Christopher P. Cannon, MD, is an Associate Professor of Medicine at Harvard Medical School and an Associate Physician in the Cardiovascular Division at Brigham and Women’s Hospital in Boston, Massachusetts.
A Fellow of the American Heart Association (AHA) and American College of Cardiology (ACC), Dr Cannon is Chairman of the Get With the Guidelines Science Subcommittee for the AHA and ACTION Registry Steering Committee for the ACC. He serves as principal investigator for several ongoing trials and is a senior investigator for the Thrombolysis in Myocardial Infarction (TIMI) Study Group, including the Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy–TIMI 18, Pravastatin or Atorvastatin Evaluation and Infection Therapy–TIMI 22, and Clopidogrel as Adjunctive Reperfusion Therapy–TIMI 28. He also led the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme.
Dr Cannon has lectured extensively and is Editor-in-Chief of Critical Pathways in Cardiology, a 35-book series, Contemporary Cardiology, and the website Cardiosource. His research in the field of acute coronary syndrome has led to the publication of more than 500 peer-reviewed articles, reviews, editorials, and book chapters. He has edited and/or authored six books, and has received numerous awards, including the Alfred Steiner Research Award, Upjohn Achievement in Research Award, and Robert F. Loeb Award for Excellence in Clinical Medicine.
Dr Cannon received his medical degree from Columbia University College of Physicians and Surgeons and completed a residency in internal medicine at Columbia Presbyterian Medical Center, both in New York. Subsequently, he fulfilled a fellowship at Brigham and Women’s Hospital in Boston.
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Hello, I am Christopher Cannon from the TIMI Study Group at Brigham and Women’s Hospital in Boston.
I have just returned from the American College of Cardiology meeting held in Chicago this year, where there were numerous exciting trials presented in the field of antiplatelet and antithrombotic therapy. There are too many to cover and I’ll touch upon on a few highlights from the meeting, and many other big trials, as well. In the field of antiplatelet therapy, we saw a theme emerging that more intensive antiplatelet therapy really does translate into improved ischemic outcomes. There also, as we'll touch upon, seems to be slightly more bleeding, not surprisingly, with more intensive antiplatelet therapy. People are realizing that we will have some different options that can improve outcomes, although we have to make sure to target them to appropriate populations.
To begin with, on Saturday at the SCAI late-breaking clinical trial session was a new analysis that Stephen Wiviott presented from the TRITON-TIMI 38 trial that was focused on the stented population. This was also simultaneously published in The Lancet. It has been previously been seen in the TRITON-TIMI 38 trial that a comparison between prasugrel*, a so-called third-generation thienopyridine, that achieves higher levels of platelet inhibition, as compared with clopidogrel that a reduction in clinical endpoints was seen in cardiovascular death, MI, or stroke, but with an increase in non–CABG-related TIMI major bleeding. Overall, the balance appropriately is becoming a theme of the net clinical benefit of reducing events, and including bleeding into that endpoint still favored the more intensive antiplatelet therapy.
The key discussion in the past year and half has been the issue of stent thrombosis following drug-eluting stents (DES), in particular. This was seen to be higher in the late and now what’s termed very late period beyond 1 year. It was of great interest to see whether more intensive platelet inhibition would translate into improved reductions in stent thrombosis (ST). What was presented was an analysis of the Academic Research Consortium definition of ST that was adjudicated by a blinded committee within the TRITON-TIMI 38 trial. Interestingly, the trial had just over 12,800 patients who had received a stent, and there was about half and half bare metal stent (BMS) and DES. What was observed was a 50% reduction in the risk of ST, and this was true regardless of the definition, although using the so-called definite ST definition, it was even greater (60%–65% reduction) in the DES patients. This was interestingly also seen in the BMS patients where it was again about a 50% reduction in ST. Then the timing of that was also examined where both early, defined as within the first 30 days, and late, between 30 days and 1 year ST were also significantly reduced in both DES and BMS. This really opened everyone’s eyes to the fact that the level of platelet inhibition really can have a major impact on the risk of ST. As was seen in the trial as a whole, there was a trend in this population to have higher risk of bleeding. But again, the investigators presented the net clinical benefits balance where there were 3 or 4 times as many clinical events prevented and stent thromboses prevented as compared with major bleeding created. Nonetheless, a theme emerged, and George Dangas, MD, was commenting on this that one would aim to target this population to those who were not at high-risk for bleeding at least in the initial approach when this would become available, if it does. This agent, as people know, is not currently FDA approved.
Continuing in this theme, the currently approved drug, clopidogrel, has been tested in a whole series of studies using higher doses. This included two studies that looked at loading doses of 900 mg and even 1,200 mg of clopidogrel prior to a procedure. One small study looking at platelet inhibition, the PRINC study, enrolled just 60 patients, but gave a double 600-mg loading dose and found that the level of inhibition was significantly higher 2 hours after that second loading dose of clopidogrel. This was maintained over the next few hours. Then they used 150-mg daily dose, as compared with the current standard of 75 mg, and similarly found a much higher level of inhibition. It was a small study, but they did seem to see differences even in the post-PCI troponin levels.
The second trial looked at the RELOAD study that looked at giving a 900-mg loading dose, and there again they found a much higher level of inhibition and a significantly higher level of inhibition as compared with 600-mg loading dose. That differed slightly from a prior smaller study, the ALBION study. These two studies were done, at least the latter one, in patients who were already receiving clopidogrel. A theme emerged that giving loading doses at the time of the procedure can increase the level of inhibition, and that may help in terms of periprocedural events, although further and larger studies would be needed.
Another study looked at the very vexing problem of recurrent ST. This is someone who had a second episode of ST. Obviously, the first one is frequently a major event but then having a second one would be all the more important to try and avoid. A review from a Dutch group compiled data on a series of patients who had had recurrent ST, and found that there was a very high risk of a repeat event. They were suggesting from their experience that targeting higher levels of antiplatelet therapy might be an approach to helping avoid this.
A final comment deals with the ACUITY trial and the HORIZONS trial that looked at bivalirudin. It had been previously noted that there was a need for clopidogrel when using a strategy of bivalirudin alone. This was reported in a poster at the meeting where they found roughly equal efficacy and safety among patients who had gotten preloaded with 300- or 600-mg clopidogrel loading dose when comparing the strategy of bivalirudin alone versus a strategy of heparin with a Gp IIb/IIIa inhibitor, where there were similar ischemic events but a lower risk of bleeding. Thus, it wasn’t clear you absolutely had to have a particular dose of clopidogrel when implementing that strategy. Many of us in the field are waiting for the publication from the HORIZONS trial to really digest all the data overall.
I’ve come home from the meeting very energized, I think, by the general concept that more intensive antiplatelet therapy, in particular in the P2Y12 inhibition arena, does correlate with clinical outcomes with a reduction in ischemic events that is balanced by an increase in bleeding events, although that benefit to risk ratio is favorable in a majority of patients. We all look forward to ongoing studies, and then finding which patient populations really benefit most from this more intensive antiplatelet therapy strategy.
*Investigational agent; not yet approved by the FDA
Dr Cannon has indicated that he receives grant/research support from Accumetrics, Inc., AstraZeneca, GlaxoSmithKline, Merck & Co., Inc., Merck/Schering-Plough Pharmaceuticals, sanofiaventis/Bristol-Myers Squibb, and Schering-Plough.
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