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Saturday, December 3, 2011


Dabigatran Receives UK Recommendation.

Boehringer Ingelheim GmbH's dabigatran [Pradaxa] blood thinner to prevent strokes in people with a type of irregular heartbeat has been recommended by the UK's medical- cost regulator." The National Institute for Health and Clinical Excellence said "any decision about whether to start treatment with dabigatran" should be "made after an 'informed discussion about the risks and benefits of dabigatran compared with warfarin.'"

Court To Keep Generic Form Of Anti-Clotting Drug Enoxaparin Off the Market.

A Massachusetts court agreed to "to block other companies from selling a generic version of the drug because those products infringed on patents belonging to Momenta." Enoxaparin [Lovenox] is currently being sold by Momenta and its partner Sandoz.

Group Recommends Against Routine Heparin Use To Prevent VTE In Hospital.

New guidelines from the American College of Physicians recommend against the routine use of heparin to prevent venous thromboembolism (VTE) in hospitalized patients, calling instead for physicians to first weigh the risk of bleeding." Researchers "found that heparin prophylaxis in nonsurgical patients did not reduce total mortality, may have contributed to fewer pulmonary embolisms (PE), and increased bleeding events." For "those with stroke, prophylaxis heparin had no effect on outcomes except for an increase in bleeding events.

Clot Lysing Melts 'Hidden Iceberg' in Bleeding Brains

A clot lytic treatment strategy with low-dose recombinant tissue-type plasminogen activator (rtPA) speeds clot removal in patients with intracerebral hemorrhage (ICH) that is complicated by intraventricular hemorrhage (IVH), results of a phase 2 trial confirm. One caveat with the novel treatment, however, is that it appears to be associated with more bleeding. Still, the aim in treating this condition, which can be almost 100% fatal, is to reduce the patient's exposure to blood, thereby reducing injury to the brain.

The current study was done to assess the safety of low-dose rtPA administered via extraventricular drainage catheter for the treatment of ICH with massive IVH with regard to mortality, ventricular infection, and bleeding events.

The study also tested whether administration of 3 mg of rtPA via external ventricular device (EVD) every 12 hours increased the rate of intraventricular clot lysis compared with placebo (normal saline)-irrigated catheters. The study included 48 patients aged between 18 and 75 years with a small supratentorial ICH of 30 mL or less and massive IVH. All had an EVD already placed for the treatment of obstructive hydrocephalus. A computed tomography scan was done to ensure that the EVD had been properly placed and that the clot was stable.The patients were then randomly assigned to receive either 3 mg/3 mL of rtPA (n = 26 patients) or 3 mL of normal saline (n = 22 patients) injected into the ventricular spaces via the EVD. This continued every 12 hours until computed tomography showed that clot resolution was sufficient for safe removal of the catheter or until the occurrence of symptomatic bleeding, infection, or death. The median duration of dosing was 7.5 days for rtPA and 12 days for placebo.

The researchers report that the frequency of death and ventriculitis was substantially lower than expected. The predicted 30-day mortality was 75% for both treatment groups. The actual mortality was 19% in the rtPA-treated group and 23% in the placebo group. Ventriculitis occurred in 8% of the rtPA-treated group and 9% of the placebo group. Symptomatic bleeding was higher with rtPA, affecting 23% of patients compared with 5% of patients receiving placebo (P = .1).The study showed that the greatest amount of lysing activity in patients receiving rtPA occurred during the first 3 days.

There was a significant beneficial effect of rtPA on the rate of clot resolution. The authors report that the estimated resolution for rtPA-treated patients during the first 3 days was 22.3% per day (95% confidence interval, 16.7% - 28.0%), and for patients receiving placebo, it was 9.9% per day (95% confidence interval, 3.5% - 16.2%).

As a result of these findings, the researchers concluded that low-dose rtPA for the treatment of ICH with IVH has an acceptable safety profile and call for more data from a "well-designed phase 3 clinical trial, such as [Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR)] III," to fully evaluate the treatment.

The current study "shows the slippery slope of using thrombolytics in cerebral hemorrhage," they note. It is nothing else but logical to accelerate clot removal with rtPA," but the trend toward more bleeding could be a signal that the expected benefit of rtPA might easily turn into harm.

Stroke. 2011;42:2999-3000

Dabigatran Recommended After 'Plausible' Cost-Estimates

The National Institute for Health and Clinical Excellence (NICE) has reviewed the numbers and is now recommending use of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) as a treatment option for the prevention of stroke and systemic embolism in individuals with nonvalvular atrial fibrillation. NICE was looking for a more plausible set of assumptions about the drug's use in clinical practice, including lower costs for anticoagulation monitoring than those suggested by the company and an analysis of patients more representative of the atrial-fibrillation patient population in the UK. The agency had requested a cost-effectiveness analysis of patients 80 years of age and younger who begin treatment with dabigatran 150 mg twice daily and patients 80 years of age and older who switch to dabigatran 110 mg twice daily from warfarin.

In its final appraisal, NICE has concluded that the "most plausible" incremental cost-effectiveness ratios for all patients eligible for dabigatran are within the range considered cost-effective for use in the UK National Health Service (NHS), that being less than £20 000 per quality-adjusted life-year (QALY) gained. Based on the review, the NICE committee recommends treatment with the novel anticoagulant "after an informed discussion between the clinician and the person about the risks and benefits of dabigatran compared with warfarin."

FDA Approves Rivaroxaban for Stroke Prevention in AF Patients

The US Food and Drug Administration approved rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Xarelto has a boxed warning to make clear that people using the drug should not discontinue it before talking with their healthcare professional. Discontinuing the drug can increase the risk of stroke. The approval is based largely on the results of Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).The new anticoagulant, a factor Xa inhibitor, met its primary end point, with rivaroxaban noninferior to warfarin in terms of reducing the risk of stroke and non-central-nervous-system (CNS) embolism.

One of the biggest hurdles rivaroxaban faced with the FDA advisory committee was in its comparison to warfarin, and more specifically, the amount of time the warfarin-treated patients spent at the optimal international normalized ratio (INR). In ROCKET-AF, the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), which was lower than in other trials with warfarin, including the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial with dabigatran etexilate (Pradaxa, Boehringer Ingelheim).

For some panelists, the TTR issue introduced some uncertainty about the efficacy of rivaroxaban, while others raised concerns about the dose tested and the risk of adverse clinical events when patients are transitioned off rivaroxaban. In the 28-day period after rivaroxaban was stopped in ROCKET-AF and patients were transitioned to another anticoagulant, there was a significantly increased risk of stroke in the rivaroxaban arm, a finding that investigators attributed to the drug's short half-life (and the lack of dual anticoagulation during the overlap period).

Newer Birth Control With Drospirenone May Increase Risk Of Blood Clots.

Study findings published online Nov. 7 in CMAJ, which found that women taking oral contraceptives containing the hormone drospirenone were at greater risk for developing blood clots compared to older versions. The risk was between 43% and 65% greater for women taking oral contraceptives containing drospirenone compared to second and third generation birth control. Drospirenone is found in brand name pills like Yaz and Yasmin.  A multivariable analysis, with adjustment for risk factors associated with thrombotic events, found the risk of deep vein thrombosis and pulmonary embolism was more than 40% greater among drospirenone users than among those using third-generation combined oral contraceptives (RR 1.43, 95% CI 1.15 to 1.78). The researchers noted some study limitations, which included "the possibility of a confounding indication if physicians preferred to prescribe drospirenone-containing contraceptives to women with a presumed higher risk of venous thromboembolism." In addition, they were unable to "verify diagnoses by examining imaging data."

Enoxaparin May Benefit Patients With Advanced Cirrhosis.

In people with advanced cirrhosis, a low molecular weight heparin can prevent portal vein thrombosis, according to research presented at the annual meeting of the American Association for the Study of Liver Diseases. "In a year-long prospective placebo-controlled trial" involving 70 patients, "the compound enoxaparin (Lovenox, Clexane) reduced the risk of thrombosis by nearly 80%," while also reducing "the risk of clinical decompensation" and improving survival overall.

US Dabigatran Label Updated With Renal Function Advice

US physicians are being advised to assess renal function prior to prescribing dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and to assess renal function in clinical situations that might be associated with declines in kidney function, according to the updated drug label. 

Revisions to the label also include information on the storage and handling of dabigatran and recommendations on use with other medications, such as dronedarone and systemic ketoconazole.

Similar to a recent European Medicines Agency update, the revised label states that renal function should be assessed prior to starting therapy and tested annually in patients 75 years of age and those with creatinine clearance (CrCl) <50 mL/min. In addition, the label now states that physicians should consider using the 75-mg twice-daily dose in patients with moderate renal impairment who are also dronedarone or systemic ketoconazole. Dabigatran should not be prescribed in patients with severe renal impairment (CrCl 15–30 mL/min).

The updated label now states that, once opened, dabigatran can be safely stored for four months, longer than the previous recommendation to use the medication within 30 days of opening the bottle, a recommendation subsequently extended to 60 days. In addition, the label states that INR testing should be avoided, as it is unreliable in patients treated with the anticoagulant.

Cangrelor May Safely Wean ACS Patients Off Oral Antiplatelets

A continuous infusion of cangrelor, an investigational P2Y12 platelet inhibitor, allowed patients with acute coronary syndromes or coronary stents to go off oral dual-antiplatelet therapy safely in advance of CABG surgery in a modest-sized placebo-controlled phase 2 study.

In the Maintenance of Platelet Inhibition with Cangrelor after Discontinuation of Thienopyridines in Patients Undergoing Surgery (BRIDGE) study, cangrelor (the Medicines Company) given IV after withdrawal of oral thienopyridines kept platelet reactivity at levels that seemed to keep the risks of major bleeding and ischemic complications down in the week leading up to surgery. But the short-acting agent's antiplatelet effects fell off quickly, allowing safe surgery, once the infusion was withdrawn.

Cangrelor wasn't associated with the dyspnea or hepatic-enzyme abnormalities sometimes seen with antithrombotics; it did seem to slightly increase the risk of minor bleeding, although the effect wasn't significant in the 210-patient trial.  The antiplatelet effects of available oral thienopyridines take several days to a week to fall off adequately for the patient to have surgery without an untoward risk of bleeding, but in the meantime patients are exposed to an increased risk of thrombotic events.

This is the first time we have a trial assessing, in a prospective, randomized, double-blind fashion, the use of a novel [antiplatelet] agent that has the ideal properties for bridging. And the trial clearly shows that we are able to achieve and sustain adequate levels of P2Y12 inhibition during the preoperative stage, with overall favorable safety signals. BRIDGE was powered for assessing platelet reactivity and safety, not hard clinical outcomes, so cangrelor's usefulness in weaning patients off oral thienopyridines before CABG requires further study in larger trials.

In the trial, 210 patients with ACS or coronary stents on ticlopidine, clopidogrel, or prasugrel (Effient, Lilly/Daiichi) awaiting CABG were randomized to receive continuous infusions of cangrelor or placebo. The trial was conducted at 125 centers in the US, 55 in the Czech Republic, 12 in the UK, 11 in the Netherlands, and seven in Austria. Within 72 hours of going off the oral antiplatelets, patients went on either cangrelor or placebo for at least 48 hours, and the infusion was withdrawn one to six hours before CABG. Platelet function was monitored using the VerifyNow P2Y12 assay (Accumetrics). Cangrelor was given at 0.75 µg/kg/min, a rate selected based on a preceding open-label dose-ranging phase.

Significantly more patients on cangrelor than placebo had low levels of platelet reactivity throughout the entire infusion, according to Angiolillo. Mean reactivity levels were comparable at baseline and after infusion withdrawal, but significantly reduced in the cangrelor patients during infusion. The rate of achieving platelet reactivity units (PRU) <240 on the VerifyNow assay during the infusion, the study's primary end point, was 98.8% for cangrelor and 19.0% among controls (p<0.0001).

There was a "numerical increase" in minor bleeding complications (about 18% vs 10%) among cangrelor recipients, "which were mostly attributable to ecchymoses at the site of venous puncture," Rates of ischemic events from randomization to the postsurgical period were not significantly different. And the patient groups were comparable with respect to CABG procedural details, including number of grafts and prevalence of arterial conduits used, Angiolillo said.

  1. The Medicines Company: Cangrelor.

Less Frequent Warfarin Monitoring May Be Safe For Some Patients.

Most people taking the blood-thinner warfarin need blood tests every four weeks to make sure they're receiving the right dose of medication, but... research" published in the Annals of Internal Medicine "suggests that some people could safely have those tests done just once every 12 weeks." Investigators "found that people who were monitored every four weeks had an optimal dose of warfarin 74.1 percent of the time, compared with 71.6 percent for the group monitored every 12 weeks."

Cardiologists Have Not Come To Conclusions On Novel Blood Thinners that are intended to replace warfarin or improve stroke prevention and dangerous blood clots. But some doctors have said the dangerous side effects and cost may outweigh the benefits of these new medications.

'Bridging' Anticoagulation May Not Be Necessary

National Heart, Lung, and Blood Institute (NHLBI)–funded study on the issue of "bridging" patients on long-term anticoagulation who need to undergo invasive procedures will help inform many unanswered questions on this controversial topic, says one expert in the field

In fact, bridging "creates all sorts of miscommunications and logistical nightmares, and it's hard to get everyone on the same page," he said. Despite the belief that bridging is required--without any scientific proof to indicate this--there is some evidence that it is unnecessary in the vast majority of patients and that routine bridging can do more harm than good, he noted. In fact, one of the few published studies to have examined this issue found that thromboembolism (TE) is uncommon in low- or intermediate-risk patients interrupting warfarin for five days or less . And, far from being benign, frequent bleeding complications can result from bridging, and these can cause incisional pain, increase the length of hospital stays, and predispose patients to infections.

Translating some of the terminology employed for attendees, he explained that "bridging in" means taking people off warfarin prior to a surgery or procedure and substituting it with another form of anticoagulation; "bridging out" refers to the postoperative period; "full bridging" means the use of full-intensity anticoagulation, such as IV unfractionated heparin; and "prophylactic bridging" indicates a low preventive dose of treatments such as low-molecular-weight heparin.

Patients who are "high risk" definitely should receive bridging,  citing among these patients those with multiple prosthetic valves or "advanced" mitral-valve disease and AF patients with a CHADS score of 3 or higher. In these people, it's important not to forget the option of intravenous unfractionated heparin given in the hospital

The NHLBI study has so far enrolled 686 out of a planned 3600 patients with AF who require temporary interruption of warfarin, and its aim is to compare the efficacy of bridging anticoagulation (with a therapeutic dose of the low-molecular-weight heparin dalteparin, 100 IU/kg subcutaneously twice daily) with no bridging (placebo) on the rate of arterial thromboembolic events (ATE) and on the rate of major bleeding.The study hypotheses are that withholding warfarin for five days prior to surgery and restarting it afterward will prove noninferior to a bridging strategy for the outcome of ATE at 30 days and that this approach will be superior to a bridging strategy for the outcome of major bleeding at 30 days.

Depending on renal function, dabigatran should be stopped between one to five days before a procedure, although longer times should be considered in those undergoing major surgery, spinal puncture, or epidural catheter. Bleeding risk in these patients can be assessed by the ecarin clotting time (ECT) or activated partial thromboplastin time (aPTT).

Negative Data for Apixaban in Extended VTE Prevention

Prolonging prophylaxis for venous thromboembolism (VTE) in medically ill patients with a 30-day course of the new oral anticoagulant apixaban (Bristol-Myers Squibb/Pfizer) was not superior to a shorter six- to 14-day course of subcutaneous enoxaparin--designed to represent standard in-hospital VTE prevention--results of the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial demonstrate. The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge," said Goldhaber in a press conference at the AHA meeting. However, the ADOPT findings, together with those from similar studies--such as the MAGELLAN trial with rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and EXCLAIM with enoxaparin--show that "it is clear that the risk of VTE increases beyond the time of hospital discharge" in this patient population, they note. One-half of all VTE events in medically ill patients occur after discharge from the hospital, with an increased risk of VTE remaining for a duration of around three months, she noted, "but we don't understand which patients are at highest risk."

The most serious sequela of VTE, pulmonary embolism (PE), is the third most common cardiovascular disease after MI and stroke. Only a couple of trials have examined this issue previously. The first study, EXCLAIM, reported in 2007, found lower rates of VTE with extended prophylaxis with subcutaneous enoxaparin for an average period of 28 days compared with placebo. However, this benefit was offset by a significant increase in major bleeding in the enoxaparin group.

Similarly, the MAGELLAN trial examined extended prophylaxis with 10 mg once daily of the factor Xa inhibitor rivaroxaban compared with short-term prophylaxis with enoxaparin (10 days, 40 mg per day) followed by placebo. Again, lower rates of VTE in the rivaroxaban group were offset by more major bleeding events.

ADOPT is akin to MAGELLAN and examines another new oral factor Xa inhibitor, apixaban, in the medically ill. In the study, 6528 patients who were acutely ill with congestive heart failure, respiratory failure, or other medical disorder and at least one additional risk factor for VTE were randomized to enoxaparin 40 mg subcutaneously once daily for six to 14 days or apixaban 2.5 mg orally, twice daily, for 30 days The trial was a double-dummy design, so those who received enoxaparin also got an oral placebo twice daily and those who were taking apixaban had daily placebo subcutaneous injections in place of enoxaparin. The primary efficacy outcome was a 30-day composite of VTE-related death, PE, symptomatic deep vein thrombosis (DVT), or asymptomatic proximal-leg DVT, as detected by ultrasound on day 30. The primary safety outcome was bleeding.

Of 4495 evaluable patients, 60 (2.71%) in the apixaban group (n=2211) met the criteria for the primary end point, compared with 70 (3.06%) (patients in the enoxaparin group (n=2284) (relative risk with apixaban 0.87; p=0.44). Major bleeding was two and a half times more likely in the apixaban group, occurring in 0.47% of patients, compared with 0.19% of those in the enoxaparin group (relative risk 2.58; p=0.04) by day 30. But Goldhaber told heartwire this magnitude of bleeding with apixaban was still pretty low, "the equivalent of what would be expected with aspirin,"

Rivaroxaban May Lower Risk Of Death In Heart Attack Patients.

Johnson & Johnson and Bayer AG (BAYN)'s blood-thinner rivaroxaban [Xarelto] cut by 16 percent the risk of a subsequent heart attack, stroke or death from heart disease in patients who recently suffered a cardiac event, according to a study. People recovering from a heart attack or severe chest pain are much less likely to suffer another heart-related problem or to die from one if they take a new blood-thinning drug along with standard anti-clotting medicines. "Rivaroxaban could become a new standard of care for up to a million Americans hospitalized each year for these conditions. A low dose of the drug substantially cut the risk of dying of any cause during the study"

study published online Nov. 13 in the New England Journal of Medicine found that heart attack patients "who took the anti-clotting drug rivaroxaban [Xarelto] daily after a heart attack or life-threatening chest pain had a lower risk of dying or suffering another heart attack than patients who took a placebo." However, taking the drug could increase risk for some serious side effects. For example, "about 2 percent of patients on rivaroxaban had internal bleeding that required hospitalization and 0.6 percent had bleeding in the brain, which can lead to lasting mental deficits like speech and memory loss."

The study, known as the ATLAS ACS study, "analyzed data from more than 15,000 people hospitalized for a heart attack or angina. The participants received either standard care with rivaroxaban or standard care with a placebo." Those taking rivaroxaban "had a 16% reduced risk of cardiovascular death, stroke or heart attack compared to the patients on placebo" with an overall 30% decrease in the "risk of all causes of death" for patients taking rivaroxaban. "However, more internal bleeding occurred among those who took rivaroxaban."

Participants received either a low dose (5 milligrams) or a very low dose (2.5 mg) of the new blood thinner or a placebo, in addition to standard care. The medications were given twice daily for an average of 13 months." Patients taking 2.5-mg of rivaroxaban had a 16% decrease in "risk of heart attack, stroke or death" and those taking 5-mg had a 15% decrease, according to the researchers. Patients randomized to 2.5 mg twice daily for 13 to 31 months were 34% less likely to die from cardiovascular disease than patients in the placebo group (HR 0.66, 95% CI 0.51 to 0.86) and 32% less likely to die from any cause (HR 0.68, 95% CI 0.53-0.87, P=0.002 for both).

Vorapaxar May Significantly Increase Risk Of Major Bleeding In ACS Patients.

The "novel oral antithrombotic agent" vorapaxar, "given to high-risk patients with non-ST-elevation ACS who were mostly already on dual-agent antiplatelet therapy, failed to hit that coveted treatment sweet-spot-reduced ischemic risk without more bleeding.  It was known that the drug, an oral protease-activated-receptor 1 (PAR-1) antagonist had safety issues because the trial was halted last January, after an unplanned safety review of TRACER data...the magnitude of the problem was not known: A 35% increase in the relative risk of major bleeding events, and more than a three-fold increase in the risk of intracranial hemorrhage. According to study results, 18.5% of patients treated with vorapaxar for two years had an adverse event compared to 19.9% of patients given placebo. The second goal of the study was to examine only cardiac death, heart attack and stroke. The study found 14.7% of patients treated with vorapaxar had an aforementioned event compared to 16.4% of patients treated with placebo. Lastly, patients on vorapaxar had a 40% higher rate of serious bleeding.

Vitamins May Reduce Effectiveness Of Warfarin.

Study findings presented at the American Heart Association's annual meeting, which found that "people with heart conditions who take vitamins may be less likely to take some of their other medications properly." The researchers surveyed "100 people with an irregular heartbeat" and "found that 62 percent of patients who were prescribed warfarin took the drug with dietary supplements, potentially reducing its effectiveness." In addition, "heart patients who took vitamins were two percent more likely to double their dose of warfarin, compared to those not taking supplements." The study concluded those on "prescription drugs should be more aware of the potentially negative side effects associated with taking dietary supplements.

Genetic Tests May Detect Patients Needing Higher Doses Of Clopidogrel.

Genetic tests can now help predict which heart patients need higher doses of a common anti-clotting drug, shows a news study that is the latest example of 'personalized medicine.' Nearly one-third of heart patients have genes that can prevent them from properly processing the drug. More importantly, Mega's study shows that tripling or quadrupling the typical dose of clopidogrel [Plavix], 75 milligrams a day, helps most patients with these genes to process the drug normally. Tripling the standard dose of clopidogrel (Plavix) was able to overcome genetic resistance to the drug.  Investigators reported that, "with a maintenance dose of 225 mg daily, patients who had one copy of an allele that confers resistance to clopidogrel were able to achieve levels of platelet reactivity similar to those of patients who responded to the standard 75-mg dose." The researchers found, however, that "patients who had two copies of the loss-of-function allele...continued to have a poor response to clopidogrel, even at a dose of 300 mg daily.

Clot-Busting Drugs May Be Okay For People With Prior Stroke, Diabetes.

Clot-busting drugs improve outcomes after stroke even in people with a history of stroke or diabetes. Outcomes were comparable to those seen among patients with neither condition." The investigators reported that, "on the basis of the analysis, there is 'no statistical justification' for denying thrombolytic drugs to patients with previous stroke or concomitant diabetes, or both.

Doctors Reserve Judgment on New Blood Clot Drugs

Cardiologists are not ready to jump to any conclusions about a closely-watched group of new anticoagulants and said serious questions about their safety still need to be addressed.Three new medicines that offer potential advantages over older drugs to prevent strokes and other dangerous conditions caused by blood clots will compete in a market worth up to $10 billion in annual sales.. Investors have tried to bet on which of the three will become the dominant player in a race between Xarelto from Bayer and Johnson & Johnson, apixaban by Pfizer Inc and Bristol-Myers Squibb, and Boehringer Ingelheim's Pradaxa. Many cardiologists at the American Heart Association meeting this week said they were reserving judgment about whether any one drug is better for their patients. Some said safety concerns and cost could outweigh their benefits.

Apixaban and Xarelto are both Factor Xa inhibitors, while Pradaxa is a direct thrombin inhibitor.The new medicines aim to replace warfarin or improve upon other older drugs. But they come with serious bleeding risks and their effectiveness has differed depending on the patients being treated and the dosage strength, complicating the picture.

Xarelto and Pradaxa are approved for use in the United States for preventing stroke in patients with atrial fibrillation. Apixaban has yet to be submitted to the U.S. Food and Drug Administration.A major part of the promise of these new drugs is that they can replace warfarin, which has been used for decades but is difficult to manage because it requires regular monitoring to prevent life-threatening bleeding. Doctors said that some patients are stable on warfarin, and they may be more likely to keep up with their prescribed regimen since it is far cheaper

Label Updated To Reflect Dexlansoprazole May Be Taken With Clopidogrel.

The labeling on the proton-pump inhibitor (PPI) dexlansoprazole (Dexilant) has been updated to reflect its compatibility with clopidogrel (Plavix), according to drug maker Takeda." The updated label "specifically states that no dose adjustment of clopidogrel is necessary when administered with an approved dose of dexlansoprazole." The label update was based on a randomized, "open-label, two-period, crossover study to evaluate the effect of dexlansoprazole on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy subjects."

Dabigatran: 260 Fatal Bleeds Since Approval Worldwide

A total of 260 people worldwide have had a fatal bleed while taking dabigatran (Pradaxa), according to an analysis of the worldwide postmarketing database conducted by the drug's manufacturer, Boehringer Ingelheim. In response, the European Medicines Agency (EMA) has issued a statement saying that it believes the deaths need to be viewed in the context of dabigatran's rapid uptake and increased awareness of possible side effects. Events occurred between March 2008 and October 31, 2011.  Dabigatran was granted US marketing approval in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation, but the drug has been available for longer and for different indications in other countries.

During the same period of time, treatment exposure to Pradaxa worldwide was estimated at 410 000 patient-treatment-years, which translates into a rate of 63 events per 100 000 patient-treatment-years.This is in line with expectations for bleeding events based on the pivotal RE-LY trial,  and are in alignment with the US prescribing information, which clearly states the benefits and risks associated with Pradaxa. Overall, the positive benefit/risk ratio of Pradaxa in nonvalvular atrial fibrillation remains unchanged.

In RE-LY, rates of fatal bleeding were numerically lower with the higher dose tested in the trial--150 mg twice daily--at 0.23% per year (230 per 100 000 patient-years) compared with warfarin at 0.33% per year (330 per 100 000 patient-years). Life-threatening bleeds in RE-LY were more common, numerically, in the 150-mg group than in the 110-mg group tested in the trial; the lower dose was not approved by the FDA, although it is on other worldwide markets.Bleeding events with dabigatran have prompted safety advisories in Japan and Australia and have led to labeling updates in Europe and the US focusing on the need for monitoring renal function, since renal impairment can increase bleeding risk.

In Europe, dabigatran was first authorized in March 2008 for primary prevention of venous thromboembolic events in adults following orthopedic surgery. In early November, the EMA, in conjunction with the manufacturer, agreed to strengthen packaging information and to send an update to physicians emphasizing the need for renal assessment.

Rivaroxaban, Dabigatran, or Warfarin?

For decades, warfarin has been the best — and pretty much only — oral anticoagulant for stroke prevention in atrial fibrillation (AF). Despite all the warts of drug–drug and drug–food interactions, the difficulty of keeping patients in therapeutic range, and the burdensome need for regular monitoring of International Normalized Ratios (INR), warfarin is an extremely effective therapy. Still, the most sincere wish of many patients and physicians has been that there should be some other option.

Other oral anticoagulants have tried and failed to beat warfarin; one of these, ximelagatran, made it through phase 3 trials and all the way to an application to the US Food and Drug Administration (FDA) before being scuppered by signals of liver toxicity.

The second of 2 alternative oral anticoagulants for the prevention of stroke or systemic embolism in AF has just been approved by FDA, with a third drug expected to be considered for approval soon. Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, was the first warfarin alternative approved, in October 2010. Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), a factor Xa inhibitor, was approved by the FDA on November 4. On the strength of 2 positive trials, AVERROES and ARISTOTLE, a third agent, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), also a factor Xa inhibitor, may not be far behind..

Taking warfarin has always been a challenge for patients, as well as physicians and the healthcare system, and now we have 2 new options that don't have that specific challenge, however there may be other challenges with the newer agents.

The problem is, there's no data that makes the comparison of dabigatran and rivaroxaban, to know which one's the best choice." Complicating this decision about rivaroxaban are issues that have been raised about the pivotal phase 3 trial, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), of rivaroxaban vs warfarin. Although the dabigatran 150-mg dose regimen was superior to warfarin in reducing stroke and systemic embolism in the RE-LY trial, supporting its approval, rivaroxaban met statistical noninferiority criteria, but did not reach superiority criteria, in the intention-to-treat analysis for both the "during treatment" and "after discontinuation" groups in ROCKET-AF.

Concern was also expressed about the lower percentage of time in therapeutic range (TTR) for INRs in the warfarin group in ROCKET-AF compared with patients receiving warfarin in the dabigatran and apixaban trials, raising the issue of whether better INR control might have affected the results.

In addition, a revision to the label issued by the FDA on November 9 advises physicians using dabigatran to assess renal function before prescribing the drug, and recommends lower doses for elderly patients who may have renal problems.

Another consideration is the cost of these new agents vs warfarin. Drug interactions with dabigatran have been seen since it was approved, he noted, which have also been outlined in the new FDA guidance, including systemic ketoconazole and dronedarone.The updated label now says that once opened, dabigatran can be safely stored longer than previous recommendations that it be used within 30 days of opening the bottle.

One very big issue with all of these new agents has been the fact that at least to date, anticoagulation cannot be immediately reversed for emergent surgical procedures or hemorrhagic complications, for example. It may also rule out use of tissue plasminogen activator (tPA) if the patient has a stroke despite anticoagulation.

There seems to be a consensus forming that activated prothrombin complex concentrates (PCCs), seem to be effective for at least reversing the clotting abnormality seen with these newer agents. Some of the companies are also starting to look at specific reversal agents for the factor Xa inhibitors, Faced with the need for reversal, "right now our protocols are to get fresh frozen plasma on board, and do other things we can to stop the bleeding," including recombinant activated factor VII.

In certain circumstances it is still possible to do a partial thromboplastin time (PTT) to determine how anticoagulated a patient is. You can also in certain circumstances do a thrombin time., and that would be another measure to know if you're over-anticoagulated. The half-life of these newer drugs is also relatively short, and they clear the system fairly rapidly when they are stopped, but at this time, there is no way to reverse them acutely.

Once they get some of the [anticoagulation] testing available for these agents, which is going to happen, I think there'll be more of a push toward using them. The major thing is they're more expensive, but I think both of them have a strong case."

Clinicians may be reluctant to switch someone doing well on warfarin, possibly for many years, unless they had a history of problems with bleeding or wanted to change because of diet limitations or problems getting in to have INRs checked. These new drugs are as good or better in certain circumstances than warfarin,. They're easier to use, they don't require monitoring, they have less food interactions and less drug–drug interactions. They have actually very acceptable, and in some cases even lower, bleeding risks, including with dabigatran, even lower intracranial bleeding risks, and they can be as good or better than warfarin.

Choosing between dabigatran and rivaroxaban is a more difficult question. The phase 3 studies of these agents, for example, were in slightly different populations: patients in ROCKET-AF were higher risk than in the dabigatran and apixaban trials, making such indirect comparisons treacherous. Meta-analyses and phase 4 surveillance studies may also provide more comparative information in the absence of direct comparison trials.

Platelet Tests Not as Helpful on Individual Patients

Absolute and relative levels of platelet inhibition based on a VerifyNow test (Accumetrics) are strong independent predictors of stent thrombosis in patients who have undergone drug-eluting stent (DES) implantation, but on an individual patient level, the test is not specific or sensitive enough to predict stent thrombosis at 30 days. These data suggest that agents that more effectively inhibit ADP-induced platelet activation should reduce 30-day stent thrombosis when applied to large patient populations.  Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents (ADAPT-DES)

The modest sensitivity and specificity of platelet-function testing, coupled with the low prevalence of events, implies that testing of platelet ADP-antagonist responsiveness is unlikely to provide useful information to guide clinical decision making in most individual patients for the prevention of stent thrombosis at 30 days. So [testing is] good on a population level, but not so helpful for individual patients.

ADAPT-DES is a large, prospective registry enrolling a planned 11 000 patients undergoing PCI with DES at 11 sites in the US and Germany. The registry as being conducted with the same rigor, prospective planning, and independent analysis as a randomized controlled trial--"not your average post hoc registry. Platelet-function tests were obtained at, on average, 19 hours post-PCI in 8575 patients. By 30 days, 39 definite or probably stent thromboses had occurred (a rate of 0.46%). In multivariate analyses, platelet-reactivity units (PRU) >208, PRU >230, and percent inhibition <11% were all independently associated with definite or probable stent thrombosis.But in an analysis looking at specificity and sensitivity of the test, investigators found substantial overlap between patients who had not had a stent thrombosis (n=8402) and those who had.

And looking only at ACS patients, DAPT hyporesponsiveness was still strongly associated with stent thrombosis, but this finding was not seen in non-ACS patients. Of note, the rate of stent thrombosis in stable patients was just 0.22%.The very low stent-thrombosis rate in patients with stable CAD, coupled with the poor prognostic utility of platelet-function testing in this setting, suggests that assessing dual antiplatelet response in patients without ACS undergoing PCI is unlikely to provide incremental clinical utility and may explain the negative results of trials such as GRAVITAS and TRIGGER-PCI.

Experts assembled to speak with the media said that they were not routinely using the VerifyNow test in clinical practice, although most were using it "selectively." After we saw that GRAVITAS was negative, we actually stopped using it, and the reason was, I think we had very strong data that more potent antiplatelet agents should be used in patients with ACS who are not at high risk for bleeding, as demonstrated by trials such as TRITON-TIMI 38 and PLATO. "We had no such data in patients without ACS, and GRAVITAS suggested that event rates were so low, this didn't affect the outcome of patients. These data confirm  that for individual patients, the sensitivity and specificity is not enough to guide usage, although as a research tool, I think it is still very, very useful and can guide additional hypotheses and other studies.

The time of doing a test for platelets and thinking it's going to give us all the answers is gone, "We have to develop a way to screen patients for MI and stent thrombosis clinically and apply the results of that test in that population and similarly take into account a bleeding risk and apply those results."

If a post-STEMI patient with thrombotic lesions who later showed high on-treatment platelet reactivity, I'd be very worried about that patient, but if [I saw] the exact same test result for a patient who came in for an elective stenting, I would not be worried about that patient. And I don't think that's well understood in the community, because we are so fixated on what these blood tests show. We should stop seeking a test that's going to speak to all patients."

Possible Rivaroxaban Antidote Identified

Results of a small study published online September 6, 2011 in Circulation show that prothrombin complex concentrate (PCC) appears to be an effective antidote for rivaroxaban that could be used to stop or prevent serious bleeding in patients taking this new anticoagulant. However, the same study showed that PCC has no influence on dabigatran .

Dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor Xa inhibitor, have shown promise as anticoagulants that can be prescribed in fixed doses and do not require frequent monitoring. But so far, no human studies have assessed whether prohemostatic agents can stop the anticoagulant effect of either drug in the patient suffering a major bleed or undergoing emergency surgery.  PCC is a good candidate for an antidote because it contains the coagulation factors II, VII, IX, and X in a high concentration and enhances thrombin generation, Eerenberg et al explain.

The researchers randomized 12 healthy male volunteers to either 20 mg of rivaroxaban twice a day or 150 mg of dabigatran twice a day for two and a half days, followed by either a single 50-IU/kg dose of PCC or a similar dose of saline. After 11 days, the patients repeated this procedure with the other anticoagulant treatment.

Rivaroxaban induced a significant prolongation of the prothrombin time (15.8 vs 12.3 seconds at baseline; p<0.001) that was immediately and completely reversed by the PCC to an average of 12.8 seconds (p<0.001). The endogenous thrombin potential, a measure of blood coagulability, was inhibited by rivaroxaban (51% vs 92% at baseline, p<0.002) and normalized with PCC (114%, p<0.001), while the saline had no effect.

Dabigatran also increased the activated partial thromboplastin time, ecarin clotting time, and thrombin time, but PCC did not restore coagulability of the blood to the baseline levels in any of these coagulation tests. "The question of how the effect of dabigatran can be antagonized remains unanswered," the authors explain. They suggest that other strategies for reversing dabigatran could include repeated doses of PCC, recombinant factor VIIa, or a combination of PCC and recombinant factor VIIa, but these strategies have yet to be investigated in trials.

This was the first study to investigate the effect of PCC for reversal of these new anticoagulant agents in humans, according to the authors, and it "may have important clinical implications," but the effects of PCC in patients with bleeding events while treated with anticoagulants will have to be studied in further trials.

Fewer INR Checks Safe in Patients on Stable-Dose Warfarin

Patients receiving long-term, steady-dose warfarin therapy who have had stable international normalized ratios (INRs) for at least 6 months can safely go 12 weeks between dose assessments, a new study indicates. In this patient population, researchers found that the 12-week interval was no worse in maintaining the INR in the therapeutic range than the conventional 4-week interval currently recommended in the United States. The coauthors of a linked commentary say that this study shows that the frequency of assessing warfarin dosing can be substantially reduced in stable patients.  250 patients who were receiving long-term warfarin therapy in a noninferiority randomized study were enrolled. All of the patients had been receiving a steady dose of warfarin for at least 6 months. For 1 year, 124 participants underwent dosing assessment every 12 weeks, and 126 patients did so every 4 weeks. To maintain blinding, patients in the 12-week assessment group were tested every 4 weeks, and sham INRs within the target range were reported for 2 of the 3 periods. Dose assessment every 12 weeks proved noninferior to conventional 4-week assessment in terms of maintaining the INR in the therapeutic range, the authors report. On average, the percentage of time in the therapeutic range was 74.1% in the 4-week group and 71.6% in the 12-week group. 

The absolute difference of 2.5 percentage points favored the 4-week group with a 1-sided upper 97.5% confidence bound of 7.3 percentage points that was within the noninferiority margin of 7.5 percentage points (unadjusted P = 0.020; adjusted P = 0.019 for tests of noninferiority).In addition, fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs 55.6%). The absolute difference was 18.5 percentage points (95% confidence interval, 6.1 to 30.0 percentage points; P = .004).

There were no between-group differences in secondary outcomes, including the number of extreme INRs, changes in maintenance dose, major bleeding events, objectively verified thromboembolism, and death. Major bleeding or thromboembolism was rare, occurring in less than 2% of patients assigned to either 4-week or 12-week assessment intervals. The trial was not powered to assess differences in clinical outcomes, the investigators note.

It should be noted, they say, that this study was "not a true evaluation" of INR monitoring and dosing assessment every 12 weeks because patients assigned to 12-week assessment had their blood drawn every 4 weeks and received telephone calls from anticoagulation staff to remind them of important factors for INR instability. A phase 3 trial comparing testing and contact every 4 weeks with every 12 weeks would be necessary before prolonged intervals for testing and dose assessment can be recommended for clinical practice. It should also be noted, they say, that the study took place at a single center and warfarin clinic, and that the results may not be applicable to other countries in which vitamin K antagonists with shorter half-lives, such as acenocoumarol, are predominantly used.

Risk Stratification of Patients With Pulmonary Embolism

It is estimated that as many as 200,000 to 300,000 deaths occur in the United States every year from PE. Interestingly, autopsy studies suggest that if a patient dies from acute PE, usually PE is not suspected until the patient is dead. In many patients, we do have a window of opportunity, and it is becoming increasingly recognized that we should risk-stratify these patients. Our general therapy is anticoagulation therapy. If we can't anticoagulate because of contraindications, then we put in an intravascular vena cava filter. Some patients have massive PE (massive PE causing extensive hemodynamic instability and right ventricular enlargement, regardless of how big the clot is), and there is agreement that these patients should be treated as aggressively as possible, or consider embolectomy if there are contraindications to thrombolytic therapy.Nonrandomized studies have provided compelling evidence that if the right ventricle is enlarged on echocardiography, mortality is higher. Also, elevated troponin levels confer a much higher mortality rate.

To stratify patients, first, you have to prove they have PE. Echocardiography gives us the best idea of right ventricular function. If the right ventricular size is more than 0.9 times the left ventricle size, we would call that submassive PE, and that would be concerning. CT scan can also show an enlargedright ventricle.The next steps are to order troponin level and use ultrasound to see if there is any residual deep vein thrombosis (DVT).

A lot of physicians do not order these tests. There are patients with normal blood pressure but with right ventricular enlargement and/or elevated troponin who we believe should be considered for more aggressive therapy. We have to individualize therapy.

We would like to risk-stratify everyone. If someone has a severe right ventricular enlargement and/or elevated troponin and extensive DVT in the legs after a diagnosis of PE, they would need more aggressive therapy. If a patient has a mildly enlarged right ventricular, normal troponin, and no evidence of DVT in the leg, some physicians would think they could be handled less aggressively, but based on right ventricular enlargement alone, they are still at risk for higher mortality.

Previously, when we saw massive PE, we would consider systemic thrombolytic therapy. Physicians are now concerned about risk of bleeding with thrombolytic therapy. In view of that, there has been increasing interest in catheter-based therapy. Some smaller hospitals may not have an interventional radiology suite or sufficient radiology staff to care for these kinds of patients, but in most hospitals, this can be done.

This requires a team approach — interventional radiologists, thoracic surgeons, pulmonary critical care doctors, hematologists, radiologists, use of echocardiography. It is prudent for these specialties to come to a consensus as to how to approach patients with massive or submassive PE. If the hospital does not have an interventional radiology suite, strong consideration should be given for referral to a larger institution. However, physicians must be careful about any potential delays in therapy. With massive PE, you often don't have time to transfer patients who are at risk of dying.

Consider echocardiography as key in stratifying patients. All PE is not the same. We need to risk-stratify patients into massive PE, submassive PE, or neither, and aggressively manage massive PE, consider being aggressive with submassive PE, and consider a catheter-based therapy.

CHADS2 Telling in AF Patients on Oral Anticoagulants

In patients with atrial fibrillation, higher CHADS2 score is associated with increased risk for stroke or systemic embolism, bleeding, and death, even with optimal anticoagulation with warfarin or dabigatran, according to a subgroup analysis of the RE-LY trial. In anticoagulated patients, "the commonly used CHADS2 risk score not only predicts stroke (as it was developed for) but also mortality and major bleeding..

CHADS2 is a simple and validated clinical prediction rule for estimating stroke risk in patients with atrial fibrillation not receiving anticoagulants, the authors note in their paper. Its value in predicting thrombotic and bleeding complications in patients receiving anticoagulant therapy is unclear.

Data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was used   to assess thrombotic and bleeding risk according to the baseline CHADS2 score. The study involved 18,112 patients with atrial fibrillation at risk for stroke who were randomly assigned to treatment with dabigatran (Pradaxa, Boehringer Ingelheim), 110 mg or 150 mg twice daily, or warfarin at a dose adjusted to an international normalized ratio (INR) of 2.0 to 3.0 for a median of 2 years.

The main RE-LY results,showed that the rates of stroke or systemic embolism and death each decreased by 0.5% per year with dabigatran, 150 mg twice daily, compared with dose-adjusted warfarin. Rates of major bleeding did not differ, but intracranial bleeding was less common with dabigatran.

The CHADS2 risk score assigns 1 point for a history of congestive heart failure, hypertension, diabetes, or age older than 75 years and 2 points for a history of stroke or transient ischemic attack. In the RE-LY cohort, 5775 patients had CHADS2 scores of 0 to 1, 6455 had scores of 2, and 5882 patients had scores of 3 to 6.

Even with anticoagulation, the risk for the primary outcome of stroke or systemic embolism increased with increasing CHADS2 score, the authors report.

Regardless of CHADS2 score, "rates of stroke or systemic embolism were lower with dabigatran, 150 mg twice daily, and rates of intracranial bleeding were lower with both dabigatran doses than with warfarin treatment.CHADS2 scores of 3 or higher identify patients with the most to gain and the most to lose by using anticoagulant therapy. Whether they receive warfarin or dabigatran, 150 mg twice daily, these patients have a 2% to 3% annual risk for stroke or systemic embolism, a nearly 5% risk for major bleeding, and a nearly 6% risk for death.

Four Medications Linked To Most Emergency Hospitalizations For Older Americans.

Blood thinners and diabetes drugs cause most emergency hospital visits for drug reactions among people over 65 in the United States," according to a study published in The New England Journal of Medicine. Researchers found that "just four medications or medication groups - used alone or together - were responsible for two-thirds of emergency hospitalizations among older Americans." The investigators looked at data from 58"hospitals...participating in a surveillance project run by the C.D.C. that looks at adverse drug events. Researchers found that "forty-six percent of hospitalizations involved medicines used to prevent blood clots; a single anticoagulant, warfarin, was responsible for one-third of hospitalizations, the report found. Another 25 percent involved diabetes medications, either insulin injections or medicines taken by mouth. Blood thinners and diabetes medicines often require blood testing and dosing changes, but these are critical medicines for older adults with certain medical conditions."

The researchers estimated that 265,802 visits to emergency departments for adverse drug events occurred from 2007 to 2009 for adults 65 or older." More than "a third of these visits, or nearly 100,000, required hospitalization." The investigators found that "unintentional overdose of medication was the most common reason, accounting for nearly two-thirds of hospitalizations.

Aspirin May Offer Little Benefit For Women's Heart Health.

According to a study published online in the European Heart Journal, aspirin may offer little heart health benefits for women. Investigators looked at data on approximately 28,000 healthy females at least 45 years of age who had been given aspirin or a placebo in a previous study. Altogether, aspirin reduced heart risks by just 2.2 to 2.4 %.

UK NICE Gives Nod to Apixaban for DVT Prevention

The UK's National Institute for Health and Clinical Excellence (NICE) has published final draft guidance recommending NHS reimbursement for the use of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) as an option for the prevention of venous thromboembolism (VTE) in adults who have undergone planned total hip or total knee replacement surgery. The committee concluded that apixaban was more clinically effective and cheaper than enoxaparin (Lovenox, Sanofi Aventis). It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and dabigatran (Pradaxa, Boehringer Ingelheim). 

The draft guidance has been sent to the formal consultees for appraisal who have 15 working days to consider whether they wish to appeal against it. Subject to appeal, the draft guidance will be used as the basis for final guidance.The NICE clinical guideline 'Venous thromboembolism: reducing the risk' recommends that people having elective hip replacement or elective knee replacement surgery should be offered low-molecular-weight heparin, dabigatran etexilate, rivaroxaban, or fondaparinux to prevent VTE.  Although apixaban had only been directly compared with one of the options recommended by the clinical guideline--enoxaparin, a low-molecular-weight heparin--the committee was satisfied that apixaban is a clinically and cost-effective option for preventing blood clots, alongside other effective treatments already recommended by NICE. NICE further notes that without anticoagulant prophylaxis the prevalence of DVT ranges from 41–85% after elective knee surgery and 42–57% after elective hip surgery. The prevalence of DVT with pulmonary embolism is up to 0.9–28% in hip replacement and up to 1.5–10% in knee replacement.

Apixaban costs £17.15, £34.30, and £102.90 for packs of 10, 20, and 60 tablets. The cost of treatment is estimated to be £41.16 for knee replacement surgery (based on 12 days' treatment) and £116.62 for hip replacement surgery (based on 34 days' treatment).

Dabigatran Poses Unique Problems in Trauma

Very little can be done for a patient taking dabigatran (Pradaxa, Boehringer Ingelheim) who suffers a traumatic injury, and this new, potentially catastrophic predicament--less of an issue in the warfarin era--underscores the need for routine surveillance of new oral anticoagulants to include hemorrhagic complications and trauma deaths.

We don't see anything but complications with these patients, we don't see the people with wonderful interactions with dabigatran. All we see is the bad, but when you do, it's a horrible feeling., you kind of roll your eyes when you hear that an [incoming trauma] patient is on Coumadin, thinking 'this is going to increase their risk,' but at least you know there are some things you can do. . . . Now, with dabigatran, if I hear a patient is on Pradaxa, I get chest pain myself when I hear it. All of us do.

Cotton and colleagues point out that trauma is the fourth-leading cause of death in the US, reaching 40 000 deaths per year among men and women over age 65. While hemorrhagic complications can also be catastrophic in people taking warfarin, patients on the older drug have the edge over those taking newer oral anticoagulants in a number of ways.

First, the degree of warfarin anticoagulation can be easily assessed, whereas no such tests exist for dabigatran. Second, there are strategies to rapidly reverse the anticoagulant effect of warfarin using vitamin K, plasma factor VIIa, and factor concentrates, Cotton et al note. By contrast, coagulopathy is mostly "irreversible" in patients taking dabigatran.

"Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert)," Cotton et al write. "The ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level one trauma centers."

Among patients taking dabigatran seen by Cotton et al, all appeared to have normal coagulation on conventional tests, but were grossly abnormal using rapid thromboelastography (rTEG). One patient who suffered a fall and developed neurological deficits died shortly after emergency craniotomy. In their letter, Cotton and colleagues urge the FDA to consider the "generalizability" of study findings for new, upcoming oral anticoagulants, and to require more pragmatic trials. "We strongly urge that hemorrhagic complications and death resulting from trauma be included as part of the routine surveillance of all newly approved oral anticoagulants," they conclude.

Cotton said he in no way expects the RE-LY investigators to go back and redo their trial, but he believes real-world trauma events should be captured in trials of other anticoagulants that are still ongoing. He also wants trauma deaths, which are not typically captured in postmarketing surveillance, to be included.

In fact, Cotton says he was surprised and pleased to get a call from Boehringer-Ingelheim after his letter was published, asking for details on the three patients, suggesting they are "taking this very seriously." They also told him that the company is actively working on an antidote to reverse dabigatran's effects.

"But until I have that in my back pocket, this is a bad problem," Cotton said, although he acknowledged a traumatic injury, itself, represents a "small risk."

Cotton hopes his letter will spur physicians to discuss the risks in the case of trauma with their patients as part of the discussion of whether to start the drug in the first place or switch from warfarin--something he thinks is not happening enough. "The harm when this happens is real and irreversible, and there ought to be a more balanced discussion between patients and physicians."

Donna Castellone

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Donna Castellone,  MS, MT(ASCP)SH

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