No one thought it would take quite so long to get this information, but in just a couple hours results from the Dual Antiplatelet Therapy (DAPT) Study will be presented at the American Heart Association Scientific Sessions 2014. The question to be answered: Is there a benefit to extending dual antiplatelet therapy (aspirin plus a thienopyridine, such as clopidogrel/Plavix, prasugrel/Effient, etc.) beyond one year after stenting?
This is a question asked back in 2006, during a special two-day FDA hearing, convened to discuss all known issues with drug-eluting stents and prompted by the “ESC firestorm” over the problems of increased incidence of late stent thrombosis in drug-eluting stents. (See “Problems Resurface with Drug-Eluting Stents” – September 9, 2006.)
Much has changed in the interim: Cordis/J&J which manufactured Cypher, the first FDA-approved drug-eluting stent, is no longer in the coronary stent business; Plavix has gone generic (as clopidogrel) and two new antiplatelet drugs have come to market: Effient (prasugrel) and Brilinta (ticagrelor); and new second and third generation stents from Abbott (Xience), Medtronic (Resolute) and Boston Scientific (Promus) have replaced the earlier Cypher and Taxus. And this afternoon that hanging question from 2006 is about to be answered.
Quick Background on DAPT and Stent Thrombosis
When a stent is implanted in an artery to push open a blockage and act as a scaffold to hold that artery open, blood flow is increased and angina/ischemia is relieved. In the case of an acute event, such as a heart attack, revascularizing the artery actually stops the infarction, limiting damage to the heart muscle. This “gold standard” treatment for MI has significantly decreased mortality and morbidity for heart attack victims.
But the body sees the metallic stent as an intruder and the blood tries to form a clot. So antiplatelet medications are administered until a layer of endothelial cells literally covers the metallic stent struts, masking the stent from the immune system. When bare metal stents started being used in the 90s, it was thought that this healing process took 4-6 weeks. Although bare metal stents were a major advance over balloon angioplasty, a new disease came about: in-stent restenosis – too much “healing” tissue grew inside the stent and the artery reblocked. In the next decade, drug-eluting stents (DES) became available. The bare metal stent was coated with a special plastic polymer which eluted a drug that slowed down the tissue growth inside the stent. Restenosis rates dropped to single digits and a new era in interventional treatment of coronary artery disease began.
Until 2006, that is, when studies started to show that blood clots inside the stent, called stent thrombosis, were occurring in DES at a higher rate than in bare metal stents, and long after the stent placement. Stent thrombosis and restenosis both result in a blocked or narrowed artery, but they are completely different biological phenomena – and stent thrombosis is most often an acute event: when it occurs, the artery becomes completely blocked very quickly, most often resulting in a heart attack and 1/3 of the time death. To be sure, the percentage of stent thrombosis was small – so small that this signal was not picked up in the 1,000 patient DES clinical trials upon which the FDA based its approvals.
These approvals, by the way, had taken into account the fact that DES slowed down the healing process of tissue growth, so the recommendation for DAPT after stenting was increased to 3 months for the Cypher stent and 6 months for the Taxus stent. But these reports of increased stent thrombosis generated a flurry of activity, culminating in the two-day FDA hearing.
On December 7 and 8, there were over 25 presentations given to an SRO crowd of 500, by industry representatives, cardiologists, surgeons, the three major professional cardiology groups. I testified and so did a patient who heard about the hearing through our Patient Forum. For two days from 8:00am on, the panelists listened and asked questions, sometimes probing, sometimes challenging, and they debated among themselves whether to recommend that the FDA attach stronger warnings, change the labels, lengthen the recommended duration of Plavix and aspirin.
The biggest problem was that there was insufficient data on the effect, good and bad, of increasing the duration of DAPT. Antiplatelet medications thin the blood and increase bleeding complications. Would the benefit of lowering late stent thrombosis (a relatively infrequent but potentially lethal complication) be enough to offset bleeding events? None of the pivotal approval trials were powered to test this issue. In fact, Plavix itself was technically not approved for use post-stenting in non-acute patients. I believe it still isn’t. But that’s another story (see my post on this Catch-22).
The conundrum of increasing duration of DAPT faced by the panelists and the cardiology community is best summed up in this exchange between panelist Dr. Chris White of the Ochsner Clinic and chairperson Dr. William Maisel:
DR. WHITE: I’m loath to change the recommendations that were made without evidence, compelling evidence to make us change. I’m also not sure that continuing Plavix to a year would have any benefit on the…thrombosis that occurs at two, three and four years. So…unless there was some evidence that using [anti] platelet therapy longer than originally had been recommended, the three to six months, that there’s some obvious benefit to that, and knowing that there is risk to that, I think we really shouldn’t be stampeded into making that kind of an emotional decision without evidence….
CHAIRMAN MAISEL: Dr. White, if you had a drug-eluting stent and no increased bleeding risk how long would you take dual anti-platelet therapy?
DR. WHITE: Indefinitely.
CHAIRMAN MAISEL: Me, too!
Laughter rippled throughout the room partially to relieve the tension, but mainly because Dr. White had put his finger on the issue. Dr. Maisel then queried guest panelist Dr. Eric Topol:
DR. TOPOL: Well, just to, I think, go along with Dr. White on this, we did a trial CREDO which actually is the only trial after stenting to look at 30 days to one year. And interestingly that showed, that was in the bare metal stent era, it showed there was, indeed, protection from major events. But interestingly they weren’t stent related. They were non-target vessel events and strokes because of the atherosclerotic underlying disease. So that confirmed a benefit in bare metal stents out to one year. There haven’t been any other trials outside of that one, so to make any kind of sweeping recommendation without data and trying to actually direct the recommendation towards stent thrombosis would be on uncertain grounds.
Current Recommendations, Newer Stents
As a result of this hearing, U.S. guidelines were changed to what they are today: at least one year of DAPT; an extended period is an option for patients who are at high risk for thrombotic events and who are not at risk for bleeding complications. European guidelines were extended as well, but not as much, to 6-12 months.
Also as a result of the issues presented at the hearing, DES usage in the U.S. dropped from 90% to 58% in a matter of months. Bare metal stents were viewed as safer.
Representatives of Abbott Vascular and Medtronic also presented at the FDA hearing: new second generation stent trials that were being conducted not in 1,000 patients, but 5,000, with longer term follow-up to five years. The panelists liked this. And within a few years, these new stents found their way into the marketplace, demonstrating greater efficacy and safety. And DES usage is back to much higher levels.
More recent studies have shown a significantly reduced incidence of late stent thrombosis. This may be due to thinner struts and more biocompatible polymers. Several studies have also been conducted to measure whether a duration of less than a year is safe. An analysis of Medtronic’s RESOLUTE program of 5,000 patients even showed no stent thrombosis increase for patients who needed to stop DAPT after one month! Because of these newer, better devices, the trend has been toward thinking of shorter rather than longer DAPT. After all, DAPT can be expensive. Even generic clopidogrel is running at $4/day. And patients may need surgery, requiring at least a temporary interruption of antiplatelet meds.
So it is with this background that we anticipate the findings of the 10,000 patient DAPT Trial this afternoon to answer the question: “Is longer better?!”