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The Take Home: AHA
The American Heart Association Scientific Sessions were held in November in Chicago. Cardiology Today’s Intervention was onsite and spoke with several experts about important trials presented during the meeting. These included Chief Medical Editor Deepak L. Bhatt, MD, MPH, from Harvard Medical School and Brigham and Women’s Hospital; Associate Chief Medical Editor Roxana Mehran, MD, from Mount Sinai Hospital; Editorial Board member Stephen R. Bailey, MD, from the University of Texas Health Science Center at San Antonio; Richard C. Becker, MD, from the University of Cincinnati; Richard Chazal, MD, from Lee Memorial Health Systems and vice president of the American College of Cardiology; Mark A. Creager, MD, from Brigham and Women’s Hospital and president-elect of the AHA; Editorial Board member Dean J. Kereiakes, MD, from the Christ Hospital Heart and Vascular Center and the Lindner Center for Research and Education at Christ Hospital in Cincinnati; and Srihari S. Naidu, MD, from Winthrop University Hospital.
IMMEDIATE PCI AFTER CARDIAC ARREST
Bailey: We heard at AHA 2014 a study examining non-trauma out-of-hospital cardiac arrest patients after successful spontaneous circulation who were admitted to a cardiac arrest center in Paris (n=1,723). Guillaume Geri, MD, and investigators studied the association between immediate PCI and survival at 30 days, 2 years and 10 years. What they found was that patients with return of spontaneous circulation who underwent PCI had about a 38% survival rate at 10 years compared with only 20% if they didn’t have PCI.
Stephen R. Bailey
That gives us some assurance to a question that we have asked often: Do we really make a difference by mobilizing everybody and trying to do this intervention? This particular study says yes. It is different than what we see in the United States. Gupta and colleagues reported in the American Journal of Cardiology in 2014 from a US population of more than 117,000 infarcts that about 1,700 of those had out-of-hospital cardiac arrest and were resuscitated. Survival rates were half of what was observed in [the Paris study], about 20%. Many patients didn’t have MI; they had cardiac arrest in the absence of MI for other reasons. We know that the Paris and US populations were much different. They were younger in Paris than in the United States in the National Cardiovascular Data Registry (NCDR). Also, the systems in Europe, particularly in Paris, are different. They are organized to have mobile coronary care units; they began hypothermia onsite very early; they had the ability to make diagnoses that in many US cities and locations we are unable to do. In Paris, 32% of cardiac arrests were in public places and 87% were witnessed arrests.
Photo courtesy of the Cardiology Today’s Intervention staff
What comes out of this is that, in this population, a group of patients are probably going to do better and benefit from the care. If you are a woman and older, you probably won’t do as well. It is important for us to understand how we can begin to categorize individuals with respect to outcome.
We are on the right track by looking at this. It requires systems that are different than how we currently treat STEMI. We need more science. We need to look carefully at what the confounding benefit of hypothermia might be. I think those are areas we are going to learn more about. But today, in my practice, if you have spontaneous return of circulation and are in our ED, we are going to move fast, we are going to work hard and we are going to accept the fact that we are going to help some of these patients.
SATELLITE-BASED ECG AND DOOR-TO-BALLOON TIMES
Naidu: One of the issues across the globe is how to appropriately triage and address the population of STEMI patients in a timely fashion. Over the years, we have done a very good job at improving door-to-balloon times when these patients come to our hospital. Most hospitals are achieving door-to-balloon times of less than 90 minutes. The biggest problem we are having today is that most patients continue to have a delay before they get to the hospital.
Srihari S.
Naidu
Results from a study of 510 patients who received primary PCI for STEMI in Qatar were presented at AHA 2014. Researchers there installed a nationwide trans-satellite wireless ECG transfer to enable quick identification of STEMI and direct transfer to the primary PCI facility in the heart hospital, and also to initiate PCI staff before the patient arrives and help eliminate delays in emergency departments. Half of the patients were transferred from the ambulance directly to the primary PCI facility via trans-satellite wireless ECG; half did not have access to trans-satellite wireless ECG and went to other hospitals first before transfer to the PCI facility. Abdurrazzak Gehani, MD, and colleagues compared the two groups in terms of achieving door-to-balloon time.
Door-to-balloon time was shorter for patients who were transferred from the ambulance directly to the primary PCI facility via trans-satellite wireless ECG (53 minutes vs. 104 minutes; P<.001). eighty-eight percent of patients in the trans-satellite wireless ecg group achieved a door-to-balloon time of less than 90 minutes, whereas only 70% in the other group achieved a time of less than 120 minutes(P<.001), per guidelines. There was also a trend toward a reduction in mortality.
This is a small study that suggests that putting into place a [trans-satellite wireless ECG] system that takes more control over the entire process from when symptoms start to when you open the artery may ultimately improve outcomes for these patients.
TRIALS OF DUAL ANTIPLATELET THERAPY
Mehran: The way I like to think about this issue is that there is a mandatory period of dual antiplatelet therapy after stenting as it is needed to curtail or prevent stent-related events, but then there is the patient with coronary disease and multiple risk factors in whom DAPT could be very effective for reducing the ischemic burden. And that is what we need to divide: the mandatory period vs. the risk–benefit ratio per patient.
Roxana
Mehran
This came to question on three important late-breaking clinical trials presented at AHA 2014: ISAR-SAFE, ITALIC and DAPT. ISAR-SAFE studied 6 vs. 12 months of DAPT and was designed to enroll 6,000 patients, but only enrolled 4,000. ITALIC studied 6 vs. 24 months of DAPT and randomly assigned 1,850 patients. In both trials, event rates were so low that one could not make an important conclusion regarding shorter duration.
The DAPT trial enrolled a large number of patients (n=9,961) who were event-free and compliant with DAPT at 12 months after PCI and were subsequently randomly assigned to either continuation of DAPT vs. aspirin monotherapy for an additional 18 months. The results showed a significant benefit in reduction of stent thrombosis (0.4% vs. 1.4%; HR=0.29; 95% CI, 0.17-0.48) and major adverse cardiac and cerebrovascular events (4.3% vs. 5.9%; HR=0.71; 95% CI, 0.59-0.85), but, interestingly, the death rate was in the other direction, with an absolute risk increase of 0.5%, a finding that was of borderline significance with a P value of .05. The absolute reduction in stent thrombosis was 1%, translating into a number needed to treat (NNT) of 100 to prevent a single episode of stent thrombosis. The magnitude of benefit was counterbalanced by an almost identical absolute risk increase of GUSTO moderate to severe bleeding (2.5% vs. 1.6%), translating into a number needed to harm of 11. This suggests that the “cost” of prolonged DAPT duration is approximately one major bleed for every stent thrombosis prevented.
I did some back-of-the-envelope calculations which show that the risk–benefit ratio varies considerably by drug-eluting stent platform. For example, in patients receiving the next-generation everolimus-eluting stent, a total of three moderate/severe bleeds will be incurred for every stent thrombosis that is prevented by a prolonged DAPT strategy. This is something that no one has commented on.
What we need to understand is the mandatory duration and intensity of DAPT after DES. Unfortunately, we just don’t know what that is. And, I would say that the DAPT study certainly did not tell us that answer. We also do not understand the lack of benefit of prolonged DAPT in certain subgroups that are expected to have a benefit, such as diabetics and women. We have to be cognizant of the balance of ischemia and bleeding, and find the sweet spot for our patients who can experience important bleeding events if they are put on prolonged DAPT but can also get the benefit of reduction in stent thrombosis and MI. We need to make choices based on each patient’s risk profile. In the future, I would like to see a definitive trial on shorter duration of DAPT with the next-generation DES. With such low event rates [in the trials presented at AHA 2014], we also have to study larger numbers of patients.
Deepak L.
Bhatt
Bhatt: DAPT has been a long-anticipated trial. I think the data confirm what a lot of us already believe: that extending DAPT might be appropriate for certain selected patients. For example, patients who have received a first-generation DES, patients with prior MI and so forth. The latter point will be further examined in the ongoing PEGASUS trial of long-term DAPT with ticagrelor (Brilinta, AstraZeneca) in post-MI patients. One point worth commenting on is that all-cause mortality was going in the wrong direction in this trial (P value of .05). The investigators of DAPT thought that was a spurious finding and I tend to agree; I don’t think protracting DAPT should increase mortality, but, on the other hand, I want to be careful before too broadly endorsing a strategy that in a large, randomized trial was associated with excess mortality. We need to factor that into decision-making.
That leaves us at a place where we cannot say that one-size-fits-all in terms of duration of DAPT in patients who have received stents. We need to continue to individualize whether a patient receives longer or shorter DAPT.
Creager: The DAPT study has provided objective evidence that prolonged DAPT in patients receiving DES was effective at reducing both adverse CV events and stent thrombosis. At the same time, there was an increased bleeding risk in those individuals.
Mark A. Creager
Doctors need to have a discussion with their patients who have received a DES that they may benefit overall from long-term DAPT with a reduction in the risk for stent thrombosis and MI. The discussion, however, also has to include the bleeding risk associated with DAPT, particularly if the patient fits into a category with established increased bleeding risk — including the very elderly, someone who has bled previously, or someone on an anticoagulation agent for another reason such as atrial fibrillation. In that case, the physician should be circumspect about recommending prolonged DAPT.
Becker: The most important takeaway from the ITALIC trial was that DAPT with clopidogrel and aspirin for 6 months performed very well in a trial using a second-generation Xience stent (Abbott Vascular). It was not evident, in the patients who were studied, that there was a benefit to prolonging therapy for 24 months. The ITALIC researchers reported no difference between the groups in the primary endpoint of death, MI, urgent target vessel revascularization, stroke and major bleeding at 12 months (24-month DAPT, 1.5% vs. 6-month DAPT, 1.6%; HR=1.072; 95% CI, 0.517-2.221) and demonstrated noninferiority of 6-month DAPT vs. 24-month DAPT (absolute risk difference, 0.11%; 95% CI, –1.04 to 1.26; P for noninferiority=.0002).
Richard C. Becker
Similarly, in ISAR-SAFE, 6 months vs. 12 months of DAPT led to similar outcomes. There was no signal of benefit for prolonged therapy and, as one might have expected, there was some element of bleeding-related harm administering DAPT for prolonged periods. The ISAR-SAFE researchers reported no difference between the groups in the primary endpoint of death, MI, stent thrombosis, stroke and TIMI major bleeding at 9 months (6-month DAPT, 1.5% vs. 12-month DAPT, 1.6%; HR=0.91; 95% CI, 0.55-1.5) and demonstrated noninferiority of 6-month DAPT to 12-month DAPT (P for noninferiority<.001).><.001).
Chazal: Kirk N. Garratt, MD, and colleagues studied 2,191 patients who had received a paclitaxel-eluting stent (Taxus Liberté, Boston Scientific) and were randomly assigned 12 months of prasugrel (Effient, Daiichi Sankyo/Eli Lilly) plus aspirin (n=1,093) or 30 months of that regimen (n=1,098). This was an interesting trial because it was dealing with a specific DES and a specific thienopyridine. The evidence seems compelling that there was an advantage to prolonged therapy. The other thing that caught all of our eyes was that at discontinuation at 30 months there seemed to be an uptick in event rates.
In real life, we see patients with a variety of different approaches with regard to stent and drug selection. In patients with a different stent or a different medication (such as generic clopidogrel), it may be more difficult to leverage the results of this particular study. Of importance, the reduction in risk with the longer duration of study did not appear related as much to stent thrombosis as to other MIs. This has potential implications with regard to long-term treatment of patients with coronary disease without a stent; we look forward to further studies to clarify this important issue.
EVOLVE II
Kereiakes: EVOLVE II is the pivotal trial for regulatory approval of the novel bioabsorbable polymer-coated everolimus-eluting Synergy stent (Boston Scientific). This trial was designed as a noninferiority trial for target lesion failure, which was a composite of cardiac death, target vessel-related MI and clinically indicated target lesion revascularization, at 1 year following stent deployment. In total, 1,684 patients were randomly assigned on a 1:1 basis to treatment with the durable-polymer Promus Element Plus EES (Boston Scientific) or the Synergy stent.
Dean J.
Kereiakes
The TLF rate at 1 year, analyzed by intention to treat, was 6.7% with the Synergy stent and 6.5% with the Promus Element Plus. The upper confidence bound was 2.68%, which fell within the noninferiority margin set at 4.4%. By per-protocol analysis, the TLF rate was 6.4% and 6.4%. Again, the upper confidence bound was 2.51%, which fell within the noninferiority margin. It is concluded that the Synergy stent is noninferior to the Promus Element Plus for TLF at 1 year. This is successful to the extent that the premise of noninferiority is proven. In addition, stent thrombosis rates in both groups were low: a total of three in the Synergy group and five in the Promus Element Plus group. Interestingly, there was no definite stent thrombosis that occurred beyond 24 hours in Synergy-treated patients, despite the complex patient population.
At this point, it is safe to say that the trial met its primary endpoint in a grand fashion.