The Take Home: ESC
From Aug. 29 to Sept. 2, 2015, the European Society of Cardiology held its annual congress, this time in London.
Cardiology Today’s Intervention was onsite and interviewed experts on breaking news presented. Those interviewed include Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, with Harvard Medical School and Brigham and Women’s Hospital; Robert Byrne, MB, BCh, PhD, with Klinik an der Technischen Universität München, Germany; Editorial Board member Ajay J. Kirtane, MD, SM, with Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation; Michael Maeng, MD, PhD, with Aarhus University Hospital; Karyn Przyklenk, PhD, with Wayne State University School of Medicine; Editorial Board member Sunil V. Rao, MD, with Duke University Medical Center; Johanne Silvain, MD, PhD, with University of Paris VI, Pitié-Salpêtrière University Hospital in Paris and the ACTION Study Group; Editorial Board Member Gregg W. Stone, MD, with Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation; and W. Douglas Weaver, MD, with Henry Ford Heart and Vascular Institute.
Kirtane: The EXAMINATION trial of patients with STEMI in particular is important because it is one of the few studies that compares a current-generation DES with a BMS control.
At 5 years, the everolimus-eluting stent (EES: Xience V, Abbott Vascular; n = 731) was superior to BMS (n = 727) for the patient-oriented endpoint of all-cause death/revascularization/recurrent MI (21.4% vs. 26%; P = .03) and also for the device-oriented endpoint of cardiac death/target vessel MI/target lesion revascularization (11.9% vs. 15.5%; P = .04).
I think that EES (and current-generation DES as a whole) are indeed effective and safe in the STEMI population, with two important caveats. The two issues of patient adherence and bleeding risk still need to be assessed at the time of implantation. First, while we would typically want to continue dual antiplatelet therapy (DAPT) for 1 year (or longer) in patients with STEMI, the data at present do suggest that the minimum duration of DAPT necessary to prevent acute or subacute stent thrombosis is still shorter for BMS than DES. So for a patient who is at high risk for discontinuation due to adherence issues, bleeding or anticipated surgery, BMS would still be preferred, even though the difference in minimum duration of DAPT is not as great as previously thought to be (currently 1 month with BMS vs. 3 to 6 months with DES). Thus, the notion that EES are safer than BMS in STEMI can only be considered to be true if patients are able to take their DAPT.
A very important point about EXAMINATION that is frequently glossed over is that much of the difference in stent thrombosis between the EES and BMS arms is related to acute stent thrombosis. If one looks at events beyond the first 24 hours, the stent thrombosis event rates are similar (and numerically worse for EES beyond 1 year). Whether these results would have been observed in the present era of more potent P2Y12 inhibitors is not certain.
Bhatt: The OPTIDUAL study included 1,385 patients with stable CAD or ACS who received a DES who were randomized to 12 or 48 months of DAPT with aspirin plus clopidogrel as opposed to aspirin alone. The overall trial did not meet the primary endpoint of net adverse clinical events (NACE; a composite of death, MI, stroke or major bleeding); numerically, it was lower in the 48-month group vs. the 12-month group, but that was not statistically significant (5.8% vs. 7.5%; HR = 0.75; 95% CI, 0.5-1.28; P = .17). For MACE, the triple ischemic endpoint again was lower with 48 months of DAPT vs. 12 months, but not statistically significant (P = .06).
In my interpretation, the OPTIDUAL trial overall is supportive of a longer vs. shorter duration of DAPT. The investigators did not find any large increase in bleeding but, on the other hand, the trial was not powered for either MACE or bleeding.
Stone: For me, the most impactful presentation was new data from the MATRIX study of patients with ACS undergoing PCI. ESC had the final presentation of all the main data from the study. Investigators had previously reported the radial vs. femoral access data, which showed less bleeding with radial intervention, but no significant difference in ischemic MACE.
Marco Valgimigli, MD, PhD, of Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands, previously presented the top-line results of the antithrombin randomization of bivalirudin (Angiomax, The Medicines Company) vs. heparin, with approximately one-quarter of the heparin patients receiving planned glycoprotein IIb/IIIa inhibitor use, which showed no significant differences in overall MACE and NACE endpoints. However, that was because the investigators used a very sensitive definition of MI. What was most striking from that randomization was that mortality was reduced with bivalirudin compared with heparin with or without a glycoprotein IIb/IIIa inhibitor, and major bleeding was reduced by 40% to 50%. That is very consistent with most other studies. The mortality reduction replicated what we saw in HORIZONS-AMI.
Now, Valgimigli presented the third randomization, which was antithrombin duration randomization, in which the patients assigned bivalirudin were randomized to a postprocedure infusion of bivalirudin for approximately 4 hours or no infusion. This was a 3,600-patient randomized trial, but it was even more complicated than that, because in the post-PCI infusion arm, the investigators initially started with a low dose of bivalirudin (0.25 mg/kg/hour), but then as studies such as EUROMAX and BRIGHT came out suggesting that the better dose to use would be the PCI dose of 1.75 mg/kg/hour, they switched over to that dose.
The overall antithrombin randomization was negative and, in fact, there were some very paradoxic, odd findings. There was less severe (BARC 3 or 5) bleeding in the patients who actually received an infusion, which is perhaps due to chance. But there was no difference in ischemic MACE. However, the high dose-infusion had a marked benefit, essentially abolishing stent thrombosis and being associated with lower mortality, whereas the low-dose infusion had worse outcomes. This again is incredibly consistent with the BRIGHT and EUROMAX trials.
There is a large amount of subgroup data in the New England Journal of Medicine. One of the most striking things to me was the reduction in mortality with bivalirudin in patients with acute STEMI compared with heparin at 30 days (2.1% vs. 3.1%).
MATRIX was a complicated study, but I believe it was very important and can clearly improve outcomes for patients with ACS.
Silvain: Based on the data presented at this meeting, I don’t see much reason to continue the infusion of bivalirudin in patients with ACS.
The main contribution of the MATRIX study was the superiority of the radial approach over the femoral approach. If you still use the femoral approach, then maybe you need to use a drug like bivalirudin to lower bleeding events.
With regard to bivalirudin vs. heparin, people in the cath lab have their habits based on what has worked well for them. The main result was neutral, as was the other main endpoint including bleeding. There was no benefit for one over the other, so I’m not sure this will prompt people to change their minds. My personal view is, if you were using unfractionated heparin before, combined with the radial approach, why move to bivalirudin?
Weaver: CIRCUS is another study looking at a mechanism to reduce reperfusion injury following angioplasty for MI. It evaluated cyclosporine in 970 patients with acute anterior STEMI and complete occlusion of the culprit coronary artery who were referred for PCI within 12 hours of symptom onset.
The CIRCUS trial was, unfortunately, another failed attempt at preventing reperfusion injury. The primary outcome — a composite of all-cause mortality, worsening HF during initial hospitalization, HF rehospitalization and adverse LV remodeling at 1 year — occurred in 59% of the cyclosporine group vs. 58.1% of the placebo group (OR = 1.04; 95% CI, 0.78-1.39; P = .77).
Przyklenk: There is a very strong and compelling rationale behind CIRCUS. First and foremost, there is very strong molecular evidence for involvement of the mitochondrial permeability transition core to reduce reperfusion injury. ... But probably the most important and the most compelling rationale for CIRCUS was the phase 2 study in Piot and colleagues [N Engl J Med. 2015;doi:10.1056/NEJMoa071142]. The obvious question is what happened here? Particularly, how can you explain these negative outcomes when compared with the results of an apparently positive phase 2 trial? There are several differences in the two protocols, including differences in the formulation of cyclosporine, differences in patient populations, changes in standard of care [and so on].
Given the history of the field of cardioprotection ... I could ask: Can any pharmacologic agent given at reperfusion meet these very stringent criteria and attenuate reperfusion injury? These, I think, are the key discussion points that we need to consider.
Maeng: This study is one of a larger number of studies that have tested treatment strategies to reduce reperfusion injury or remodeling in the period after STEMI. In my opinion, so far there have not been any positive or convincing results in that field. This study was well performed but neutral. There was no difference between those assigned injection of a bioresorbable cardiac matrix (IK-5001, Bellerophon BCM, LLC) and those assigned injection of saline in change in LV end-diastolic volume index (6-month point estimate, 3.8; 95% CI, –0.5 to 8) or in other outcomes. Unfortunately we didn’t see any indication in this study that this technology will work in the future.
Stone: PLATFORM was an interesting nonrandomized study examining the potential utility of CT-derived fractional flow reserve (FFR-CT) in patients with chest pain intended for invasive catheterization or noninvasive testing. In patients planned for invasive catheterization, 12.4% in the FFR-CT arm and 73.3% in the usual care arm had the procedure despite the absence of obstructive CAD (risk difference, 60.8%; 95% CI, 53-68.7; P < .0001). The results suggest that one might be able to use this noninvasive test to avoid many unnecessary coronary angiograms that will demonstrate nonobstructive CAD, while still being able to detect an equivalent number of patients with obstructive CAD who need revascularization. This sets the stage for a randomized clinical trial powered for outcomes as well as for reduced procedures and costs.
TRANSRADIAL PCI GUIDELINE
Rao: The strong recommendation in the new ESC guideline on management of patients with ACS for the transradial approach to PCI, presented at the ESC Congress and published in the European Heart Journal, is the right move. In the classification system used by the American College of Cardiology and the American Heart Association, a 1A recommendation is usually based on multiple randomized trials showing the same result. We now have multiple randomized trials showing that transradial access reduces vascular complications. Whether this will impact adoption of the transradial approach in the United States is a question of what affects physician behavior, which can be difficult to determine. Guidelines certainly have an effect on that, but probably not as great as all of us would hope.
ABSORB JAPAN AND TROFI II
Stone: There were two randomized trials of the Absorb bioresorbable vascular scaffold (Absorb BVS, Abbott Vascular) presented, both of which were positive.
ABSORB Japan was the pivotal approval trial for Absorb in Japan. It randomized 400 patients with one or two de novo lesions, and was not powered for clinical events. It showed very comparable 1-year outcomes between Absorb BVS (Abbott Vascular) and a cobalt chromium EES in workhorse lesions, and identical rates of stent or scaffold thrombosis (1.5% in both arms). This was the first trial that reported routine 1-year angiographic follow-up between the two devices. Those results were similar with Absorb and the EES. While not definitive because of its size, overall, it supports the safety and efficacy of Absorb compared with EES in workhorse lesions.
Of course, many high-risk patients with complex lesions are excluded from that type of experience, and that’s where TROFI II came in. It is the first randomized comparison of Absorb with an EES (Xience, Abbott Vascular) in patients with STEMI. At 6 months, the primary endpoint was the so-called healing score as assessed by optical coherence tomography. It demonstrated that Absorb was healing at least as well as Xience and had fewer malapposed struts. That was because it had a slightly greater amount of neointimal hyperplasia, likely because of the thicker struts compared to the thin stent struts of Xience. So it had somewhat more complete tissue coverage with somewhat better healing.
Byrne: There has been great interest in bioresorbable stents (BRS) over the last decade or so and we have experience in Europe with two devices that are approved for use: the Absorb BVS and the DESolve bioresorbable coronary scaffold (Elixir Medical). However, only now are we learning data from the first randomized clinical trials vs. standard metallic DES, so this is an exciting time for the technology.
For me, the use of BRS in patients undergoing primary angioplasty for acute MI is of particular interest. Patients with STEMI are usually younger, often present with focal disease, and have lesions with low degrees of calcification. This means that they may be particularly well suited to BRS treatment.
The main finding of TROFI-II was that “healing scores” by optical coherence tomography were comparable in both groups.
One of the main limitations is that the OCT healing score used is not well established, so we don’t have a good read on how relevant it is for clinical practice. In fact, OCT technology still has some way to go in terms of assessment of healing. In addition, the particular score used by the authors has not been well-validated in animal studies. Finally, metal stents produce significant signal artefact (called blooming), whereas BRS do not, making comparative analysis by OCT a little challenging.
ABSORB Japan, on the other hand, included predominantly stable patients with relatively straightforward lesions. The comparator stent was the well-performing metallic EES. The main finding was that both stents performed comparably in terms of clinical outcomes at 12 months. This is indeed very encouraging for this new technology. However, we must remember that only carefully selected patients were included. So if physicians use this stent in their practice, they should equally carefully select patients in line with the criteria used in the trial.
Although the concept of self-degrading stents is intuitively attractive, more data are eagerly awaited. Event rates with BVS have been slightly higher than with conventional stents. Therefore the advantages with BVS must be evident and clear; otherwise acceptance of this additional burden will not be broad.
Disclosures: Bhatt reports advising for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology and Regado Biosciences; receiving research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis and The Medicines Company; serving as a site co-investigator for Biotronik and St. Jude Medical; and involvement with unfunded research for FlowCo, PLx Pharma and Takeda. Byrne reports receiving lecture fees from B. Braun Melsungen, Biotronik and Boston Scientific. Kirtane reports receiving research grant support via his institution from Abbott Vascular, Boston Scientific and Medtronic. Maeng reports serving on an advisory board for AstraZeneca. Rao reports consulting for Medtronic and Terumo Medical. Silvain reports receiving research grants via his institution from Boehringer Ingelheim, BRAHMS, Daiichi Sankyo, Eli Lilly, and Sanofi Aventis; consultant fees from AstraZeneca, Daiichi Sankyo, Eli Lilly and The Medicines Company; and lecture fees from AstraZeneca, Cordis, Daiichi Sankyo, Eli Lilly, Iroko Cardio International and Stentys. Stone reports consulting for Reva Medical; he was also an investigator on ABSORB Japan. Przyklenk and Weaver report no relevant financial disclosures.