Optimal Heparin Dosing From ISAR-REACT 3A


Hello. I'm Dr. Melissa Walton-Shirley coming to you from Stockholm. It's Day 2 of the European Society of Cardiology (ESC) Meeting 2010. Thank you for joining me with the Day in Review.

Today, I'll be reviewing several important trials that deal with novel antiplatelet cocktails, a look at optimal heparin dosing in biomarker-negative patients, enoxaparin utilization in ST-elevation myocardial infarction (STEMI) as well as a head-to-head comparison between the Xience V® (Abbott Vascular; Santa Clara, California) and Taxus® (Boston Scientific; Natick, Massachusetts) stents. I'll also tell you what's interesting about bilateral mammary artery implants.

Let's get started with the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 3A trial presented by Dr. Stefanie Shulz of Munich. Dr. Shulz began by stating that studies looking at optimal dosing of heparin in biomarker-negative patients have not been carried out since the late 1990s. The finding of a comparable net clinical outcome with 140 units per kilogram of heparin vs bivalirudin was noted earlier in the ISAR-REACT 3 trial, but with excess bleeding in the heparin arm. The ISAR-REACT 3A, a trial also studying a biomarker-negative population, looked at 2 different arms of heparin dosing, a higher 140 U/kg dose and a lower 100 U/kg dose. The outcome demonstrated a significant reduction in the primary quadruple endpoints, which included death, myocardial infarction (MI), urgent target vessel revascularization, and major bleeding. The lower unfractionated heparin (UFH) dose at 30 days provided a better 7.3% incidence of the net clinical outcome vs the high dose at 8.7%. Specifically looking at major bleeding alone, the lower UFH dose demonstrated a better 3.6% risk of bleeding vs 4.6% in the higher dose group. Furthermore, noninferiority of the primary quadruple endpoint was demonstrated when low-dose UFH was compared with bivalirudin. The presenter concluded that reducing the heparin dose to 100 U/kg provides a net clinical benefit for biomarker-negative percutaneous coronary intervention (PCI) patients and is noninferior to results with bivalirudin.

Next, Dr. Sunil Rao from Duke University presented the INNOVATE PCI (Randomized Trial to Evaluate Intravenous and Oral PRT060128, a Selective and Reversible P2Y12-Receptor Inhibitor, as a Novel Antiplatelet Therapy in Patients Undergoing Non-Urgent Percutaneous Coronary Interventions) trial, a fascinating look at a novel intravenous (IV) and oral P2Y12 inhibitor, elinogrel, in a nonurgent PCI population. This was a randomized dose-ranging trial comparing the novel agent with clopidogrel. The patients were randomized into 2 arms: 1 received an oral clopidogrel load at either 300 or 600 mg followed by 75 mg daily. The other arms all received 80 mg of IV elinogrel, but with different oral dosing ranging from 50-150 mg orally twice daily. During the trial, the 50-mg dose was discontinued and the IV dose was increased to 120 mg on the basis of a recommendation by the Data and Safety Monitoring Committee. The study was not powered to determine efficacy, but will provide the basis for further study. The key finding presented today was that the higher the elinogrel dose, the more platelet inhibition was observed. Elinogrel appeared to be more potent than clopidogrel. Another interesting aspect revealed today was that the half-life of the novel antiplatelet agent is a short 12 hours.

Next, we have the ATOLL (Acute STEMI Treated with primary angioplasty and intravenous enoxaparin Or UFH to Lower ischemic and bleeding events at short- and Long-term follow-up) trial presented by Dr. Gilles Montalescot of Paris.This phase III randomized trial studying PCI in STEMI compared a 0.5 mg/kg dose of enoxaparin with 50-70 IU [international units] of UFH and each arm was compared with or without 2b3a inhibitors. Although the choice of arterial access technique was left to the discretion of the investigators, it is interesting that 68% of the cases were radial access cases, 75% of patients received 2b3as, and two thirds of the patients received high-dose clopidogrel. This was a high-risk population with 18% classified as elderly or older than 75 years of age and 5% presented with shock or cardiac arrest. The primary endpoint was a composite of death, complications of MI, procedural failure or non-coronary artery bypass graft (CABG) major bleeding at 30 days. The results were that although the enoxaparin arm demonstrated a reduced primary endpoint, it was not statistically significant. However, it was a much different story with the secondary endpoint. The endpoint was a classic triple ischemic composite of death, re-infarction, or urgent revascularization and was reduced by 41% by enoxaparin. The presenter's conclusion was that this strategy of enoxaparin on top of intense antiplatelet therapy is easier to use and it is also more effective at reducing the most serious complications of STEMI treated with primary PCI.

Now, let's discuss the LESSON-1 (Long-term comparison of Everolimus-eluting and Sirolimus-eluting Stents for cOronary revascularization) trial. This trial, presented by Dr. Windecker of Bern, compared 1601 patients with everolimus coding or the Xience V® stent with 1532 patients implanted with the sirolimus stent coding or the Taxus® stent. The premise of this propensity score-matched analysis is that the everolimus stent should demonstrate a decrease in in-stent thrombosis. The primary endpoint was a composite of death, heart attack, or repeat intervention. The results demonstrated that up to 3 years following the procedure, there was a 17% relative risk reduction in the Xience® stent group for the primary endpoint, but this fell short of statistical significance. The strength of the Xience® stent was most pronounced with regard to the heart attack rate, which demonstrated a significant 38% relative risk reduction with a P value of .02. The presenter stated that we may look forward to even more information on the topic at the Transcatheter Cardiovascular Therapeutics meeting 2010 as the SORT-OUT IV (Randomized Clinical Comparison of the Xience V® and the Cypher Coronary Stents in Non-selected Patients With Coronary Heart Disease) trial would be presented at that time.

Finally, we have the ART (A randomized trial to compare survival following bilateral versus single internal mammary grafting in coronary revascularization) trial, a trial randomizing patients to either bilateral mammary artery implants or single mammary artery implants. The final data reporting is set for some time in 2015, but the subject for today was the safety data for up to 1 year following randomization. The trial was presented by Dr. David Taggart of Oxford and president of the Cardiac Surgery Society in the United Kingdom. There were a few historic and demographic pieces of information that you might find interesting.

First, this is one of the largest randomized cardiac surgery trials in history, enrolling 3100 patients. We learned that less than 10% of European CABG patients and less than 5% of US patients received bilateral mammary artery implants. The patency for left internal mammary artery grafts at 10 years is 90%, whereas the saphenous vein graft patency is approximately 25%-50%, with many of the remaining grafts being diffusely diseased. There are also many reports of patent mammary artery grafts well into the third decade. An interesting point in this trial was the fact that 40% of the cases were performed off-pump, which is a large cohort of patients. The conclusion of this study was that neither risk for stroke, MI, 30-day and 1-year mortality, or the duration of stay was increased by performing a bilateral implant. At this time, a 4- to 5-year cost effectiveness and quality-of-life study is planned and in 2015, we will have our answer regarding overall mortality, patency rates, stroke, and MI in patients who receive bilateral mammary artery implants in the long-term intense study. The discussant for this trial, Dr. Kappitein from The Netherlands, noted that the crossover rate for the intended surgery was 16%. In this percentage of patients, the bilateral mammary artery implant could not be performed.

Well, that concludes our review of "What's Hot on Day 2 of the ESC" here in Stockholm. Please join me again tomorrow for the Day in Review when I'll bring you even more exciting late-breaking information in the ever-changing and fast- paced world of cardiology. Thank you.