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New In Coagulation

Monday, April 4, 2011

WHAT'S NEW IN COAGULATION: APRIL 2011

GP IIb/IIIa Blockers Should Still Play a Role in Elective PCI

GP IIb/IIIa blockers still provide clinical benefit in the current era of elective PCI performed with stents and thienopyridines. The analysis, published in the March 8, 2011 issue of the Journal of the American College of Cardiology. GP IIb/IIIa blockers have been shown beneficial during PCI, but most of the studies were conducted before the routine use of coronary stents and thienopyridines.

To investigate the effect of GP IIb/IIIa blockers in the more contemporary setting, they analyzed the results of all randomized studies of such agents vs control in patients undergoing elective PCI with stenting who were routinely treated with thienopyridines. A total of 22 studies with 10 123 patients were included. Nonfatal MI was defined preferentially as two to three times the upper limit of the normal range of the locally available creatine kinase myocardial-band assay.

Results showed that at 30 days, patients receiving GP IIb/IIIa blockers had a significant reduction in MI without a significant increase in major bleeding. Minor bleeding, however, was increased.

The use of IIb/IIIa blockers has fallen somewhat out of fashion in recent years. The current trial involved only trials in elective PCI. GP IIb/IIIa blockers are used more in the higher-risk ACS setting, but Bavry points out that even in this scenario, they have not been given a class I indication in major guidelines. He suggests that GP IIb/IIIa blockers would probably be more beneficial in the unstable setting, but the risks of bleeding may also be higher. His group is working on another meta-analysis looking at their use in ACS. Other factors are also changing that might encourage the use of GP IIb/IIIa blockers. These include delivery by intracoronary infusion, which may be associated with better results and reduced costs, and the increase in radial-access PCI, which reduces bleeding, allowing more potent antithrombotic strategies to be reconsidered.

Changes in Inflammatory and Coagulation Biomarkers

J Acquir Immune Defic Syndr. 2011;56(1):36-43.

Objectives: Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART.
Methods: Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naïve to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6.
Results: At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm³ higher than for the DC group (590 versus 400 cells/mm³). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels.
Conclusions: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.

FDA Approves First New Lupus Treatment In Over Five Decades.

The US Food and Drug Administration (FDA) has approved the use of belimumab (Benlysta, Human Genome Sciences and GlaxoSmithKline) in combination with standard therapies to treat active autoantibody-positive systematic lupus erythematosus. This is the first lupus drug to be approved since 1955, when the FDA approved hydroxychloroquine (Plaquenil) and corticosteroids. In 1948, aspirin was approved to treat lupus. Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells, which is hypothesized to be a mechanism of action in lupus.

The safety and effectiveness of belimumab was demonstrated in 2 clinical trials that randomized a total of 1684 patients to receive either belimumab or placebo in combination with standard therapy. Treatment with belimumab plus standard therapy reduced disease activity and possibly decreased the number of severe flares and steroid use. Patients with active lupus that involved the kidneys or central nervous system and those who were previously treated with a B-cell-targeted therapy or intravenous cyclophosphamide were excluded from participating in the trials.

Study participants of African American or African descent did not significantly respond to belimumab. Additional studies will be conducted to definitively determine the safety and efficacy of belimumab in this population. Common adverse effects reported with belimumab include nausea, diarrhea, fever, and infusion-site reactions. It is suggested that patients be treated with an antihistamine prior to a belimumab infusion.

A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo. Live vaccines should not be administered during treatment with belimumab.

It is estimated that lupus afflicts up to 1.5 million Americans, and it disproportionately affects black women.

Scientists Make Discoveries in the Biology of Lupus

Researchers think they may have discovered the mechanism that drives the body’s attack on its own cells and tissues in the autoimmune disease lupus. Two new studies published in the journal Science Translational Medicine point to a cycle of cell death and chronic inflammation involving blood cells called neutrophils, versatile soldiers of the immune system that race to the site of infection to destroy invaders, as a key engine in the disease.

The disease can affect many different parts of the body, including the skin, joints, lungs, heart, blood, and kidneys, which often makes it a challenge for doctors to diagnose.One of the hallmarks of lupus is that patients make antibodies to their own DNA, called anti-nuclear antibodies, or ANAs. Blood tests for ANAs are sometimes helpful as an initial step in diagnosing lupus.

Researchers had long wondered how that happens since DNA was thought to be protected inside cells. Then, in 2004, a team of researchers discovered that neutrophils can die in an explosive way, shooting strings of cellular material studded with proteins and bits of nuclear DNA out like webs to entangle harmful bacteria, viruses, or fungi.

These neutrophil extracellular traps, or NETs, get slung outside the cell.In healthy people, once these NETs enter the liquid space between cells, the bits of nuclear DNA degrade quickly and probably don’t cause any problems, patients with lupus have antimicrobial proteins called LL37 and HNP that appear to protect these bits of DNA from being broken down by the body. Together, these proteins and DNA can trigger another type of immune cell, a kind of chemical factory called a plasmacytoid dendritic cell, which pumps out proteins that stoke the immune response.

One of those proteins, called type 1 interferon, is often present in high amounts in patients that have lupus, which has largely been another mystery of the disease. Type 1 interferon, it turns out, triggers neutrophils to release more NETs, setting up an apparently self-perpetuating disease process. This suggests is that there is a vicious cycle between the production of interferon, the way the neurtrophils die and the increase in the production of auto-antibodies, so this is a very, very efficient pathogenic loop that amplifies itself.

It really provides a model for understanding why interferon is released, and that’s important because the more we understand why this very inflammatory cytokine is released, the more we can think about therapeutic options to block its production.

Aspirin Linked To Stomach Bleeding Risks

According to a study in the journal Circulation, patients taking low doses of aspirin to protect their heart could be at risk for stomach bleeding. Also, patients taking both aspirin and other common medications may have an increased risk of bleeding. For the study, investigators analyzed a database of 2,049 primary care patients in the UK that included all cases of stomach bleeding between 2000 and 2007. The researchers also looked at 20,000 people who were similar to the primary care patients, but who had not had a stomach bleed during the same period. They found that of all patients who had a stomach bleed, 31 percent were taking low-dose aspirin at the time of the bleed versus 19 percent of patients in the comparison group who did not have a stomach bleed.

Which Heparin for Cerebral Vein Thrombosis

Researchers from the University of Amsterdam have published a nonrandomized, prospective cohort study comparing the effects on clinical outcomes of unfractionated vs low-molecular-weight heparin in the treatment of cerebral venous thrombosis.

The cohort included 624 patients from the International Study on Cerebral Vein and Dural Sinus Thrombosis. The primary endpoint was functional independency at 6 months, indicated by a modified Rankin scale score ≤ 2. Secondary endpoints were complete recovery, mortality, and new intracranial hemorrhages.One hundred nineteen patients received low-molecular-weight heparin, and 302 patients received unfractionated heparin. Significantly more patients treated with low-molecular-weight heparin were functionally independent after 6 months (odds ratio [OR], 2.1; confidence interval [CI], 1.0-4.2).

Low-molecular-weight heparin was associated with fewer new intracerebral hemorrhages (adjusted OR, 0.19; CI, 0.04-0.99). There was no difference in complete recovery or mortality. The investigators conclude that low-molecular-weight heparin seems preferable over unfractionated heparin for the initial treatment of cerebral venous thrombosis.

PPIs and Clopidogrel: New Theory May Explain CV Risk Signal

Authors of yet another analysis trying to get to the bottom of the real or perceived risk of combining clopidogrel with a proton-pump inhibitor (PPI) have a new and provocative theory as to just where the signal of increased events may be coming from. No differences were seen in one- and six-year major adverse cardiac event (MACE) rates among their series of propensity-matched, post-PCI patients taking both clopidogrel and a PPI vs those taking clopidogrel alone. But what they did see was that many of the patients who went on to have a MACE while taking both clopidogrel and a PPI had filled prescriptions for nitroglycerin and a first-time or alternate PPI within 30 days of their adverse event. They propose that physicians faced with a patient complaining of nonspecific chest pain or epigastric discomfort sometimes hedge their bets by prescribing both an antianginal drug and a PPI. And in some of these cases, those symptoms are a harbinger of the coming MACE. As such, PPIs aren't a causal factor but rather a marker for what they term "misindication bias."

"We just had this gut feeling, after observing how patients are put on and off PPIs, that physicians were prescribing a PPI concomitantly with antianginal drugs, because there is huge misdiagnosis of angina, which is often due to confusion with gastroesophageal reflux disease or other epigastric-discomfort–like symptoms that are treated very commonly with antacids and PPI. 30 days prior to a MACE event, rescue use of nitroglycerin was significantly higher in patients who were on a PPI vs those who are not, suggesting that these patients were having [cardiac] symptoms 30 days before their MACE events and that those symptoms were not always being recognized."

Most studies looking for an interaction between clopidogrel and PPIs have looked only at discharge medications, rather than trying to understand drug prescription and adherence patterns in the months and years postdischarge. COGENT, the only randomized clinical trial comparing the two strategies, was stopped prematurely but found no increased risk of concomitant drug use. For their study, they looked at rates of all-cause death, nonfatal MI, repeat revascularization, and MACE combined over a six-year period among 23 200 post-PCI patients, all of whom were discharged with a clopidogrel prescription. They then used pharmacy databases to gauge whether patients continued to fill their clopidogrel prescriptions over time and whether they were also getting prescriptions for PPIs and other drugs.

They report that while unadjusted analyses pointed to an increased risk of MACE among patients taking both PPIs and clopidogrel, this risk disappeared when patients were propensity-matched according to baseline risk for events. The lack of an association was seen regardless of whether patients were taking both clopidogrel and a PPI continuously or whether they stayed on clopidogrel but were switched on and off one or more PPIs. Results were similar between groups in the first year of taking both drugs and out to six years.

Strikingly, however, one-year MACE rates were significantly higher among patients prescribed "rescue-PPI" therapy (prescribed <30 days prior to a MACE). Use of rescue nitroglycerin was also twice as high among patients taking both clopidogrel and a PPI as in patients taking clopidogrel alone.

If you are taking a PPI that interferes with 2C19 activities, such as omeprazole, you are going to have a significant reduction in the generation of the active metabolite of clopidogrel as well as its pharmacodynamic effects. And the whole reason we are using clopidogrel is to achieve platelet inhibition in a high-risk patient; if we know that there are any ways that the effects of the drug could be mitigated, we are automatically putting that patient at an increased risk.

Antidepressant Use May Be Associated With Increased Risk For Stroke.

According to a study published online March 15 in the American Journal of Psychiatry, "antidepressant use may be associated with an increased risk for stroke." After analyzing data on some 24,214 stroke patients, researchers found that "antidepressant use in the two weeks before the stroke was associated with a 48% higher risk for stroke (95% confidence interval, 1.37 – 1.59)." Notably, "use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk for stroke than use of other types of antidepressants."

Drugs That Regulate Levels Of Cholesterol May Also Reduce Risk Of Clots

Drugs which can regulate levels of cholesterol in the blood may also reduce the risk of dangerous clots, say scientists.In the study, funded by the British Heart Foundation and Heart Research UK, the researchers targeted" a protein called LXR "in mice with experimental drugs." The investigators "found that the treatment allowed small clots to form but acted quickly to inhibit their formation by about 40 per cent, preventing them from blocking blood vessels and so potentially triggering a heart attack." The research is published in the journal Blood.

Antidepressants May Be Linked to Increased Stroke Risk Underlying Mechanisms Unclear, Researchers Say

Antidepressant use may be associated with an increased risk for stroke, according to new research published online March 15 in the American Journal of Psychiatry.. Depression is known to be an independent risk factor for stroke, but whether treating depression with antidepressants reverses this risk is not known. Concerns about the cerebrovascular effects of antidepressants have increased since a growing body of evidence has shown that antidepressants — particularly selective serotonin reuptake inhibitors — may induce bleeding complications and vasoconstriction of the large cerebral arteries, the study authors note.

To shed more light on whether the risk for cerebrovascular events was associated with the use of antidepressant medications, Dr. Wu and coauthors conducted a case-crossover study of 24,214 patients with stroke who were enrolled in the National Health Insurance Research Database in Taiwan from 1998 to 2007.

The analysis showed that the mean age at stroke onset was 68.6 years (SD, 12.0). Nearly half (48.3%) of the study subjects were women, 36.3% had mood disorders, and 75.9% had ischemic strokes.

Antidepressant use in the 2 weeks before the stroke was associated with a 48% higher risk for stroke (95% confidence interval, 1.37 – 1.59). However, there was no association with the number of antidepressant prescriptions in the previous year, the study authors note.In addition, there was no statistical association between antidepressant use in the 2 weeks before the stroke and stroke risk for patients with 3 to 5 prescriptions in the previous year.However, patients who had more than 6 antidepressant prescriptions had a lower stroke risk and those who had 1 or 2 prescriptions had the greater stroke risk, the study authors report.

Use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk for stroke than use of other types of antidepressants.

In addition, there are several limitations inherent in using claims databases, including an inability to accurately measure adherence. Despite these limitations, the study authors conclude that their results have major clinical and public health implications.

They recommend starting antidepressants at low doses and monitoring for adverse effects, particularly in individuals at risk for cerebrovascular events, because the stroke risk appears to be dose related and noted in the first few prescriptions.

New Blood Conservation Guidelines on Antiplatelet Therapy

The new guidelines on blood conservation in surgery incorporate recent evidence on antiplatelet therapy while continuing to emphasize the importance of preoperative risk assessment .The 2011 update to the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) blood conservation clinical practice guidelines, published in the March 2011 issue of the Annals of Thoracic Surgery, include significant changes to the societies' first set of blood conservation recommendations in 2007.

Not all patients undergoing cardiac procedures have equal risk of bleeding or blood transfusion. An important part of blood resource management is recognition of patients' risk of bleeding and subsequent blood transfusion. There is almost no evidence in the literature to stratify blood conservation interventions by patient risk category. Nonetheless, logic suggests that patients at highest risk for bleeding are most likely to benefit from the most aggressive blood management practices."

An important component of preoperative risk assessment identified in the new guidelines but not addressed in the 2007 version is the identification and management of preoperative antiplatelet drug therapy. "Persistent evidence supports the discontinuation of drugs that inhibit the P2Y12 platelet binding site before operation, but there is wide variability in patient response to drug dosage (especially with clopidogrel)," the guidelines authors explain. "Newer P2Y12 inhibitors are more potent than clopidogrel and differ in their pharmacodynamic properties. Point-of-care testing may help identify patients with incomplete drug response who can safely undergo urgent operations."

Ferraris said that the writing committee is also working on finding a better way to disseminate these guidelines and teach physicians about them beyond just publishing them in a journal. "We'd like to find a forum that isn't so cumbersome." For example, the STS and SCA may develop an iPhone application or a set of flash cards to help users learn the guidelines more easily. "One of the benefits of the guidelines is that you find out where there is a lack of evidence or gaps in the knowledge base, so guidelines serve to generate hypotheses about what needs to be done next. So somehow we need to figure out how to disseminate these more widely."

Ferraris V, Brown J, Despotis G, et al. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines. Ann Thorac Surg 2011; 91:944-82. Abstract

Apixaban Clears EU Hurdle for VTE Prevention

A new factor Xa inhibitor, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), has cleared the penultimate hurdle on the road to European formularies [1]. The product has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP), for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.A positive opinion from the CHMP is a prerequisite to pan-EU approval of a product by the European Commission, which has 67 days from the date of the opinion to grant approval.

The apixaban decision is likely based on pooled data from the ADVANCE clinical-trial program, showing that the new agent is more effective than enoxaparin (Lovenox, Sanofi-Aventis) for VTE prevention. Apixaban is one of a host of novel oral anticoagulants nearing or already on the market, hoping to replace warfarin for a variety of indications, including prevention and treatment of VTE and prophylaxis of stroke in patients with AF. Some agents are also in trials for acute coronary syndrome (ACS), but development here is a little further behind; in fact, an ACS trial with apixaban, APPRAISE-2, was stopped at the end of last year because of an unacceptable bleeding risk in the apixaban group.

Two of these new anticoagulants, another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), have been available for VTE prevention for some time in a number of countries, and dabigatran has also recently been approved for stroke prevention in AF in the US and Canada.

TRIGGER-PCI Halted: Low Events Stymie Platelet Reactivity Trial With Prasugrel, Clopidogrel

Sponsors of the TRIGGER-PCI trial announced today that they are halting the trial after a preliminary, blinded analysis of patients enrolled to date made it clear that the trial was not going to see enough primary end point events to deliver any meaningful results. TRIGGER-PCI, which was comparing clopidogrel and prasugrel (Effient, Eli Lilly/Daiichi Sankyo) based on platelet reactivity testing in stable coronary artery disease patients post-stenting, excluded patients with ACS; prasugrel is currently FDA approved for ACS patients treated with PCI. It's important to understand that there are no efficacy or safety concerns with the drug [prasugrel], These aren't the patients for whom we are labeled, [which are] ACS patients who are undergoing PCI, who are at higher risk of complications.In this ACS group,the drug has been shown to be effective, and the discontinuation of TRIGGER PCI doesn't impact those patients.

In the cohort that we chose to investigate--that is elective patients with successful PCI, excluding very old patients and patients with previous stroke--the event rate is extremely low irrespective of the response to antiplatelet therapy. Apart from the question of whether or not we could achieve statistical significance with a reasonable number of patients in this study, the question arises if the risk is so low, can you gain anything more by adding more effective antiplatelet therapy? And my impression is that, at least in this cohort . . . there is nothing much to be gained by increasing the efficacy of antiplatelet therapy."

The trial was designed to enroll 2150 patients, to be followed for six months, with a primary end point of MI or cardiovascular death. Riesmeyer explained to heartwire that the study was designed on the assumption of a 7% primary end point event rate (GRAVITAS had anticipated 5%, and saw just 2.3%). An analysis of the 432 patients enrolled to date (of whom 250 had reached the six-month mark), suggested that the projected event rate, should the trial continue, would be "even lower" than the 2.3% seen in GRAVITAS.

Both GRAVITAS and TRIGGER-PCI used the VerifyNow assay (Accumetrics, San Diego, CA), a test that has in the past been assailed as a being less sensitive than lab-based tests. And whereas GRAVITAS used an aggregation cut-off of 230 platelet reactivity units (PRU), TRIGGER-PCI enrolled patients with a PRU >208 as its definition of high platelet reactivity.the relative sensitivity of VerifyNow, and even the cut-points used, are not major points for discussion with today's announcement, since a more sensitive test or a lower cut-point would not have radically upped the number of patients in the study who went on to have events.

Another trial comparing clopidogrel and prasugrel is still ongoing, TRILOGY ACS, this one in ACS patients with either unstable angina or non-ST-elevation MI, who are being managed medically.

Stroke Risk Higher in Patients With Retinal Vein Occlusion

A new study has found that contrary to previous reports, patients with retinal vein occlusion have an almost 2-fold greater risk for stroke. The company-sponsored retrospective study included 4500 patients with retinal vein occlusion and 13,500 controls. Using a US population-based healthcare claims database, they identified patients and checked for instances of cardiovascular or cerebrovascular events.

The adjusted relative risk for myocardial infarction was 1.03 (95% confidence interval [CI], 0.75 - 1.42; P = .85). The adjusted relative risk for cerebrovascular accident was 1.72 (95% CI, 1.27 - 2.34; P = .001).

Previous studies have suggested that patients with retinal vein occlusion are not at increased risk for stroke. "In general, most of these studies were small retrospective case series in which a cohort of patients with known retinal vein occlusion was followed up for morbidity or mortality related to cerebrovascular accidents," the authors note.

Investigators conducted a similar large national database study but found an increased risk for cerebrovascular events only in patients age 60 to 69 years.Despite the conflicting evidence, her team recommends that physicians and patients continue managing modifiable risk factors.Another interesting finding is that we were able to identify differences in the risk factors for cerebrovascular accident in patients with branch and central retinal vein occlusion. These results suggest that these subtypes of retinal vein occlusion may have different clinical manifestations with separate demographics and unique predictive factors.

Arch Ophthalmol. 2011;129:326-331

Risk of Venous Thromboembolism Increased During IBD Flares

Inflammatory bowel disease (IBD) activity is an independent risk factor for venous thromboembolism (VTE). Six large studies have shown an increased risk of VTE in IBD patients relative to non-IBD patients, with odds ratios ranging from 1.48 to 3.6. Factors associated with VTEs in this patient population include increasing age, higher comorbidity scores and a diagnosis of ulcerative colitis rather than Crohn's disease, according to the report.

As for prevention, the potential benefits of anticoagulation may outweigh the risks in these patients, the team advises. The American College of Chest Physicians strongly recommends pharmacological VTE prophylaxis in acutely ill patients with IBD who are hospitalized and bedridden, and sequential compression devices for those with contraindications to anticoagulation.

But the authors note that in an ambulatory (i.e., nonhospitalized) patient with an IBD flare, the risk of VTE is less than half what it is in a hospitalized patient (6.4 vs 13.0 per thousand patient-years). Therefore, they say, even if anticoagulation cut the relative risk of VTE by half in the outpatient setting, you'd have to treat 312 patients to prevent one event.

Am J Gastroenterol 2011.

PROTECT: LMWH Not Superior to UFH in Critically Ill

A multicenter trial comparing low-molecular-weight heparin (LMWH) (dalteparin) and unfractionated heparin (UFH) to prevent proximal deep vein thrombosis, bleeding, and other outcomes in critically ill patients has found that dalteparin is not superior to unfractionated heparin .

Results of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) .

Previous studies comparing the two types of heparin for thromboprophylaxis in critically ill patients have been mixed, with one study favoring UFH over placebo, another favoring LMWH over placebo, and two direct comparisons yielding "inconclusive results," the authors note. In PROTECT, 3764 patients were randomly assigned to receive subcutaneous LMWH (5000 IU once a day) or UFH (5000 IU twice daily) with an additional placebo being given to the LMWH group to ensure blinding. Study drugs were given for the duration of the patients' time in intensive care (a median of seven days).

During this period, rates of proximal leg deep vein thrombosis were not statistically different between both groups, ranging from 5.1% to 5.8% in the LMWH and UFH groups, respectively. According to the authors, the confidence intervals around the hazard ratio for this primary end point were wide, "so it did not exclude either a 32% benefit or a 23% harm associated with dalteparin."

Rates of patients with pulmonary emboli, a secondary end point, were significantly lower in the LMWH group (1.3%) vs the UFH group (2.3%; p=0.01), as were rates (albeit rare) of heparin-induced thrombocytopenia; however, there were no differences in the rates of venous thrombosis, venous thromboembolism, major bleeding, or death. Among critically ill patients with medical or surgical admissions, dalteparin as compared with unfractionated heparin did not decrease the incidence of proximal deep vein thrombosis.

PROTECT investigators. Dalteparin vs unfractionated heparin in critically ill patients. N Engl J Med 2011; DOI:10.1056/NEJMoa1014475. Available at: http://www.nejm.org.

Adding Therapies to Aspirin Increases Risk of GI Bleeds

Doctors should take the potential gastrotoxicity of all medications into account when deciding upon antiplatelet and other therapies for patients, as well as considering the absolute risk of a gastrointestinal bleed in each individual and the absolute benefit provided by medication in each case. The use of low-dose aspirin alone was associated with an almost two-fold increase in the risk of upper GI bleeding compared with non-use, and that this risk was increased further in those taking clopidogrel, oral anticoagulants (mostly warfarin), non-steroidal anti-inflammatory drugs (NSAIDs) or high-dose oral corticosteroids.The relative risk of UGIB associated with use of low-dose aspirin (75 to 300mg/day), clopidogrel and other commonly co-administered medications was estimated by multivariate logistic regression.

The risk of UGIB was increased in current users of low-dose aspirin (RR 1.80) or clopidogrel (RR 1.67) compared with nonusers, and the combination of aspirin plus clopidogrel had a synergestic effect (RR 3.71) vs nonusers. Compared with low dose aspirin monotherapy, the risk of UGIB was significantly increased when low-dose aspirin was co-administered with clopidogrel (RR 2.08), oral anticoagulants (RR 2.00), low/medium dose NSAIDs (RR 2.63), or high-dose corticosteroids (RR 4.43). But there was no increased risk of UGIB with concomitant use of aspirin and statins (RR 0.99) or aspirin/low-dose oral corticosteroids, the researchers note (RR 1.01).

They point out that low-dose aspirin monotherapy and clopidogrel monotherapy increase the risk of UGIB to a similar extent, "which suggests that neither therapy is superior to the other in terms of their UGIB risk profile."

The particularly large increased risk of UGIB with concomitant use of low-dose aspirin and high-dose steroids "suggests that caution is warranted before prescribing such a combination of treatments," they observe, especially given that no such interaction was seen with low-dose aspirin and low/medium dose steroids.

The incidence of UGIB has been estimated to be between 0.5 and 1 per 1000 person-years in the general population,with current use of dual antiplatelet therapy in the present study [compared with no use] would "translate to an excess risk of UGIB in the order of 1.4 to 2.7 cases among 1000 exposed individuals annually.

FDA Says Bottled Dabigatran Good for 60 Days

Almost two months after heartwire first reported on the 30-day expiry date with dabigatran (Pradaxa, Boehringer Ingelheim)--and that even an investigator for the pivotal RE-LY trial was unaware of this issue--the FDA's MedWatch has issued a public alert about the drug's stability, explaining what it calls "special storage and handling requirements. Due to the potential for product breakdown from moisture and loss of potency, Pradaxa capsules should only be dispensed and stored in the original bottle or blister package.

Packaging information for Pradaxa currently advises patients to discard the drug after the bottle has been opened for 30 days. The FDA alert, however, reminds patients to open only one bottle of a time and cites a 60-day expiry date. Although the current Pradaxa label states that the product should be discarded 30 days after the original bottle is opened, data currently under review by the FDA indicate that the product maintains its potency up to 60 days after bottle opening, as long as it is stored in the original bottle and the handling requirements are met--including that the cap is closed tightly after each use and the bottle is kept away from excessive moisture, heat, and cold.

That advice is important because it's not uncommon for patients to have more than one bottle of their medication on the go at the same time--one at work and one at home, for example. Many people also like to transfer their medications into dispensers to remind them whether they've taken their drug that day. The FDA now says "the manufacturer is gathering more information on whether the product can be used after 60 days, and this information will be added to the Pradaxa label when FDA's review is complete."

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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