EXPERT OPINION FROM THE AHA SCIENTIFIC SESSIONS
CHICAGO (FRONTLINE MEDICAL NEWS) – Clinicians managing patients who have just received drug-eluting coronary stents need to individualize the duration of the antiplatelet therapy they prescribe and stop thinking that a single length of treatment works best for all patients, based on results from a trio of newly reported trials, as well as earlier study findings.
In general, the new findings seemed to show that following percutaneous coronary intervention (PCI) with a stent, patients with a low risk for stent thrombosis, myocardial infarction, or another type of ischemic event, as well as those with a high bleeding risk, fare best when their duration of dual antiplatelet therapy (DAPT) with aspirin plus a thienopyridine ends after 6 months, while patients with a low bleeding risk and a high risk for an ischemic event will usually do better when their DAPT continues well beyond 12 months, for 30 months and possibly longer.
“We now have results from 35,000 patients in randomized trials that addressed the question of duration of DAPT. We need to make up our minds, and it’s probably an individualized decision,” Dr. Gilles Montalescot said at the American Heart Association Scientific Sessions.
“The patients [in the three newly reported studies] were generally doing well, and so we are operating at the edge of competing risks” they face for ischemia and bleeding. “We need individualization of treatment, but what remains to be determined is, how do we make that decision? Who is more at risk for ischemic events and less at risk for bleeding, and who is more at risk for bleeding and less from ischemia?” commented Dr. Elliott M. Antman , professor of medicine and associate dean for clinical and translational research at Harvard University in Boston.
The DAPT trial
Drug-eluting stent recipients at increased risk for bleeding who are good candidates for a briefer, 6-month duration of DAPT include those with a history of a prior bleed, advanced age, pending need for surgery, patients who need anticoagulation treatment such as those with atrial fibrillation, patients with one or more comorbidities that put them at higher bleeding risk such as gastrointestinal disease or a history of stroke, and patients with a “nuisance” bleed, said Dr. Montalescot , a professor of cardiology at the University of Paris and director of the cardiac care unit at Pitié-Salpêtrière Hospital in Paris.
These conclusions emerged from a surge of new data from three studies presented at the meeting that all addressed DAPT duration following PCI.
Perhaps most noteworthy and anticipated were results from the Dual Antiplatelet Therapy study , a randomized trial that had its beginnings in 2006 when cardiologists first became alarmed by the potential risk from stent thrombosis associated with the use of first-generation DES, specifically the original sirolimus-eluting ( Cypher ) and paclitaxel-eluting ( Taxus ) models. At the urging of staffers at the Food and Drug Administration, a group of eight stent manufacturing companies and pharmaceutical companies joined together to sponsor the DAPT study, which started with nearly 23,000 patients who received a DES and, after their first year of DAPT treatment, whittled down to 9,961 patients who were eligible for randomization to either stop DAPT after 1 year or continue on DAPT for an additional 18 months (30 months total time on DAPT).
The results showed that this highly selected group of patients – who went through their first year on DAPT with no bleeding event, no ischemic event, and who were willing to be randomized – those assigned to 30 months of DAPT had a 1% absolute and 71% relative reduction in stent thrombosis, compared with patients who stopped DAPT after 12 months, and a 1.6% absolute and 29% relative reduction in their rate of major cardiovascular or cerebrovascular events, statistically significant differences for the study’s two primary endpoints. The reduction in major events was driven mainly by a 2% absolute reduction in the rate of myocardial infarctions, reported Dr. Laura Mauri at the meeting, and in a report simultaneously published online ( N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1409312]).
Counterbalancing this benefit was a statistically significant excess of moderately severe bleeding events among patients on longer-term DAPT, who had a 0.7% absolute increased rate, and a trend toward increased severe bleeds, with a 0.2% absolute increased rate. Patients on longer-term DAPT also showed an unexpected, 0.5% increased rate of both all cause death and noncardiovascular death. Detailed analysis indicated that this seemed to result from a “chance imbalance” in randomization that put an excess of patients with cancer into the 30-month DAPT subgroup, said Dr. Mauri , professor of medicine at Harvard Medical School and an interventional cardiologist at Brigham and Women’s Hospital, both in Boston.
DAPT treatment extending longer than 12 months switches the focus from preventing stent thrombosis to secondary prevention of all ischemic events, including those that occur elsewhere in a patient’s coronary arteries, noted Dr. Montalescot, who served as the meeting’s designated discussant for the DAPT trial and the other reported DAPT studies. This option, which can now be offered to appropriate patients, also raised the possibility of continuing DAPT indefinitely beyond 30 months in patients who continue to show no bleeding risk and can pay for ongoing treatment with a thienopyridine. But he advised waiting on the use of very prolonged DAPT until results arrive next year from the PEGASUS study.
ITALIC and ISAR-SAFE
Results from two other studies reported at the meeting looked at the other end of the spectrum, the safety of stopping DAPT after just 6 months. One of these, the ITALIC study , randomized 1,850 patients to 6 months or 24 months of treatment with aspirin and clopidogrel, and exclusively enrolled patients who received the Xience V everolimus-eluting, third-generation coronary stent. The results showed low and nearly identical 1.5% and 1.6% rates of the combined endpoint of major adverse events, including bleeds, in the two comparator arms after 24 months of follow-up. The results also appeared in an article published simultaneously online ( J. Am. Coll. Card. 2014 [doi:10.1016/j.jacc.2014.11.008]).
A similarly designed study, ISAR-SAFE , randomized 4,005 PCI patients who received a DES to DAPT with aspirin and clopidogrel for either 6 or 12 months, and also showed a similar and low, roughly 1.5% rate of combined major adverse cardiovascular events and bleeds in both treatment arms, reported Dr. Stefanie Schulz-Schüpke , an interventional cardiologist at the German Heart Center in Munich.
These two studies, along with five prior reports that collectively randomized nearly 16,000 patients to 6 months of DAPT or a longer duration show a statistically significant reduction in major bleeds with good protection against ischemic events when DAPT stopped after 6 months, said Dr. Montalescot. “We can accept that 6 months is safer than 12 months of DAPT,” and it makes sense to stop after 6 months in a patient with a bleeding risk or in a patient with a high ischemia risk such as those with left main coronary disease, a history of stent thrombosis or myocardial infarction, a patient who received a first-generation DES, patients with extensive coronary disease or coronary stenting.
While Dr. Montalescot, Dr. Antman, and others who heard these results agreed that they all pointed to the need for individualized decisions on DAPT duration, they also said the new findings were unlikely to change current guidelines. Existing PCI guidelines from the American Heart Association and American College of Cardiology call for a standard 12 months of DAPT in DES recipients, but offer clinicians to reduce or extend the duration when judged appropriate ( J. Am. Coll. Cardiol. 2011;58:e44-e122 ). Guidelines from the European College of Cardiology call for 6 months of DAPT as standard, but also suggest that clinicians can reduce or lengthen the duration when appropriate ( Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu278]).
According to three staffers from the FDA who also spoke at the session, the agency is also unlikely to change its guidance on DAPT in the immediate future, even though it triggered launch of the DAPT trial.
The DAPT trial “is large enough to allow us to answer some really critical public-health questions, and to potentially expand the indications for drug-eluting coronary stents,” said Dr. Bram D. Zuckerman, director of the division of cardiovascular devices of the FDA. But he and his colleagues who spoke during the session said that the agency will not update its recommendations or labels until the FDA staff has had a chance to study in detail the full data set collected in the DAPT trial. Concurrent with Dr. Mauri’s report, the agency issued a statement calling on physicians to continue to prescribe DAPT as they have in the past and for patients to continue to take all their prescribed medications.
Many physicians have already concluded that 6 months of DAPT is a practical way to enhance patient compliance with their regimen and minimize the money they spend on these medications, commented Dr. Richard C. Becker, professor of medicine and director of the Cardiovascular Institute at the University of Cincinnati. The three trials reported at the meeting “do not answer the question [of whether 6 months is adequate] because in each trial patients had already tolerated a period of DAPT before entering the study” Dr. Becker said in an interview.
The question of DAPT duration “is a question that clinicians will need to have with each of their patients, especially those who are tolerating DAPT,” commented Dr. Richard A. Chazal , an interventionalist and medical director of the Heart and Vascular Institute at the Lee Memorial Health System in Fort Myers, Fla.
Dr. Montalescot has been a consultant to more than a dozen pharmaceutical and device companies, including companies that market antiplatelet drugs. Dr. Antman has received grant support from Daiichi Sankyo. Dr. Mauri received personal fees from Medtronic, Recur, St. Jude, and Biotronik, and grant support from nine device manufacturer and drug companies. Dr. Schulz-Schüpke, Dr. Zuckerman, Dr. Becker, and Dr. Chazal had no relevant disclosures.
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