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New In Coagulation
Sunday, October 4, 2009
October 2009: What's New In Coagulation
GP IIb/IIIa Inhibitor of No Benefit in AMI Patients With Cardiogenic
Shock
Routine upfront use of the GP IIb/IIIa inhibitor abciximab (Reopro, Lilly) during primary PCI was of no benefit in patients with acute MI (AMI) complicated by cardiogenic shock, according to the results of a new study, PRAGUE. The outcome for patients with AMI complicated by cardiogenic shock--a state of hypotension and poor blood flow resulting from ventricular failure--is generally dire and that prior to an early revascularization strategy, which was shown to be superior to conservative management in the SHOCK trial, the death rate was close to 100%. Registries had shown further therapeutic benefit from the administration of GP IIb/IIIa inhibitors, but there were no randomized data to support this approach, hence the decision to conduct PRAGUE 7. The hypothesis that GP IIb/IIIa inhibitors could be beneficial in this indication still has "a strong rationale" and that the PRAGUE-7 findings contradict those of prior studies.
In PRAGUE-7, an open-label trial in four centers in the Czech Republic, 80 patients with AMI complicated by cardiogenic shock received standard antithrombotic and anticoagulant treatment--either during transport or directly at the cath lab--and coronary angiography. They were then randomized to either up-front treatment with abciximab, a bolus followed by an infusion for 12 hours, or standard periprocedural treatment, where the decision about use of abciximab during PCI was left to the discretion of the interventional cardiologist.Abciximab was used in all the patients in the up-front-treatment group compared with 35% of those in the standard-therapy arm.
The primary end point of PRAGUE-7 was a 30-day combined outcome of death/reinfarction/stroke/new renal failure. Secondary end points were left ventricular ejection fraction assessed by echocardiography on day 30 (in those who survived), major bleeding complications, myocardial blush grade after PCI, and TIMI flow after PCI.The primary end point was reached in 17 patients in the up-front-treatment group (42.5%) and 11 in the standard-therapy arm (27.5%; p=0.24). There were 15 patients who died during hospitalization in the up-front group (37.5%) compared with 13 receiving the standard treatment (32.5%; p=0.82). There were no significant differences between the two groups in any of the other outcomes.
Antiplatelet drugs, PPIs can be simultaneously prescribed to heart patients, investigators say.
According to Bloomberg News (9/1, Cortez), approximately "two million people worldwide undergo procedures to clear heart arteries each year, then take aspirin plus Plavix [clopidogrel] or Effient [prasugrel] from Eli Lilly & Co. and Daiichi Sankyo Co. to prevent re-clogging." What's more, these patients are "routinely prescribed pills" like Nexium [esomerprazole magnesium] or Prilosec [omeprazole], which are proton-pumps inhibitors (PPIs), "to reduce...stomach acid at the same time, since the other medications can cause gastrointestinal trouble." There have been "concerns that mixing the medications may reduce the effectiveness of" the "blood thinner."
Dow Jones Newswires (9/1, Favole) notes that "earlier this year, the FDA asked Plavix marketers Bristol-Myers and Sanofi to update the drug's label to warn of risks with the drug when used in combinations with PPIs." But new research by Brigham and Women's Hospital appears to contradict earlier studies.
For the study appearing online in The Lancet, WebMD (8/31, Boyles) reported, investigators analyzed the results of two trials -- TRITON-TIMI 38 and PRINCIPLE-TIMI 44 -- with the "larger of the two" including "about 13,600 patients who had a previous heart attack or unstable angina treated with one of the two drugs." One-third of the participants "were also taking a PPI, but PPI use was not found to be associated with an increased risk of a second heart attack, stroke, or cardiovascular death with either of the two anti-clotting drugs."
But "evidence of the pharmacodynamic effect of the PPI-thienopyridine interaction was clear in data from the PRINCIPLE trial," MedPage Today (8/31, Peck) pointed out. Ralph G. Brindis, MD, MPH, President-elect of the American College of Cardiology, said that "even though there is evidence in the test tube that inhibition of platelet aggregation is diminished with PPI therapy, there is no clinical effect." The new findings should not "be construed as a signal to return to routine prophylaxis with PPI," he added. "But for high risk patients who need these drugs, I think we can be a little more confident using PPIs." Reuters (9/1, Hirschler) also covers the story.
FDA approves six new marketable volumes, concentrations of heparin.
The AP (9/1) reports, "Drug delivery system and device maker Hospira Inc. said Monday it received Food and Drug Administration approval to market the blood thinner heparin in six new volumes and concentrations." The doses "range from one milliliter to 30 milliliters in size," according to Hospira, and the "concentrations range from 1,000 units per milliliter to 10,000 units per milliliter." The AP adds, "The approval covers three single-dose vials and three multiple-dose vials."
Study suggests warfarin therapy for atrial fibrillation may be most beneficial for older patients, those at high risk of stroke.
HealthDay (8/31) reported that "older patients, or those with a prior history of stroke, are most likely to get a benefit when using warfarin to treat atrial fibrillation," according to a study published in the Annals of Internal Medicine. Investigators looked at data on nearly "13,600 adults with atrial fibrillation treated within Kaiser Permanente of Northern California from 1996 to 2003."
MedPage Today (8/31, Emery) reported that, "as a group, patients with a history of ischemic stroke saw an adjusted net clinical benefit of 2.48 percent per year (95 percent CI 0.75 percent to 4.22 percent), and those 85 and older saw a 2.34 percent annual benefit." The researchers said that "the benefit for these subgroups was significantly higher than the overall clinical benefit seen for all patients taking warfarin, which was 0.68 percent per year."
Study indicates nadroparin may reduce blood clot risk in patients undergoing chemotherapy.
HealthDay (9/1, Dotinga) reported that, according to a study published online in The Lancet Oncology, "a blood-thinning drug could cut the risk" of blood clots in "cancer patients who receive chemotherapy" in half. In the past, "researchers haven't been certain that blood-thinning drugs could help ambulatory chemotherapy patients avoid developing...clots." In the current study, investigators "examined nadroparin, a form of heparin," in "1,150 Italian patients over the age of 18 who were receiving chemotherapy for advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer." They found that "two percent of those who received nadroparin via a daily injection under the skin developed a blood clot during the first four months of chemotherapy, compared to 3.9 percent of the patients who were given placebos."
MedPage Today (9/1, Neale) reported, "More patients in the nadroparin group had a major bleeding event (0.7 percent versus 0 percent), but the difference did not reach statistical significance (P=0.18)." Furthermore, "rates of serious adverse events and mortality one year after randomization were similar in the two groups."
Non-TIMI Major Bleeding Just as Important as TIMI Major Bleeding in Predicting Mortality in PCI Patients
In patients undergoing PCI with stable or unstable ischemic heart disease, the occurrence of a non-CABG major bleed within 30 days has an independent statistically significant impact on one-year mortality, comparable to that of having an MI, and non-TIMI major bleeding is just as important as TIMI major bleeding in predicting mortality, a new analysis shows.
Data from the pooled analysis of the three major bivalirudin trials--REPLACE-2, ACUITY, and HORIZONS--found that while bleeding meeting the TIMI major criteria has a large impact on subsequent mortality, major bleeding not meeting the TIMI criteria also increases mortality to a similar degree. But hematoma alone does not appear to increase subsequent mortality.
Non-TIMI major bleeding was just as important as TIMI major bleeding in predicting mortality. This may surprise some people, as it is thought that TIMI major bleeds are the most severe, but we have definitely shown that we should not be discounting the non-TIMI major bleeds. If you discount them you are discounting a very important component of bleeding."In contrast, the results showed that hematoma >5 cm, which is often included in major bleeding definitions, was not associated with increased mortality at one year.
Thromboembolic Events in Cancer Patients Halved in PROTECHT Study
In ambulatory cancer patients receiving chemotherapy, the risk for a thromboembolic event was almost halved by the prophylactic use of the low-molecular-weight heparin derivative nadroparin.
The trial involved patients with a variety of cancers, including lung, gastrointestinal, pancreatic, breast, ovarian, and head and neck, who were receiving chemotherapy on an outpatient basis. They were randomized in a 2:1 fashion to receive either nadroparin, at a dose of 3800 IU anti-Xa injected subcutaneously once daily, or a parenteral placebo. Prophylaxis continued for the duration of the chemotherapy or for a maximum of 4 months. This is a rather short time period, the researchers note, but there were ethical concerns over the use of a parenteral placebo.Thromboembolic events occurred in 2% of patients in the nadroparin group (15 of 769 patients; P = .02) and 3.9% of patients in the placebo group (15 of 381 patients; P = .02).
Serious adverse events were reported in 17.6% of the placebo group and 15.7% of the nadroparin group. Major bleeding events were reported in 5 patients (0.7%) in the nadroparin group and in 0 patients in the placebo group. Minor bleeding events were seen in 7.4% of patients in the nadroparin group and in 7.9% of patients in the placebo group (P = .18)
The study was not powered to show a difference in the rate of bleeding between the 2 treatment groups, the researchers note. However, the finding that the rate of minor bleeding events was similar in the 2 groups is "somewhat reassuring, as minor bleeding is considered to be a surrogate for major bleeding. Overall, the rate of bleeding was low and consistent with that seen in other studies.
Warfarin Use in Patients With End-Stage Renal Disease May Increase Stroke Risk
Use of warfarin as chemoprophylaxis in patients with atrial fibrillation and end-stage renal disease (ESRD) may paradoxically increase stroke risk, according to the results of a cohort study reported in the August 27 Online First issue of the Journal of the American Society of Nephrology.
"Use of warfarin, clopidogrel, or aspirin associates with mortality among patients with ESRD, but the risk-benefit ratio may depend on underlying comorbidities," write Kevin E. Chan, MD, from Fresenius Medical Care NA in Waltham, Massachusetts, and colleagues. "We previously reported a significant excess mortality associated with anticoagulation and/or antiplatelet use in a large, heterogeneous population of incident hemodialysis (HD) patients."
The purpose of this follow-up study was to evaluate the potential risk-benefit ratio of warfarin, clopidogrel, and aspirin specifically in dialysis patients with coexisting atrial fibrillation. The investigators looked at the association between these medications and new stroke, mortality, and hospitalization in a retrospective cohort of 1671 patients with preexisting atrial fibrillation who were receiving hemodialysis. Average follow-up of patient outcomes was 1.6 years from the time dialysis was started.
Patients receiving warfarin therapy had a significantly increased risk for new stroke vs patients not taking warfarin (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.29 - 2.90). Risk for new stroke was not associated with clopidogrel or aspirin use.
There appeared to be a dose-response relationship between the degree of anticoagulation and new stroke in patients receiving warfarin, based on an analysis using international normalized ratio (INR; P = .02 for trend). Compared with nonusers of warfarin, those users who had no INR monitoring in the first 90 days of dialysis had the highest risk for stroke (HR, 2.79; 95% CI, 1.65 - 4.70). Use of warfarin was not statistically significantly associated with any increases in all-cause mortality or hospitalization rates.
J Am Soc Nephrol. Published online August 27, 2009. Abstract
Snuff and Chewing Tobacco Linked to Increased Risk of Fatal MI or Stroke
Smokeless tobacco--such as snuff and chewing tobacco--is not harmless when it comes to heart health, according to a new meta-analysis [1]. A review of 11 studies from Sweden and the US, almost entirely in men, showed that smokeless-tobacco users had an increased risk of death from myocardial infarction (MI) or stroke.The study, by researchers at the International Agency for Research on Cancer (IARC), is published online August 18, 2009 in BMJ. Contrary to common belief that smokeless tobacco has very little effect on health, these products have been shown to increase cancer risk, coauthor and IARC researcher Dr Kurt Straif (Lyon, France) told heartwire .
Types of smokeless tobacco used in North America and Europe include dry snuff that is inhaled, as well as moist snuff (called snus in Sweden) and chewing tobacco (or spit tobacco), which are sucked inside the cheek.These products have been around for centuries, and after a decline in consumption for most of the 20th century, use has rebounded in the past few decades, the authors write.
In 2000, 23.9% of men and 4.1% of women in Sweden reported using snus daily or occasionally. In the same year, in the US, 4.4% of men and 0.3% of women were current users of snuff or chewing tobacco.
To determine whether users of smokeless tobacco are at increased risk of death from MI or stroke, the researchers systematically reviewed worldwide studies published until 2009.The meta-analysis included eight studies from Sweden--where the use of snus is widespread--and three studies from the US. Ten studies were in men only, and apart from two studies, all were in people who had never smoked tobacco.Smokeless-tobacco use was linked with a greater risk of cardiac fatalities. In eight studies, compared with nonusers, smokeless-tobacco users had a relative risk of fatal MI of 1.13 (95% CI 1.06-1.21).Similarly, in five studies, compared with nonusers, smokeless-tobacco users had a relative risk of fatal stroke of 1.40 (95% CI 1.28-1.54)
Results were comparable in studies from Sweden and the US.
FDA Official Explains the Prasugrel Review
The FDA approved prasugrel on July 10, 2009, but before it did it sorted through a number of "complex issues," according to Unger, including an analysis of data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38). That analysis included an assessment of bleeding risks, a possible cancer signal, and the reduction in the primary end point, which was driven primarily nonfatal MIs, some of which were detected by enzymatic measurements.
In the perspective, Unger notes that prasugrel was associated with an approximate 30% increase in the risk of bleeding. In weighing the risks and benefits, the FDA reviewers felt primary that end point represented "irreversible tissue damage" and that the benefit of reducing this risk was worth the bleeding events, as these have no irreversible consequences. Bleeding events that have serious consequences, such as intracranial hemorrhage, were included in the primary end point, notes Unger, and there were few fatal bleeding events.These concerns about bleeding, however, led to several strategies to reduce the possible risks, according to Unger, including a boxed warning that lets physicians know the drug can cause significant, sometimes fatal, bleeding and that it should not be used in patients with active pathological bleeding, a history of ministrokes (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft (CABG) surgery. The boxed warning also underscores the increased risk in patients over 75 years and includes a medication guide that warns patients about the bleeding risk.
Regarding the cancer risk, Unger notes that there were excess neoplasms with prasugrel compared with clopidogrel, and while it was unlikely the drug is carcinogenic, given that the TRITON-TIMI 38 was short at 15 months and many of the tumors emerged early, there were concerns that prasugrel might stimulate the growth of existing tumors. With this in mind, the agency asked Lilly to perform "tumor-progression" studies in human colon, lung, and prostate tumor-cell lines grown in vitro and in vivo in mice. These studies found no link between prasugrel and cancer growth. The FDA concluded that causality of cancer was unlikely but has asked the sponsor to collect baseline and subsequent cancer data in a large, ongoing clinical trial.
Experts Question Routine Aspirin for Patients With Type 2 Diabetes
The widespread recommendation for the routine use of low-dose aspirin in primary prevention of cardiovascular events for all patients with type 2 diabetes should be revisited, experts said at the European Society of Cardiology 2009 Congress.
"If a patient has had a prior event, there is no question that he or she should be on aspirin, regardless of whether the patient is or is not diabetic, because we have plenty of evidence there," Patrono commented to heartwire . "But we don't have evidence for the efficacy and safety of low-dose aspirin in diabetics without a prior vascular event or without overt vascular disease. We need direct randomized evidence."
Indeed, aspirin may be harmful for people with diabetes. "Diabetes mellitus is not only a risk factor for the occurrence of a serious vascular event, which is increased by about two-and-a-half fold, it is also a risk factor for major bleeds, which increase by about 50% in association with diabetes. So we should be very careful in seeking adequate evidence for both efficacy and safety of aspirin in this subgroup," Patrono said.
There may be specific reasons why aspirin is not as effective in diabetic individuals, These include Cox-1 glycation, faster recovery of Cox-1 activity due to accelerated platelet turnover in a fraction of the diabetic population, and enhanced platelet Cox-2 expression that might be associated with accelerated platelet turnover.
They tested 100 patients with type 2 diabetes on chronic low-dose (100-mg/day) aspirin, synchronizing their aspirin administration at 8 pm and then again the following day at 8 am, when they took an additional blood sample every three hours to cover the 12- to 24-hour dosing interval. After obtaining a total of five blood samples, they then studied the time course of recovery of platelet Cox-1 and Cox-2 activity in these individuals and found that some patients demonstrated a very slow recovery, comparable to healthy, nondiabetic individuals; others showed intermediate recovery, and still other subjects demonstrated a substantial recovery of platelet Cox-1 activity.
Net Clinical Benefit of Warfarin in AF Is Highest in Prior Stroke Victims and the Very Old
Existing guidelines for warfarin therapy are based on "old data-randomized clinical trials completed in the 1990s, for the most part," Singer explained to heartwire , "and they don't completely take into consideration the risk of intracranial hemorrhage [ICH]. We were looking to see, 'What is the net benefit of warfarin?'-the good things, ie, a reduction in clot strokes-vs the bad things, ie, increased bleeding into and around the brain."They found that the net benefit of warfarin was highest among patients with the highest untreated risk for stroke, because the absolute increase in risk for ICH due to warfarin remains fairly stable across thromboembolic risk categories. These included those with a history of ischemic stroke and those in the highest CHADS2 category (where patients score 1 point each for congestive heart failure, hypertension, age, and diabetes and 2 points for stroke). Those with a CHADS2 score of 0 or 1 gained no benefit from warfarin, with net benefit being seen in those with a CHADS2 score of 2 or greater.Notably, the benefit was greater the older the patient, Singer said, so one of the important messages of this study is that age should not be a barrier to warfarin treatment, as long as the patient "is not falling and is not terribly demented. We can't go out and anticoagulate everyone over 85, but if you think they are reasonable candidates, the data suggest they will benefit."
The net clinical benefit of warfarin was defined in the study as the reduction in ischemic stroke and systemic embolism balanced against the increase in ICH (the latter weighted by a factor of 1.5 because of the severity of the health consequences of intracranial bleeding).The researchers did not include extracranial bleeding, because 90% of deaths attributed to warfarin involve ICH, but the editorialists say they believe this to be an oversight that may have led to an overestimation of the net clinical benefit of anticoagulation.
Researchers say enoxaparin instead of UFH may be cost-effective in STEMI patients undergoing thrombolysis.
HeartWire (9/22, Nainggolan) reported that "using enoxaparin...instead of unfractionated heparin (UFH) as adjunctive therapy in patients with ST-elevation MI (STEMI) who undergo thrombolysis is cost-effective," according to research published in the Journal of the American College of Cardiology. Dr William Weintraub, senior author of the paper, said, "The advantage of enoxaparin is that it's much easier to give than UFH, and you tend to save a little bit of money, so in people who aren't going to the cath lab, this is a very reasonable thing to do."
Anti-fibrinolytic Agents in Post Partum Haemorrhage: A Systematic Review
Background: Post partum haemorrhage is a leading cause of maternal death worldwide. It also contributes to maternal morbidity as women may require a hysterectomy to control bleeding, or may require a blood transfusion, which can transmit viral infections. Anti-fibrinolytic agents have been proposed as a treatment for post partum haemorrhage. We conducted a systematic review to assess the effectiveness and safety of anti-fibrinolytic agents in post partum bleeding.
Methods: All randomised controlled trials of anti-fibrinolytic agents given for bleeding during the postpartum period were included in this review. We searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled trials, Web of Science, metaRegister of controlled trials, LILACS, Reproductive Health Library, African healthline, POPLINE, MedCarib, CINAHL, Clinicaltrials.gov and the reference lists of eligible trials. Two authors extracted data. Methodological quality was assessed by evaluating allocation concealment. The primary outcome was maternal mortality. Secondary outcomes were blood loss, blood transfusion, hysterectomy, mean haemoglobin concentration, thrombo-embolic events and other adverse effects.
Results: We identified three randomised controlled trials involving 461 participants. The trials compared tranexamic acid with no treatment and reported blood loss after delivery. In all three trials, allocation concealment was either inadequate or unclear. The administration of tranexamic acid was associated with a reduction in blood loss of 92 millilitres (95%CI 76 to 109). The most frequently reported adverse effect of tranexamic acid was nausea, although the increase was easily compatible with the play of chance (RR 4.63, 95%CI 0.23 to 95.14).
Conclusion: Tranexamic acid may reduce blood loss in post partum haemorrhage. However, the quality of the currently available evidence is poor. Adequately powered, high quality randomised controlled trials are needed.
Research suggests specific allele may raise cardiovascular risk in certain carriers taking Plavix.
The gene thought most likely to be responsible for a poor response to clopidogrel (Plavix) may raise cardiovascular risk for homozygous carriers even when they aren't on the antiplatelet drug," according to researchers at the VA Boston Healthcare System. The "few patients with two copies of the loss-of-function CYP2C19*2 allele had a 2.38-fold higher risk of major adverse cardiovascular events while on clopidogrel compared with those who had only the wild-type variant." However, the "homozygous group also tended to be at risk even when on placebo compared with wild-type-only patients." Notably, these "findings countered those from a recent genome-wide association study that had shown an effect of the *2 allele on outcomes only while patients were actively taking clopidogrel without much risk in those who had already discontinued the drug."
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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