accelerated by use of these drugs.
Of the 1062 subjects, 363 (34.2%) had used any antithrombotic agent. Of these, 245 (23.1%) took platelet-aggregation inhibitors, including 67 who used aspirin and 141 taking carbasalate calcium.
Compared with nonusers, those taking platelet-aggregation inhibitors had a significantly increased prevalence of cerebral microbleeds. The relationship between microbleeds and anticoagulant use was not significant.
Arch Neurol. Published online April 13, 2009. Abstract
Donna Castellone
|
|
About the Author
Donna Castellone,
MS, MT(ASCP)SH
View Complete Profile
Links
Previous Posts
Archives
|
|
