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Learning Center
New In Coagulation
Sunday, January 3, 2010
WHAT'S NEW IN COAGULATION: January 2010
Thrombectomy Can Improve DVT, VTE Outcomes
Major changes in the most recent version of the American College of Chest Physicians (ACCP) guidelines could lead to improved outcomes for patients with extensive deep vein thrombosis (DVT). All physicians need to do is follow them, but widespread adoption of these changes will take time, venous thrombectomy is now recommended for extensive DVT [i.e., iliofemoral DVT]. Before 2008, anticoagulation was the standard of care. Thrombectomy was added to the ACCP guidelines for the treatment of extensive DVT on the basis of data from a randomized controlled trial showing that thrombectomy with arterio-venous fistula was superior to anticoagulation. Arterio-venous fistula added to thrombectomy increases the blood flow velocity after the clot is removed, reducing the likelihood of rethrombosis.
In addition, 2 randomized trials from Europe showed that catheter-directed thrombolysis of iliofemoral DVT improved patency, reflux, and length of hospital stay compared with anticoagulation.. The guidelines suggest pharmacomechanical prophylaxis instead of catheter-directed thrombolysis alone to shorten treatment time.
Smoking Interaction With Clopidogrel Seen in CHARISMA; Effects of Other Antiplatelets Unclear
More data suggesting that clopidogrel may have a greater effect in smokers than in nonsmokers have come from a new analysis of the CHARISMA study. Smoking causes increased platelet activation and that clopidogrel has been reported to result in greater inhibition of platelet aggregation in smokers than nonsmokers. In studies that assessed the variability of platelet response to clopidogrel, smokers were less likely than nonsmokers to be hyporesponders, but whether smoking affects clinical outcomes in patients receiving clopidogrel remains uncertain.
To look at this issue, they evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA trial who had established cardiovascular disease. CHARISMA compared clopidogrel 75 mg/day vs placebo long-term in patients at high risk for cardiovascular events. Results showed that after a median follow-up of 28 months, clopidogrel was not significantly more effective than placebo in reducing the rate of MI, stroke, or cardiovascular death.
Results of the present analysis showed that current smoking was associated with an increase in all-cause mortality, cardiovascular mortality, and cancer mortality compared with never smoking.
The risk of bleeding also appeared to differ according to smoking status, with clopidogrel associated with a significantly increased risk among current smokers but a smaller and nonsignificant increase among never-smokers.
Two possible reasons for the observation of an enhanced effect of clopidogrel in smokers:
- Smokers could just represent a higher-risk group. Their platelets may be more active, so they would be expected to benefit more from any antithrombotic intervention. A similar enhanced effect in smokers has also been reported with lytics and GP IIb/IIIa blockers, which gives weight to this explanation.
Smoking is known to induce the CYP1A2 enzyme that is involved in the conversion of clopidogrel to its active metabolite, and this would therefore be expected to result in increased concentrations of the active metabolite, which may translate into an increased effect on clinical events and
References
1. Berger JS, Bhatt DL, Steinhubl SR, et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120:2337-2344. Abstract
Small Trial Probes Risks, Benefits of Stopping Aspirin in CV Patients With Bleeding Ulcers
A new randomized trial--albeit a small one--suggests that continuing aspirin in patients with cardiovascular disease who develop peptic-ulcer bleeding will, not surprisingly, double their risk of bleeding but may also radically reduce their risk of all-cause mortality The increased bleeding was seen despite all patients receiving a 72-hour infusion of the proton-pump inhibitor (PPI) pantoprazole, followed by oral pantoprazole, after undergoing endoscopic therapy.
The study enrolled 156 patients already taking aspirin for secondary prevention of cardiovascular or cerebrovascular events who developed peptic-ulcer bleeding; after diagnosis and treatment (hemostasis achieved) of a bleeding ulcer, patients were randomized to receive low-dose aspirin or placebo for eight weeks. (Of note, patients taking clopidogrel were included in the study, but clopidogrel was stopped until the ulcer was completely healed.) Three patients withdrew during the course of the study.
In an intention-to-treat analysis, recurrent ulcer bleeding at 30 days--the study's primary end point--was nearly twice as high in the aspirin group as the placebo group. For the secondary end point of all-cause mortality, placebo-treated patients had a more than 10-fold increase in events, a statistically significant difference. Aspirin-treated patients also had lower rates of mortality due to cardiovascular, cerebrovascular, or gastrointestinal events.
Long-term effects of bleeding include future ischemic events and CV mortality, he added. What the study underscores is the need to evaluate patients on a case-by-case basis, he continued. Some patients on antiplatelet medication who develop bleeding may have good indications for continuing on aspirin.
"On the basis of all available data, international consensus recommendations (including the results from Sung and colleagues) concluded that patients with upper gastrointestinal bleeding who require secondary cardiovascular prophylaxis should resume low-dose aspirin therapy as soon as the cardiovascular risks outweigh the gastrointestinal risks (usually within seven days)," they note. "Until additional data become available to better guide management, clinicians will need to rely on limited evidence and appropriate use of common sense that considers the patient as a whole without focusing on a specific organ system to the detriment of another."
Author disclosures are listed in the paper.
References
1. Sung JJY, Lau JYW, Ching JYL, et al. Continuation of low-dose aspirin in peptic ulcer bleeding. Ann Intern Med 2009; available at: http://www.annals.org.
2. Barkun AN and Bardou M. Aspirin withdrawal in acute peptic ulcer bleeding: Are we harming patients? Ann Intern Med 2009; available at: http://www.annals.org.
SUBDURAL BLEEDING IN INFANTS
Nonaccidental head injury is the most common cause of subdural bleeding (SDB) in infants below 12 months of age, according to findings from an autopsy review by German investigators. 12% to 30% of infants with SDB will die as a result, and 60% to 70% of survivors will have significant neurologic deficits.
They emphasize that, "because every case of unexplained SDB in infants raises immediate concerns about the possibility of nonaccidental head injury, the differential diagnosis of SDB in infants is crucial." In recent years, however, a so-called "unified hypothesis" has "become the center of an ongoing debate" because it suggests that SDB in infants is not necessarily a result of abuse. Instead, it postulates that infants may develop SDB from a combination of severe hypoxia, brain swelling, and increased central venous pressure, which causes blood to leak into the subdural space.
In their review of autopsies performed at their hospital between 1956 and 2005, the authors found that 715 were in infants less than 1 year old, and 50 were in babies with SDB. Death was due to nonaccidental head injury in 17 cases and possibly related in two more. Fourteen had SDB.
Patients with nonaccidental head injury tended to be significantly older than patients with SDB caused by other events and patients with neither nonaccidental head injury nor SDB (mean ages 140 days vs 76 days vs 74 days, respectively).
SDB was present in 82.4% of babies with nonaccidental head injury but in only 5.2% of infants with other causes of death.
Two observations contradict the unified hypothesis -- the rarity of SDB and unexplained SDB, as well as the lack of correlation between brain weight (a marker of brain swelling) and the presence of SDB.
"If hypoxia and/or brain swelling has a possible role in the pathogenesis of infantile SDB, according to the unified hypothesis, then the incidence of SDB in infants' autopsies should be very high," the authors point out.
Pediatrics 2009;124:1587-1594.
Pradaxa may be as safe, effective as warfarin.
Bloomberg News (12/6, Kresge) reported that the "blood-thinning pill Pradaxa [dabigatran] may provide a more convenient alternative to" warfarin, "the standard therapy for potentially deadly clots," according to a study published in the New England Journal of Medicine and presented at the American Society of Hematology conference. Pradaxa "'is a far more convenient drug,' since levels in the body don't react with foods and other medicines the way warfarin does, researchers...wrote in the study." The investigators found that "Pradaxa reduced the risk of bleeding by 29 percent compared with warfarin."
MedPage Today (12/5, Gever) reported that "there were no significant differences in safety outcomes, including bleeding events, acute coronary syndrome, and abnormal liver function tests," according to the researchers.
Risk of Venous Thromboembolism Greater, Lasts Longer, Than Thought
New research in middle-aged women suggests that the risk of venous thromboembolism (VTE) after many different types of surgery is greater and lasts for longer than has previously been appreciated [1].
The findings are crucial because they show that the risk is greatest in the first six weeks following surgery, peaking around three weeks afterward. But most patients receive prophylaxis only for the duration of their hospital stay, which averages around six days. The risk of VTE also remains high for 12 months postoperatively.
National Health Service (NHS) hospital admission and death records for 947 454 middle-aged women recruited from 1996 to 2001. They excluded 207 302 women who had had surgery in the previous year or who had had a hospital admission for VTE before recruitment, history of a blood clot, or a previous cancer.During follow-up (average 6.2 years), there were 239 614 hospital admissions for surgery and 5419 admissions for VTE, and a further 270 women died from VTE. Compared with the risk without surgery, women were almost 70 times more likely (relative risk 69.1) to be admitted with VTE during the first six weeks after an inpatient operation--with the peak incidence being three weeks afterward--and almost 10 times more likely after a day case operation (RR 9.6).
The fact that day surgery was associated with an increased and prolonged risk of VTE--albeit a lesser one than that for inpatient surgery--is important because preventive treatment for thrombosis is not normally used in day surgery patients, the researchers say.
The risks were lower but still elevated seven to 12 weeks after surgery, with those women almost 20 times more likely to suffer VTE compared with those undergoing no surgery (RR 19.6). And in most cases, an increased risk remained for at least one year, the researchers note. Risk also varied considerably by type of surgery, being highest after inpatient surgery for hip or knee replacement (relative risk 220.6) and cancer (RR 91.6) within the first six weeks postoperatively. This confirms in clinical practice previous findings from clinical trials about the highest-risk surgical groups for VTE,
Dabigatran Can Replace Warfarin in Venous Thromboembolism: RECOVER
Results
The new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) could replace the older product, warfarin, say researchers presenting new data from a large clinical trial in patients with acute venous thromboembolism (the RECOVER study). The results show that dabigatran is as effective and as safe as, if not safer than, the older agent, but it also offers the advantage of a fixed dose and no need for blood monitoring, as opposed to the regular monitoring and dose adjustment needed with warfarin.
The lack of a need for monitoring would "be welcome news for both patients and their physicians.An oral agent that frees patients from these concerns about diet and drug interactions and that behaves in a predictable manner is a very positive development. These factors will simplify the use of anticoagulants, and he predicted that patient compliance and adherence to treatment will be greatly improved. Warfarin has a very narrow therapeutic index, with a small difference between the dose that is therapeutic and the dose that is toxic, there is no more dangerous drug on the market."
Third Major Indication
The use of dabigatran for venous thromboembolism, which was explored in the RECOVER study, represents a third major indication for the drug. A second similar trial, known as RECOVER-2, is underway..
Venous thromboembolism, which covers both deep vein thrombosis and pulmonary The initial indication for dabigatran, and the only one that is currently approved - but not in the United States - is for prophylaxis in orthopedic surgery patients. Dabigatran was approved for this use in Europe and Canada in 2008, on the basis of 2 large trials (the RE-MODEL study in patients undergoing total knee replacement and the RE-NOVATE study of total hip replacements), which showed that dabigatran was comparable to enoxaparin 40 mg once daily in preventing venous thromboembolism. However, a similar study conducted in North America in knee replacement (RE-MOBILIZE) used a higher dose of enoxaparin (30 mg twice daily) and showed dabigatran to be inferior, so the company did not file in the United States, Dr. Schulman explained. A new North American trial in hip replacement patients (RE-NOVATE 2) is now underway, and is using the enoxaparin 40 mg dose, he said.
The second potential indication for dabigatran is in atrial fibrillation, and highly positive results in this population were recently reported in the RE-LY study. A long-term safety follow-up study of these patients is currently underway (RELY-ABLE). The company has said that it plans to file for registration for this indication in 2010.
All of these studies have been funded by the manufacturer, Boehringer Ingelheim.
Details of RECOVER Study
The RECOVER study was conducted in 2539 patients with acute symptomatic venous thromboembolism who were randomized to 6 months of treatment with either dabigatran 150 mg twice daily or warfarin once daily, given in doses adjusted to an international normalized ratio (INR) of 2 to 3. All patients received initial treatment for 6 days with a parenteral anticoagulant (either intravenous heparin or a subcutaneous low-molecular-weight heparin derivative), to allow the dose of warfarin to be adjusted to achieve an INR of 2 to 3.
The final analysis was conducted on 1274 patients who received dabigatran and 1265 who received warfarin.
The primary end point was recurrent venous thromboembolism or fatal pulmonary embolism, which was confirmed in 2.4% of patients receiving dabigatran and 2.1% of patients receiving warfarin. There was 1 death in each treatment group. The hazard ratio was 1.1 (95% confidence interval [CI], 0.65 - 1.84), and this shows noninferiority, Dr. Schulman reported.
Major bleeding was seen in 1.6% of patients receiving dabigatran and in 1.9% of patients receiving warfarin, which is not significantly different, he said.
However, when major bleeding was combined with clinically relevant nonmajor bleeding events, there was a significant difference, with such events being confirmed in 5.6% of patients receiving dabigatran and in 8.8% patients receiving warfarin. The hazard ratio was 0.63 (95% CI, 0.47 - 0.84; P = .002).
The difference was also significant for any bleeding event, which was seen in 16.1% of patients receiving dabigatran and in 21.9% receiving warfarin. The hazard ratio for this was 0.71 (95% CI, 0.59 - 0.85; P < .001), which represents a 29% risk reduction, and this was highly significant.
Clopidogrel Resistance: Is It Just Noncompliance?
In a new paper that turns the notion of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) nonresponsiveness on its head, researchers propose that a high rate of noncompliance may explain the variability in platelet inhibition that has been associated with the drug [1].
To look at the issue of compliance in patients taking clopidogrel chronically, Serebruany et al retrospectively analyzed blood samples from 422 heart disease patients and 209 poststroke patients who had had their platelet activity tested before and after clopidogrel use in various trials. They measured levels of clopidogrel, the inactive carboxyl metabolite, and the active thiol metabolite. Clopidogrel noncompliance was defined as plasma concentration of inactive carboxyl metabolite <5000 ng/mL in any posttreatment evaluable sample after at least one month of clopidogrel maintenance therapy.
The nonactive metabolite of clopidogrel was used to evaluate compliance, as this is much more stable than the active metabolite. "We were dealing with samples from blood drawn seven or eight years ago. It is much more reliable under these conditions to test for the nonactive metabolite, as it will still be present, whereas the active metabolite is unstable and might have disappeared."
As expected, they found that of the three biomarkers assessed, only the inactive carboxyl metabolite of clopidogrel was consistently present in large quantities in the blood samples. The active thiol metabolite was mostly undetectable, whereas unchanged free clopidogrel was successfully recovered in about half of the patient samples.
Stroke Patients Had Worst Compliance
Based on the noncompliance definition, 138 patients (22%) were identified as noncompliant. There were more noncompliant subjects among poststroke victims (n=79, 38%) as compared with 59 patients with heart disease (14%).
There was a strong correlation between inhibition of platelet activity (IPA) and plasma levels of all three biomarkers indicative of clopidogrel metabolism. Low IPA in the range of −5% to 20% was consistently observed in noncompliant patients, with a strong predictive value (C statistic=0.911).
"We found that some of the patients whom we would classically describe as 'resistant' to clopidogrel, in that they showed low levels of platelet inhibition, in fact didn't actually have clopidogrel on board. Future antiplatelet trials should recognize noncompliance as a critical confounding factor, and every attempt should be made to minimize and strictly monitor prescribed antiplatelet regimens.
Once-daily dose of enoxaparin may be feasible for children at high risk of VTE.
MedPage Today (12/9, Susman) reported, "Researchers said it is feasible to provide once daily dosing of the low molecular weight heparin enoxaparin (Lovenox) to children at high risk of venous thromboembolism." The study presented at the American Society of Hematology meeting used "pharmacokinetic modeling and data from 126 children -- including neonates, infants and children -- who were administered enoxaparin off-label" to perform "pharmacokinetic analyses." The lead researcher said, "According to these results...a once-daily enoxaparin dosing regimen seems to be feasible for at least 50% of this population."
Nearly 20% of stroke survivors fail to take medications to prevent another episode.
University of California-Los Angeles researchers discovered that "about one-fifth of ischemic stroke survivors don't take medications that can reduce their risk of another stroke." According to the paper in the American Journal of Preventive Medicine, "men, older patients, and non-Hispanic patients were more likely to take blood thinners," whereas "19 percent" of the 4168 participants studied "didn't take blood thinners."
Different Antithrombotic Combinations up Risks for Bleeding and Recurrent MI
A nationwide survey of patients taking antithrombotic medications after an MI indicates that a combination of clopidogrel plus a vitamin-K antagonist (typically warfarin) or a combination of warfarin, clopidogrel, and aspirin carries a far higher risk of bleeding than aspirin alone.
Different Combinations, Different Risks
The study looked at prescription claims and bleeding events among all patients admitted for a first-time MI in Denmark between 2000 and 2005: a total of 40 813 patients. During a mean follow-up of approximately 15 months, 1852 patients (4.5% of the original group) were readmitted to the hospital with nonfatal bleeding, mostly gastrointestinal in nature; an additional 115 died from a bleeding event.
Compared with aspirin alone, rates of fatal and nonfatal bleeding were higher for clopidogrel and for any combination of antithrombotic drugs (use of a vitamin-K antagonist as monotherapy was not associated with a significant increase in bleeding, compared with aspirin). Strikingly, the risk of clopidogrel plus vitamin-K antagonist, which has in the past been recommended as a potentially safer combination than aspirin, clopidogrel, and vitamin-K antagonist, was only slightly lower than the combination of all three drugs. Risk of bleeding was amplified in older patients and in those who'd had a previous bleeding event.
The more antithrombotic treatments you receive, the greater the risk for being admitted for the bleeding diagnosis. Aspirin and clopidogrel, gave only a slightly increased risk of being admitted with a bleeding diagnosis. Other combinations such as a vitamin-K antagonist and clopidogrel, or all three drugs, carried a three to four times higher risk of being admitted to the hospital with bleeding.The study also illuminates an association of increasing concern to physicians: namely, the poorly understood link between increased risk of bleeding and higher MI rates. In their study, 37.9% of the 1852 patients with a nonfatal bleed had a subsequent MI or died over the follow-up period. That's compared with 18.4% of 38 960 patients who were not hospitalized for bleeding.
Defining the Link Between CYP2C19*2 and Clopidogrel Response
JAMA. 2009;302:849-857
Summary
The authors of this study had 3 aims: (1) to establish whether laboratory response to clopidogrel is an inherited trait; (2) to identify genetic variants that predict platelet inhibitory response to clopidogrel; and (3) to demonstrate the clinical importance of these variants by association with clinical outcomes.
First, by studying a large population of related Amish individuals, they demonstrated that laboratory response to clopidogrel is a highly heritable trait. Furthermore, the authors estimated that the genetic contribution far outweighs non genetic contributions such as age, body mass index, and lipids.
To meet their second objective, the authors used the same population to conduct a genome wide screen of more than 500,000 genetic variants and found that 1 variant, CYP2C19*2, was most closely associated with poor laboratory response to 7 days of clopidogrel dosed at 75 mg/day. Individuals carrying 2 copies of this genetic variant receive, on average, a 40% inhibition in platelet aggregation with clopidogrel. In contrast, those who do not carry this genetic variant have 65% inhibition with clopidogrel.
Finally, by genotyping a large group of patients undergoing elective percutaneous coronary intervention, the authors demonstrated that patients who carry the CYP2C19*2 variant experience a reduced platelet inhibitory response to clopidogrel and have a 3- to 4-fold increased risk for cardiovascular events in the subsequent year. Most important, the authors also demonstrated that patients were not at an increased risk for events when not treated with clopidogrel.
Celebrex may interfere with cardioprotective benefit of aspirin
The pain killer celecoxib (Celebrex) may interfere with the cardioprotective benefit of low-dose aspirin, researchers found." The researchers reported online in the Proceedings of the National Academy of Sciences that celecoxib "tightly binds to one form of Cox-1 that prevents aspirin from reaching its antiplatelet target." In addition, the researchers "confirmed that celecoxib and aspirin given together did not prevent clotting to the same degree as aspirin alone in an animal model."
Bleeding Patterns May Be Better Controlled With a 21 vs 24-Day Oral Contraceptive Pill
Cycle control may be better with a 21-day norgestimate/ethinyl estradiol 25-µg regimen vs a 24-day drospirenone/ethinyl estradiol 20-µg regimen of oral contraception, according to the results of a study by Andrew M. Kaunitz, MD, from the University of Florida College of Medicine in Jacksonville, and colleagues, reported in the December issue of Obstetrics & Gynecology.
Abnormal bleeding (breakthrough bleeding) on oral contraceptive pills (OCPs) is one of the leading reasons that women discontinue OCPs. The 24/4 design has generally (although not consistently) demonstrated better inhibition of follicular development (and endogenous estradiol production) compared to 21/7 formations. Based on this, 24/4 pills may be superior compared to 21/7 formulations in the treatment of premenstrual symptoms, acne, and dysmenorrhea.
The goal of this 3-cycle, open-label, multicenter study was to compare bleeding patterns with a 21/7-day triphasic norgestimate/ethinyl estradiol 25-µg OCP vs a 24/4-day drospirenone/ethinyl estradiol 20-µg OCP among healthy, sexually active women. To ensure balanced allocation distribution between regimens for "fresh starts" and "switchers," randomization was stratified. An interactive voice-response system allowed daily collection of bleeding data. Criteria endorsed by the 2007 US Food and Drug Administration's Reproductive Health Drug Advisory Committee were used to define bleeding.
Across the 3 cycles, there were fewer unscheduled bleeding days in the 21/7-day OCP group (n = 165) vs the 24/4-day OCP group (n = 167; mean, 4.6 vs 6.1 days; P = .003). There were significantly fewer episodes of unscheduled bleeding in women using the 21/7-day OCP vs those using the 24/4-day OCP (mean, 1.47 vs 2.01 days; P = .001), and women using the 21/7-day OCP had a significantly lower absence of scheduled bleeding at each cycle (P < .001). Tolerability was good for both regimens.
This study suggests that unscheduled bleeding is less common with 25 mcg OCs given in the 21/7 formulation compared to the 20 mcg EE/drospirenone in a 24/4 schedule, at least for the first 3 months. For women who are particularly prone to discontinuation of OCs due to any breakthrough bleeding, the 25 mcg EE/norgestimate selection may be a better first choice. An accounting of overall patient satisfaction scores between the two different formulations would be enlightening and helpful to the clinician. For instance, it is conceivable that some patients may be more willing to tolerate occasional unscheduled bleeding if premenstrual symptoms were improved with the 24/4 20 mcg EE/drospirenone pill compared to the 21/7 25 mcg EE/norgestimate brand.
ERASE-MI: Initial Results With Elinogrel--A New IV/Oral P2Y12 Antiplatel
Initial phase 2 results with a new antiplatelet agent that has both intravenous and oral formulations have been published The agent, elinogrel (Portola Pharmaceuticals), is a P2Y12 ADP-receptor antagonist similar to clopidogrel, but it is the first agent in this class to be developed in both intravenous and oral formulations, which will give it an advantage, particularly when being used acutely in the cath lab.The current phase 2 study, ERASE-MI, published in the December 2009 issue of the American Heart Journal, was conducted by a team led by Dr Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).
The second author of the paper, Dr Matthew Roe (Duke Clinical Research Institute), explained to heartwire that an intravenous agent would give immediate platelet inhibition. "This would be great for use acutely, particularly in urgent PCI," he noted. He added that the P2Y12 antagonists currently available come only as oral formulations and take a couple of hours to reach maximal platelet inhibition. The first intravenous agent to be developed, cangrelor, was tested in the CHAMPION trials, which were presented at last month's American Heart Association meeting, as reported by heartwire . In these trials, cangrelor did inhibit platelet activity more effectively than clopidogrel, but this was not translated into a reduction of the primary end point. Many possible reasons for this anomaly were suggested.
One of the reasons put forward was that there might have been some interaction between cangrelor and clopidogrel when transitioning patients from the intravenous drug to the oral drug. An agent that is available as both intravenous and oral formulations, such as elinogrel, would therefore alleviate any concerns about possible interactions between different agents when transitioning from the IV to oral products.
In the ERASE-MI trial, 70 STEMI patients were randomized to one of four doses of elinogrel or placebo before the start of the diagnostic angiogram preceding primary PCI. All patients also received a 600 mg clopidogrel loading dose, followed by a 300 mg clopidogrel loading dose four hours after PCI.
Results showed that the incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel and in those treated with placebo. No differences were demonstrated between elinogrel and placebo in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count, or ST resolution.
A second part of the trial was planned as a dose-confirmation study using the highest tolerated dose from the first part of the study. Although no safety issues emerged in the first part, the trial was prematurely terminated after its completion by the sponsor, so the dose-confirmation part was not conducted.
Roe told heartwire that the company had decided not to continue with the ERASE-MI study because it was instead going ahead with a different phase 2 study with a new design. ERASE-MI was evaluating the intravenous formulation of elinogrel only and the transitioning of patients onto oral clopidogrel, but the new trial, INNOVATE, will evaluate the use of both the intravenous and oral formulations of elinogrel.
The authors conclude: "Given the unique properties and dual formulations of elinogrel, this novel P2Y12 ADP-receptor antagonist may have broad applications for patients with acute myocardial infarction, those undergoing PCI, and other patient groups typically treated with P2Y12 inhibitors."
The ERASE-MI study was funded by Portola Pharmaceuticals.
References
1. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009; 158:998-1004.e1. Abstract
Low-Dose Aspirin During Pregnancy Has No Adverse Impact on Preterm Infants
Preterm infants whose mothers took low-dose aspirin (LDA) exhibit no negative long-term effects and may have fewer neurobehavioral difficulties as children, according to a study published online December 21 in Pediatrics.
Aspirin is well tolerated by the fetus and seems to produce a moderate reduction of several different risks (preeclampsia, delivery before 37 weeks of gestation, and fetal growth restriction) without increasing infant bleeding, To determine the effects of LDA on preterm children, researchers studied 656 children born in France in 1997 before 33 weeks' gestation. Newborn data were gathered from the Etude Epidemiologique des Petites Ages Gestationnels (EPIPAGE) cohort study, which primarily measured mortality and cerebral lesions. Obstetric records confirmed LDA intake. After 5 years, the investigators examined the children for incidence of cerebral palsy, behavioral issues, and cognitive ability.Researchers concluded there was no significant relationship between LDA and any long-term outcome. Furthermore, they reported an association of LDA with a decrease in behavioral difficulties.
The cerebral palsy rate at 5 years of age did not differ according to LDA treatment nor did the rate of low MPC [mental processing composite] or low sequential processing scores (<70). The rate of simultaneous processing scores of <70 was significantly lower in the LDA group than in the no-LDA group (7% vs 19%; P = .04), but not after adjustment for PS [propensity score], prognostic factors, and social class (adjusted odds ratio [aOR]: 0.59 [95% confidence interval (CI): 0.17-2.06]). Results showed a reduction at the limit of significance in total behavioral difficulties (aOR: 0.44 [95% CI: 0.19-1.02]) and hyperactivity (aOR: 0.43 [95% CI: 0.17-1.05]) associated with LDA treatment after adjustment for PS and prognostic factors.
The study authors acknowledged several limitations, including the fact that 25% of the children were not evaluated as 5-year-olds. They also stated that the rate of loss to follow-up was higher in the control group vs the LDA faction, which "may have resulted in an underestimation of neurodevelopmental impairments in the no-LDA group.
Pediatrics. Published online December 21, 2009.
Optimal Duration of Dual Antiplatelet Therapy After DES: 12 Months, But More Data Coming
A review paper published in the December 2009 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions tackles the issue of the optimal duration of dual antiplatelet therapy following drug-eluting stent (DES) implantation, and while the authors are reluctant to prescribe a one-size-fits-all approach, the currently recommended 12 months of therapy is the right option.
Clinical trials are lacking, more data are coming, with numerous ongoing studies addressing different durations of dual antiplatelet therapy. In the meantime, "the take-home message is that we need to comply with the guidelines; whether we agree or disagree with them.
The evidence examining the relationship between dual antiplatelet therapy and stent thrombosis, noting that the strongest predictor of stent thrombosis is stopping thienopyridine therapy within six months of stent implantation. Observational studies have also shown that extending dual antiplatelet therapy from six to 12 months was not associated with reductions in late or very late stent thrombosis. If treatment extends beyond 12 months, clinicians should realize they are treating systemic disease rather than issues related to the stent implantation.
The largest of the studies is the Dual Antiplatelet Therapy (DAPT) study, a 20 000-patient, $100-million, multisponsor randomized clinical trial testing optimal duration of dual antiplatelet therapy following stent implantation. DAPT is comparing 12 vs 30 months of dual antiplatelet therapy among 15 000 patients who have been treated with a drug-eluting stent, powered to assess the primary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety end point for DAPT is major bleeding. An additional 5000 patients treated with bare-metal stents will also be enrolled.
The ISAR-SAFE study, a 6000-patient study, is testing dual antiplatelet durations of six months vs 12 months in patients treated with a drug-eluting stent. The primary end point is death, MI, stroke, and TIMI major bleeding at 15 months.
References
1. Kandzari DE, Angiolillo DJ, Price MJ, Teirstein PS. Identifying the "optimal" duration of dual antiplatelet therapy after drug-eluting stent revascularization. J Am Coll Cardiol Cardiovasc Intervent 2009; 2:1279-1285.
Donna Castellone
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Donna Castellone,
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