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Learning CenterNew In CoagulationMonday, October 3, 2011
WHAT'S NEW IN COAGULATION: OCTOBER 2011ARISTOTLE Results: Apixaban Lowers Stroke Risk, Increases Survival In Afib Patients.An experimental drug designed to "prevent blood clots exceeded already high expectations as a better therapy for millions of people with atrial fibrillation according to final results of the ARISTOTLE trial presented Sunday at the European Society of Cardiology congress in Paris. Over an average "1.8 years," Eliquis prevented "21 percent more strokes" than the blood-thinner warfarin, which is the "standard treatment for heart arrhythmia. and- will be submitted for FDA review later this year. Eliquis also reduced the number of major bleeding incidents among the study patients by 31%; and it lowered their mortality risk by 11%. Notably, severe bleeding is one of the adverse events associated with warfarin. Analysts are predicting Eliquis will "lead the market for stroke-preventing blood thinners" because of the "'best-in-class' clinical trial results that marry safety with effectiveness. ARISTOTLE: A Major Win for Apixaban in AFAlthough the ARISTOTLE results were very good, apixaban did not show a reduction in ischemic stroke, whereas the 150-mg dabigatran dose in RE-LY did. He said he would position the ARISTOTLE result "somewhere in between the two doses of dabigatran in RE-LY." The ARISTOTLE trial randomized 18 201 AF patients to apixaban (5 mg orally twice daily) or warfarin (target INR of 2.0 to 3.0). After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk of stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality. Combining the Advantages of Both Dabigatran Doses Noting that the 150-mg twice-daily dose of dabigatran showed a reduction in stroke but a similar rate of bleeding (and an increase in GI bleeding) vs warfarin in the RE-LY trial, whereas the 110-mg twice-daily dose of dabigatran showed a similar stroke rate to warfarin with reduced bleeding, Granger commented to heartwire : "Apixaban appears to combine the advantages of both doses of dabigatran, with greater reductions in both stroke and bleeding (including GI bleeding) than warfarin." The MI data are also reassuring in ARISTOTLE. There was some concern raised about a possible increase in MI rate with dabigatran vs warfarin in RE-LY, but this was not seen in ARISTOTLE. Granger said: "The MI issue with dabigatran was never a particular concern for me, as warfarin is very effective at reducing MI, but we were pleased to see a lower numerical rate with apixaban than with warfarin in ARISTOTLE." The higher dabigatran dose gave the best results, because of the reduction in ischemic stroke. "With this, we are trading a reduction in ischemic stroke for an increase in GI bleeding, so it would probably depend on the profile of the patient which drug I would choose. What About Rivaroxaban? Meanwhile, rivaroxaban was shown to be noninferior to warfarin in preventing stroke, but the superiority analysis drew questions when, in the intention-to-treat group, the drug failed to demonstrate superiority, statistically, over warfarin, although rivaroxaban was statistically superior in an "as-treated" analysis. Moreover, in ROCKET AF, intracranial and fatal bleeding was lower with rivaroxaban, while other major bleeding was similar to warfarin. Once- vs Twice-Daily Dosing Rivaroxaban does, however, have the advantage over the other two drugs of being the only one with a once-daily dosing regimen, a factor that is considered important in boosting compliance. There are now potentially three new drugs and five well-done clinical trials. The totality of the data is strikingly consistent across the trials, with reductions in stroke and non-[central nervous system] CNS embolism and significant reductions in intracranial hemorrhage and fatal bleeding. While indirect comparisons will be made across the three agents, until we have direct comparisons with randomized trials, the decision about which specific agent to use will need to be made by individual physicians and patients based on applicability of the specific trial findings and preferences. Replacing Warfarin Addressing the question of whether these new oral agents will completely replace warfarin, they overcome the need for monitoring with warfarin and have shown encouraging results in many different subgroups, but "switching to a newer agent may not be necessary for the individual patient in whom the INR has been well controlled with warfarin for years. The superior data for these new drugs presents a challenge for anyone to continue on warfarin. "The one issue that might prevent people from switching is cost. These new drugs will be much more expensive. And I think if we have to make decisions on whom to give these new drugs to, we will start first with new patients and switch over those not managing well on warfarin.” So far, dabigatran is the only one of the new oral agents to be approved for the AF indication, but its uptake has been slower than expected, with one estimate that it has only 6% of market share. ACOG Issues Guidelines to Prevent Thromboembolic EventsAll women undergoing cesarean delivery should undergo thromboembolism prophylaxis at the time of delivery, according to an American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin published in the September 2011 issue of Obstetrics & Gynecology. The new bulletin, entitled "Thromboembolism in Pregnancy," aims to summarize evidence and recommendations regarding risk factors, diagnosis, management, and prevention of thromboembolism, especially venous thromboembolism (VTE), in pregnancy. "VTE is a major contributor to maternal mortality in this country. The risk of VTE is increased during pregnancy and the consequences can be severe. The recommendations explain how to monitor women for these events, address certain risk factors, and treat suspected or acute cases of VTE. It's important for ob-gyns to adopt these recommendations to help reduce maternal deaths. Compared with nonpregnant women, pregnant women have a 4-fold to 5-fold increased risk for thromboembolism. About 80% of thromboembolic events during pregnancy are venous, with pulmonary embolism and other VTE responsible for 1.1 deaths per 100,000 deliveries, or 9% of all maternal deaths in the United States. In the developing world, the leading cause of maternal death is hemorrhage; however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death. The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. Physiologic and anatomic changes during pregnancy increase the risk for thromboembolism. Hypercoagulability, increased venous stasis, decreased venous outflow, uterine compression of the inferior vena cava and pelvic veins, reduced mobility, and changes in levels of coagulation factors normally regulating hemostasis all result in an increased thrombogenic state. Risk for deep vein thrombosis during pregnancy is greatest in the left lower extremity.Other risk factors for VTE unrelated to pregnancy include a personal history of VTE, thrombophilia, obesity, hypertension, and smoking. The only specific Level A ACOG recommendation (based on good and consistent scientific evidence) is that compression ultrasonography of the proximal veins is the recommended initial diagnostic test when signs or symptoms suggest new onset deep vein thrombosis. ACOG Recommendations Level B ACOG recommendations and conclusions (based on limited or inconsistent scientific evidence) include the following:
Level C ACOG recommendations (based primarily on consensus and expert opinion) include the following:
Studies Confirm Safety, Efficacy Of Xience.Two studies confirmed the safety and efficacy of second and third generation drug-eluting stents, particularly in the setting of ST-elevation myocardial infarction (STEMI), but the Xience (everolimus-eluting) stent failed to best a bare-metal comparator in hard clinical endpoints, researchers reported. In the EXAMINATION trial, "the Xience (everolimus-eluting) stent had significantly lower rates of definite and definite/probable stent thrombosis at one year compared with a bare-metal stent." In the other "study -- the Bern-Rotterdam Cohort study -- the Xience stent had a 1.4% stent thrombosis rate at four years, compared with two first-generation drug-eluting stents." Many Afib Patients Not Being Prescribed Anticoagulants.A first look at a massive international registry of treatment for atrial fibrillation indicates that a high percentage of individuals are not being prescribed anticoagulation treatment that can reduce their risk of stroke. Of the nearly 10,000 patients in the initial cohort of the Global Anticoagulant Registry in the Field (Garfield), CHADS2 scoring showed 55% of them to be eligible for anticoagulation therapy, but 33% of them didn't get it." Guidelines call for treatment with anticoagulation to prevent strokes in patients with CHADS2 scores of 2 or higher." FDA Staff Recommends Against Approving Xarelto For Preventing Strokes In Afib.The Food and Drug Administration staff have recommended that Xarelto (rivaroxaban) not be approved to prevent strokes in individuals with the heart condition known as atrial fibrillation. The FDA reviewers said the crucial clinical trial did not prove it was as good as warfarin. The report adds that there are several reasons to deny the makers' request to include a claim in the detailed package insert that Xarelto is superior to warfarin. Among the reasons, it says such a claim 'might induce physicians to switch patients who are doing well on warfarin.' FDA Advisory Panel Recommends Rivaroxaban Be Approved To Prevent Stroke.An FDA advisory panel has recommended that Xarelto (rivaroxaban) be approved to prevent stroke in patients with atrial fibrillation. The "vote came two days after F.D.A. staff recommended against approving Xarelto, saying it had not been proven to be as effective as warfarin. Detection and Localization of Peripheral Vascular Bleeding Using Doppler UltrasoundHemorrhage from wounds in the extremities is the leading cause of preventable death on the battlefield. To successfully treat these injuries, the exact source of bleeding must be localized. Objective: The purpose of this study was to determine the feasibility of using Doppler ultrasound to precisely detect and localize peripheral vascular bleeding. Methods: Injuries were produced in common femoral arteries (diameter of ~5 mm) of 28 pigs in vivo. Single puncture injuries were produced using 6 French (F) (n = 10), 9 F (n = 22), and 12 F (n = 12) catheters. In addition, multiple punctures were made (using 6 F and 9 F catheters) in eight common femoral arteries to simulate bleeding from multiple injuries. Finally, laceration injuries were produced using a scalpel in 10 femoral vessels. Results: In color Doppler images, bleeding was observed as a turbulent jet flow originating from the injury site in the vessel. This jet flow had checkered red-blue color pattern at the bleeding site, as opposed to a uniform color pattern in an intact artery. Peak systolic velocity at the injury site, measured using pulsed Doppler, was elevated to up to 152.0 ± 81.6 cm/s, as compared to 78.8 ± 17.5 cm/s in normal arteries. Further, end diastolic velocity increased from 6.1 ± 4.9 cm/s before the injury to up to 59.1 ± 33.1 cm/s after the injury. Resistance index was significantly lower (0.6 for 9 F and 12 F punctures, and 0.8 for 6 F punctures) at the bleeding site in injured arteries as compared to the resistance index of intact arteries (of 0.9). Conclusion: Our results showed a characteristic change in the systolic and diastolic velocities, as well as resistance indices at the injury site in peripheral arteries. These findings may serve as groundwork for development of automated bleeding detection and localization methods, and facilitate various hemorrhage control treatments. Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin TherapyThe literature suggesting a relevant interaction between acetaminophen and warfarin is inconsistent. Considering the ubiquitous use of acetaminophen, a review of the effects on international normalized ratio (INR) in patients taking warfarin was necessary. Thus, we performed a search of the PubMed (1966–November 2010) and International Pharmaceutical Abstracts (1970–November 2010) databases to review the available literature addressing an acetaminophen-warfarin interaction and its possible mechanisms. A sample of case reports, in addition to all English-language studies were evaluated, and relevant references were examined for additional articles. Reports of nonwarfarin coumarin anticoagulants were excluded. Published documentation reporting an interaction between acetaminophen and warfarin is limited. Small prospective studies of various designs and case studies describe aberrant INR results in patients using acetaminophen while receiving warfarin. These INR elevations typically involved acetaminophen ingestion of at least 2 g/day for several consecutive days. In several small prospective studies, INR results were elevated to a statistically significant extent that would require a change in warfarin dosing and monitoring in clinical practice. The mechanism for this interaction remains to be elucidated yet is suggested to occur through alterations in hepatic metabolism. The use of moderate-to-high doses of acetaminophen while receiving warfarin results in supratherapeutic INRs in some patients. The characteristics that may predispose a patient to this interaction are unclear, yet the widespread use of acetaminophen calls for enhanced clinician awareness and reinforcement of patient education about this interaction. Study Finds Statins Do Not Increase Risk Of Hemorrhagic Stroke.Researchers in Canada reviewed a large patient database to compare people who had an ischemic stroke and received statins to those who did not," and "found no significant difference in the two groups regarding the rates of hemorrhagic stroke." The story notes that an accompanying editorial to the study pointed out that "other studies have suggested that statin use does increase the risk of brain bleeding," so that "people at higher risk of a brain hemorrhage may want to avoid statins New Guidelines: Hs-Troponin, Ticagrelor in; Clopidogrel OutThe European task force for the management of ACS patients presenting with non-STEMI has released new guidelines here at the European Society of Cardiology (ESC) 2011 Congress [1]. The guidelines update a previous version issued in 2007, and according to members of the writing group, contain a number of important new recommendations. High-Sensitivity Troponin and CT Angiography The guidelines recommend the use of high-sensitivity (hs) troponin assays: a rapid rule-out protocol (within zero to three hours of symptoms) using hs-troponin is given a class Ib recommendation in the new guidelines. They also, for the first time, support a role for coronary CT angiography (CTA) as an alternative to invasive angiography to exclude ACS in patients with a low to intermediate likelihood of CAD, when both troponin tests and an ECG are inconclusive (class IIa, level of recommendation B). Prasugrel and Ticagrelor Whereas the ACC/AHA guidelines earlier this year included the newer antiplatelet agent prasugrel (Effient, Lilly), the European guidelines make space for both prasugrel and the new, reversible, P2Y12 inhibitor ticagrelor (Brilique, AstraZeneca). Of note, clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is now recommended only for patients who cannot take ticagrelor or prasugrel (class Ia).A proton-pump inhibitor (but "preferably not omeprazole") is recommended for patients taking dual antiplatelet therapy with a history of gastrointestinal bleeding or ulcer and "is appropriate" for patients with multiple risk factors for a GI bleed, the new guidelines say. Finally, the European guidelines also stress the need for physicians to keep tabs on just how well they are actually adhering to evidence-based guidance. "Continuous monitoring of performance indicators is strongly encouraged to enhance the quality of treatment and minimize unwarranted variations in evidence-based care. FDA Will Argue Against Rivaroxaban Approval for AF IndicationThe Food and Drug Administration (FDA) will recommend against approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in atrial-fibrillation patients. The critical FDA review states the drug should not be approved because "there is a lack of substantial evidence that rivaroxaban will have its desired effect when used as recommended in labeling." Specifically, the agency review is concerned about dosing in the warfarin arm of ROCKET-AF, the large clinical trial showing that rivaroxaban was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non–central nervous system (CNS) embolism. The FDA is concerned because the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), the time spent at the optimal international normalized ratio (INR), which was lower than in other trials with warfarin. According to the FDA, any study testing a new anticoagulant that protects atrial-fibrillation patients from the risk of thrombotic events must show that the "new therapy . . . be as effective as an approved therapy when the approved-therapy drug is used skillfully." This is a requirement based on an FDA policy for drugs for conditions that are "life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack). Rivaroxaban is currently approved by the FDA for prevention of deep venous thrombosis in the setting of knee- or hip-replacement surgery. In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, a study of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs warfarin for stroke prevention in patients with atrial fibrillation, the average TTR was 64% and the median TTR 67%. Last October, the FDA voted to approve dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug is available in two doses, 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily. In the review, the FDA states that patients might be at a higher risk of harm from stroke and/or bleeding than those taking warfarin at therapeutic doses. For this reason, the review recommends that rivaroxaban not be approved until Bayer/Johnson & Johnson provide more data showing that it is as safe and effective as warfarin in a subgroup of patients where the TTR is greater than 67%. That said, the review also notes that if clinicians are in need of an additional oral anticoagulant, it might make sense to approve rivaroxaban as a second- or third-line agent in atrial fibrillation. When the ROCKET-AF study was presented, and reported by heartwire at that time, study investigators pointed out that the patients in ROCKET-AF were fairly sick, with 90% of patients hypertensive, 62% having congestive heart failure, and 55% having a prior history of stroke, transient ischemic attack, or non-CNS systemic embolism. In addition, 90% of the patients had a CHADS2 score of 3 or higher, much higher than scores of patients enrolled in comparable studies, and because of these factors, the INR might have been more difficult to manage, said investigators. In addition to concerns about warfarin dosing, the FDA review questions the 20-mg once-daily dosing of rivaroxaban, saying the evidence supporting the rationale for evaluating the dose is not strong. In addition, the FDA is troubled by the rebound effect that occurs when patients stop taking rivaroxaban and the sponsor's proposed label instructions for the transition from rivaroxaban to warfarin. The review notes there were an excessive number of strokes in the rivaroxaban arm when the patients were transitioned from the blinded study drug to warfarin at the end of the study, an increased risk that was likely the result of the study design. At the completion of ROCKET-AF, the blinded study medication was stopped and patients were transitioned to alternative anticoagulant therapy, usually warfarin. However, unlike RE-LY and other studies, patients did not undergo a short-term period of dual anticoagulant therapy--rivaroxaban and warfarin--during the lag period of INR control at the beginning of warfarin therapy. Rivaroxaban has a half-life of six to eight hours, so that a patient starting warfarin the day after rivaroxaban was stopped would not receive adequate anticoagulation for about five days, assuming it would take five days to reach an INR of 2.0. As a result, there were significantly more strokes in the rivaroxaban study arm compared with warfarin--22 vs six events--from the end of the on-treatment period to day 30, with most events occurring early.Bayer/Johnson & Johnson are proposing labeling instructions to assist physicians with the transition from rivaroxaban to warfarin, calling for a period of dual therapy with warfarin and rivaroxaban until the INR is under control. However, the FDA review notes that the recommendations are based on pharmacokinetic and pharmacodynamic modeling and have not been tested in studies. Twice-Daily Aspirin Betters Platelet Inhibition in DiabeticsTwice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity, and might enhance cardiovascular protection, according to an Italian group here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting. Aspirin is currently recommended for cardiovascular protection in patients with type 2 diabetes mellitus, but primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B2, the hydrolysis product of thromboxane A2 and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients had 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily, 200 mg daily, or 100 mg twice daily for 28 days. Recovery of COX-1 activity was then determined on day 29 during the 12 to 24 hour dosing period. The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. Independent predictors of the slope of thromboxane B2 recovery were mean platelet volume, higher body mass index, and age. None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B2. In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. The researchers conclude that neither 24-hour glucose control nor other glycemic indices affected the recovery rate of platelet COX-1 activity. They surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Twice-daily aspirin administration can overcome the inadequate thromboxane inhibition seen with once-daily dosing. NICE Approves Final Ticagrelor Guidance.The UK National Institute for Health and Clinical Excellence (NICE) has issued its final guidance on the new antiplatelet agent ticagrelor (Brilique, AstraZeneca), endorsing its use in combination with aspirin for up to 12 months as an option to treat adults with acute coronary syndromes." Although ticagrelor was "technically approved for use in the UK prior to this decision -- because it was cleared for marketing through the European Union's central process -- NICE endorsement dictates use of the drug in England and Wales." Moreover, considering that many "other countries pay heed to NICE guidance," the endorsement may have an expanded effect. Novel Drug May Reduce Blood Clots In Patients Undergoing Joint Replacements.The UK's Daily Telegraph reported that apixaban, which Bristol-Myers Squibb and Pfizer "have been working since 2007 to develop," represents a "new option in clot prevention for UK surgeons." Clinical trials "involving more than 8,000 patients, all of whom had undergone planned hip or knee replacement surgery, found that it reduced the risk of blood clots while not putting them at greater risk of bleeding. ... 'Blood clots are responsible for around 25,000 preventable deaths in the UK annually and preventing them following, for example, major joint surgery, is a priority for the NHS. EMA Committee Recommends Rivaroxaban For Clots In Legs Or Lungs.Bayer AG (BAYN)'s Xarelto [rivaroxaban] won the backing of" the European Medicines Agency's Committee for Medicinal Products for Human Use "for use in irregular-heartbeat patients." It "also recommended Xarelto to treat deep vein thrombosis, or clots in the legs or lungs." The company said that it "expects a decision from the European Commission during the fourth quarter FDA Concerned By Higher Risk Of Blood Clots In Women Using Drospirenone.The Food and Drug Administration said preliminary results of an agency-funded study show women using Yaz and other birth control pills with the synthetic hormone drospirenone face ... a 1 1⁄2 times greater risk of experiencing" blood clots "compared with women using other, older birth control pills," according to study of "800,000 women in the US." The FDA announced that it "has not yet reached a conclusion, but remains concerned, about the potential increased risk of blood clots for women who use drospirenone-containing birth control pills. All birth control pills come with an increased risk of blood clotting and says that the FDA found differing risks identified by different studies. Bayer, which sells drospirenone, says the risk is similar to that of other oral contraceptives. The risk to any one woman remains small: overall, the risk of a VTE is about six women per 10,000 users for the older contraceptives versus 10 per 10,000 using the newer versions. Rivaroxaban: CHMP Recommends New AF, DVT IndicationsAdvisors for the European Medicines Agency (EMA) have paved the way for two new indications for rivaroxaban (Xarelto, Bayer) in Europe. The EMA's Committee for Medicinal Products for Human Use (CHMP) issued two "positive opinions" for the oral factor Xa inhibitor yesterday: one in the setting of the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation (AF), and two, for the treatment of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) [1]. A 10-mg dose of rivaroxaban was already approved in the EU for the prevention of VTE in adults undergoing hip and knee replacement surgery. The latest CHMP recommendation is for two new indications for the 15-mg and 20-mg tablets:
The CHMP recommendation to approve rivaroxaban for stroke prevention in AF is based on the results of ROCKET AF, while the positive recommendation for the DVT/PE indication comes from the EINSTEIN-DVT and EINSTEIN-Extension studies. Earlier this month, the US Food and Drug Administration's (FDA’s) Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2, with one abstention, in favor of recommending the approval of rivaroxaban for the prevention of stroke in patients with AF, although FDA staff reviewers had been less convinced by the data. A number of other oral anticoagulants have also been approved or recommended for approval in Europe for one or more of these three indications, including apixaban and dabigatran. Another direct factor Xa inhibitor, edoxaban, was approved in Japan earlier this year for the prevention of VTE following orthopedic surgery. 600-mg Clopidogrel Loading Dose in STEMI Still SuperiorThe first prospective, randomized study to compare a 600-mg loading dose of clopidogrel with a 300-mg dose in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI has shown that those treated with the higher dose had a smaller infarct size and greater improvements in other outcomes with, importantly, no increase in bleeding, compared with those who received the lower dose [1]. The findings confirm that the 600-mg loading dose is preferable in this setting and show that "clopidogrel is still a good drug, at the right dose, for the right patient. The results from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Myocardial Infarction (ARMYDA-6 MI) study. Clopidogrel costs less, it's more available, people have more experience with it, and the bleeding profile is better. The latter is important because bleeding has a negative prognosis, even long-term, so this is a very important issue. Our results confirm you can give a higher loading dose of clopidogrel without complications. Although this is a small randomized trial, it's still proof of concept, and it's about time that we can write this in stone that, indeed, 600-mg loading dose of clopidogrel is better than 300 mg in STEMI patients. Operators should feel very comfortable about this." New Guidelines Recommend 600-mg Clopidogrel and Newer Agents In the paper, the researchers note that the latest European guidelines on myocardial revascularization [2] do recommend the 600-mg loading dose of clopidogrel over 300 mg in the context of primary PCI for STEMI, but with a class I level C recommendation, given the absence of randomized studies. A post hoc analysis of the HORIZONS-AMI study provides support for the 600-mg dose, as do prior observational data. In contrast, in the guidelines newer antiplatelet agents, prasugrel (Effient/Efient, Eli Lilly/Daiichi Sankyo) and ticagrelor (Brilique, AstraZeneca), received a higher recommendation (class I, level B) for use in STEMI patients undergoing PCI, but, points out Di Sciascio, "clopidogrel is still widely used, especially in the presence of high bleeding-risk features, such as . . . GI or genitourinary lesions, older age, low body weight, and previous stroke, or for cost reasons." In ARMYDA-6, 201 patients were randomized--within 12 hours of an acute MI who were slated for primary PCI at five European hospitals--to a loading dose of clopidogrel of 600 mg (n=103) or 300 mg (n=98). PCI was performed according to standard procedure (GP IIb/IIIa inhibitors at the physician's discretion). All patients went on to receive aspirin 100 mg/day and clopidogrel 75 mg/day after their procedure. The primary study end point was infarct size, and secondary outcomes included TIMI flow pre- and post-PCI, left ventricular ejection fraction (LVEF) at discharge, 30-day major adverse coronary events (MACE), and bleeding complications. Infarct size was significantly lower in the high-dose clopidogrel group, as measured by median creatinine kinase-myocardial band (CK-MB) and troponin I. Secondary outcomes also improved. Of note, there was no increase in bleeding/entry-site complications with the higher loading dose compared with the lower one. The lower incidence of MACE at one month and improvements in angiographic results, infarct size, and cardiac function in the high-dose clopidogrel arm need to be confirmed in larger randomized studies, as does any future impact on survival, the researchers say. Strong Rationale for Aggressive Antiplatelet Strategy in STEMI They note that there is a "strong rationale" for using an "aggressive" antiplatelet strategy in patients with STEMI undergoing primary PCI, because a correlation between platelet reactivity and extent of myocardial necrosis has been demonstrated, and platelet reactivity on admission predicts the rate of MACE during follow-up. However, it is not always possible to use the newer, more potent agents such as prasugrel and ticagrelor, says Di Sciascio, either for economic reasons or because these agents can increase bleeding. And often, when patients come to the lab in the midst of an acute MI, "there is not time to assess whether the patient has a high bleeding risk or not," he explained. In these situations, a 600-mg loading dose of clopidogrel is a good choice of therapy, he said, noting that 300 mg "would not even have time to work, since these patients go immediately into the cath lab." Beware Bleeding With SSRIs and AntiplateletsSelective serotonin-reuptake inhibitor (SSRI) antidepressants appear to increase the risk of bleeding in patients taking antiplatelet agents following an MI, a new study suggests [1]. While the mechanism is not completely clear, it is thought that blockade of serotonin reuptake into platelets somehow causes the platelets to become less reactive. Doctors prescribing either antiplatelet agents or antidepressants need to be aware of this interaction with SSRIs and try to balance the increased bleeding risk with the risk of depression. Of the 27 058 patients included, 14 426 were taking aspirin alone; 2467 were on clopidogrel alone; 9475 were on both aspirin and clopidogrel; 406 were taking aspirin and an SSRI; 239 were taking aspirin, clopidogrel, and an SSRI; and 45 were taking clopidogrel and an SSRI. Results showed that after adjustment for baseline demographics, adding an SSRI to aspirin increased bleeding risk by 42% and adding an SSRI to dual antiplatelet therapy increased bleeding risk by 57%; both these increases reached statistical significance. There were not enough patients taking the combination of clopidogrel plus an SSRI for a meaningful result, but the bleeding risk was still numerically higher in those taking both drugs compared with clopidogrel alone. The researchers did not find any difference in bleeding risk with individual SSRIs. Donna Castellone
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