The Take Home: ESC

Source: Cardiology Today’s Intervention staff

Cardiology Today’s Intervention was onsite in Munich for the European Society of Cardiology Congress from Aug. 25 to 29. This year’s meeting featured a number of landmark studies in interventional cardiology, as well as cardiology overall.

Several experts offered their insights on these studies, including Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School; Morton J. Kern, MD, MSCAI, FACC, FAHA, from the University of California, Irvine, and VA Long Beach Healthcare System; Cardiology Today’s Intervention Associate Medical Editor Roxana Mehran, MD, FACC, FAHA, MSCAI, FESC, from Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation; Cardiology Today’s Intervention Editorial Board Member Gilles Montalescot, MD, PhD, from Pitié-Salpêtrière Hospital, Paris; Ashish Pershad, MD, FACC, from Banner – University Medicine Clinics, Phoenix; Michael J. Reardon, MD, from Houston Methodist DeBakey Heart and Vascular Center; Holger Thiele, MD, from the Heart Center Leipzig at the University of Leipzig, Germany; and Marco Valgimigli, MD, from Inselspital, Bern University Hospital, Switzerland.

GLOBAL LEADERS

Bhatt: This widely anticipated GLOBAL LEADERS trial included 15,000 patients with ACS or stable angina who were undergoing stenting and were randomly assigned to 1 month of dual antiplatelet therapy that included aspirin plus ticagrelor (Brilinta, AstraZeneca), followed by twice-daily ticagrelor or, in the control arm, the ACS patients received aspirin and ticagrelor for 1 year followed by daily aspirin, and the stable patients received aspirin and clopidogrel for 1 year followed by daily aspirin. This was a complex design.

Overall, there was no benefit of the experimental strategy of aspirin/ticagrelor for 1 month followed by twice-daily ticagrelor; it was not superior to the conventional regimen of DAPT for 1 year followed by aspirin. The primary endpoint — a composite of all-cause mortality or nonfatal Q-wave MI confirmed by ECG at 2 years — occurred in 3.81% of the experimental group vs. 4.37% of patients in the control group (rate ratio = 0.87; 95% CI, 0.75-1.01). This was an important neutral result. There was no harm per se, but no benefit. The bottom line is, the standard of care in terms of DAPT should remain the same, and ticagrelor monotherapy doesn’t have a role in the post-stented patient. However, there are other ongoing trials such as TWILIGHT that are testing this strategy of ticagrelor monotherapy in slightly different populations.

CULPRIT-SHOCK

Thiele: The major results of CULPRIT-SHOCK showed that at 30 days there was a significant reduction in the composite primary endpoint of all-cause mortality or renal replacement therapy with culprit lesion-only PCI in 706 patients with acute MI, cardiogenic shock and multivessel CAD, which was mainly driven by an absolute reduction in all-cause mortality of greater than 8%. These results can now be confirmed for the 1-year follow-up, which showed a persistent reduction in the composite endpoint (52% vs. 59.5%; RR = 0.87; 95% CI, 0.76-0.99). Mortality reduction was confined to the first 30 days, and thereafter, between 30 days and 1 year, there was no difference in mortality.

These results have already impacted current guideline recommendations, with a downgrading of immediate multivessel PCI to a class IIIB recommendation in the current ESC/European Association for Cardio-Thoracic Surgery Guidelines on Myocardial Revascularization.

I believe that the major unanswered question from this study is when to perform staged revascularization in the culprit lesion-only PCI strategy. Furthermore, we currently do not know if a possible subgroup exists who would possibly benefit from immediate multivessel PCI. However, in the predefined subgroup analyses, we could not find a subgroup that may benefit.

Bhatt: The 1-year results of CULPRIT-SHOCK are particularly important for the interventional realm and even for general cardiology. The 1-year results confirmed what was seen at 30 days: There was no significant benefit on hard endpoints with a strategy of complete revascularization at the index procedure.

Some had hoped that a later benefit would emerge. While there were some signals with respect to endpoints such as HF, there was still no benefit on hard endpoints such as mortality, and there was early harm with respect to renal dysfunction with the complete revascularization strategy. So, for the time being, even though it is different from how many of us have been practicing, in a patient with an MI that comes in with shock, just open up the culprit vessel, assuming it is STEMI and you know which vessel is the culprit, and do not go after the other lesions in that index procedure. You might want to go after them later on during that admission or posthospitalization if the patient survives. But I think the real message is to not go overboard during that index procedure.

BASKET-SMALL 2

Mehran: This is the first randomized trial of a paclitaxel-coated balloon (SeQuent Please, B. Braun Medical) compared with mostly best-in-class drug-eluting stents. The DES group was initially implanted with a paclitaxel-eluting stent (Taxus Element, Boston Scientific), but about one-quarter of the way through enrollment, that stent was pulled from the German market because of a lawsuit, and subsequent patients in the DES group received an everolimus-eluting stent (Xience, Abbott Vascular).

The researchers assigned 758 patients with small-vessel disease and reference vessel diameter > 2 mm to < 3 mm to receive the drug-coated balloon or a DES. This was a very important trial on a subset of vessels that present complex anatomic and clinical scenarios. Noninferiority was met for the primary endpoint of MACE, defined as cardiac death, nonfatal MI and target vessel revascularization at 12 months (HR = 0.97; 95% CI, 0.58-1.64; P for noninferiority = .0217). Of note, the rate of cardiac death was numerically higher in the DCB group (3.1% vs. 1.3%; HR = 2.33; 95% CI, 0.82-6.61), which probably needs further evaluation.

Small vessels are more prevalent in women and in diabetic patients. I would have expected to see higher rates of these important subsets in this trial.

Other limitations include that 25% of the DES arm having Taxus could have led to a negative impact on that arm, the long introduction period could lead to selection bias and you have to wonder if these are truly small vessels when you are including vessels just under 3 mm.

We saw that the DCB is safe and comparable to DES in terms of MACE and it offers an important alternative in patients with small-vessel disease. The potential benefit of having a nonpermanent implant in our patients with diffuse long lesions is tremendous. This sets the stage for a larger study in patients with truly small-vessel disease, ie, in vessels < 2.5 mm in diameter.

MATRIX

Valgimigli: The MATRIX trial of 8,404 patients confirmed that transradial access for coronary angiography, followed by PCI if indicated, is superior to transfemoral access, even when evaluated remotely from the procedure, which tells us that the use of transradial access leads to better outcomes not only shortly after intervention but also at longer-term follow-up.

At 1 year, MACE — defined as all-cause mortality, MI or stroke — numerically, but not significantly, favored the transradial group over the transfemoral group (14.2% vs. 15.7%; rate ratio = 0.89; 95% CI, 0.8-1). Net adverse clinical events — defined as all-cause mortality, MI, stroke or non-CABG-related BARC 3 or 5 major bleeding — were lower in the transradial group (15.2% vs. 17.2%; rate ratio = 0.87; 95% CI, 0.78-0.97).

Additionally, bivalirudin does not mitigate the risks of ischemic or ischemic and bleeding endpoints compared with unfractionated heparin (our standard of care). There was no difference in bivalirudin vs. heparin for 1-year MACE (15.8% vs. 16.8%, respectively; rate ratio = 0.94; 95% CI, 0.83-1.05) or net adverse clinical events (17% vs. 18.4%, respectively; rate ratio = 0.91; 95% CI, 0.81-1.02). Yet, I remain convinced that this drug has value. In particular, our most recent data suggest that the drug should be used by prolonging the PCI regimen well after the end of the procedure. In those patients in whom the drug was used as such, there was a remarkable reduction in ischemic events, not only compared with bivalirudin without post-PCI infusion but also compared with unfractionated heparin.

I think, and hope, that the MATRIX trial will reinforce the message that transradial access should always be considered first in patients with ACS. We now have clear data showing that the benefit is durable over time. That was the only missing piece of evidence for transradial vs. femoral access. Now, it is difficult to find a justification for practicing femoral interventions unless transradial access is not technically feasible or possible. I hope that the American community will reflect on these findings and find a way to incorporate the preferential use of transradial access into practice.

On a parallel note, when bivalirudin is used, I think the drug should now always be prolonged after PCI at the full-PCI regimen. The prolongation of the low dose seems to be not only ineffective in reducing the ischemic risk but also dangerous compared with intraprocedural bivalirudin only.

FUTURE

Kern: The FUTURE trial is interesting because it is the only fractional flow reserve trial conducted during the last 15 years that has shown that FFR is not beneficial. This is surprising, and the explanations are lacking. The study was stopped after 938 patients were enrolled; results from a safety analysis then confirmed a significantly increased mortality risk in patients whose treatment was guided by FFR vs. angiography (HR = 2.39; 95% CI, 1.05-5.43).

In the study, issues regarding patient assignment based on the prevalence of diabetes, three-vessel disease and ACS account for some of the events. Additionally, the high SYNTAX score of greater than 32 in some of the patients is also associated with worse FFR outcomes. It is a little mind-boggling that the event rates would be higher in this group in the intention-to-treat analysis, but the trial is still an outlier among all of the other FFR studies, so until there is a better explanation for this particular response, I am not sure we should change practice based on these results.

I do think, however, that in patients with very high SYNTAX scores, revascularization with PCI always carries a higher risk, even when directed by FFR, regardless of the FFR findings in some cases. Other than that, though, it is a puzzle that all-cause mortality was greater with FFR. At this point, I am unsure that even the study authors have a very good explanation for why this was the case.

FAME 2

Kern: The post-hoc analysis of the FAME 2 trial emphasized the determination of the treatment for patients who had silent or asymptomatic ischemia, meaning positive FFRs but no symptoms, compared with those who had symptoms. There was a benefit to FFR in patients with silent ischemia who were treated with PCI: They had a lower rate of death or MI compared with those who received medical therapy alone (HR = 0.236; 95% CI, 0.084-0.658).

What these results mean to me is that those patients with silent ischemia need to have their lesions assessed to determine if ischemia is indeed present based on FFR. Obviously, if it isn’t, then they should do as well with medical therapy.

The finding that the death rate is higher in patients with silent ischemia compared with patients with stable angina (HR = 1.68; 95% CI, 0.61-4.61) is explainable. In patients with stable angina, symptoms drive earlier revascularization. We know from FAME 2 that patients with ischemia, as demonstrated by FFR, fare better with revascularization than with medical therapy. This is enlightening in terms of guiding our management for those patients with silent ischemia. The message is that we should double-check the FFR and make sure these patients are treated.

VERDICT

Montalescot: The VERDICT trial tested the hypothesis that invasive coronary angiography within 12 hours of randomization would improve outcomes, compared with the standard of care, where coronary angiography is performed within 48 to 72 hours. A total of 2,147 patients, with clinical suspicion of non ST-elevation ACS (NSTE-ACS), increased troponin or ischemic ECG, were recruited in nine Danish hospitals. With a median follow-up of 4.3 years (interquartile range, 4.1-4.4), the researchers did not find any significant difference regarding the primary composite endpoint of all-cause death, MI, readmission for refractory myocardial ischemia or HF (early invasive strategy, 27.5%; standard invasive strategy, 29.5%; HR = 0.92; 95% CI, 0.78-1.08). However, a subgroup analysis showed that, among patients with GRACE score > 140, early revascularization was associated with a significant reduction of the primary endpoint (HR = 0.81; 95% CI, 0.67-1), while a trend was observed among patients with increased troponin levels (HR = 0.85; 95% CI, 0.72-1.01). Of note, nearly one-third of randomized patients did not present any coronary stenosis overall.

What are the takeaways of the study? Although a very early invasive look-up in all-comers with suspicion of NSTE-ACS is safe, it did not result in improved outcomes. Moreover, such strategy would likely be logistically challenging to implement in some centers and potentially cost-ineffective. This study confirms previous similar studies and meta-analyses, including studies which tested primary PCI in NSTE-ACS. In line with these studies and the TIMACS study in particular, the VERDICT trial suggested that specific subgroups at high risk (GRACE score > 140 or increased troponin) could benefit from a more rapid invasive coronary angiography performed within 12 hours of admission with subsequent coronary revascularization.

FRANCE-TAVI

Reardon: Long-term mortality and early valve dysfunction in the FRANCE-TAVI registry was studied according to anticoagulation use with the primary objective to identify mortality association and the secondary objective to identify correlation to biologic valve dysfunction at 3 years. Despite the use of this large, prospective national registry of 12,804 patients, the main message from this study is that we still do not know the best anticoagulation scheme for transcatheter aortic valve replacement.

The strongest independent correlates of 3-year mortality were male sex (adjusted HR = 1.63; 95% CI, 1.44-1.84), history of AF (aHR = 1.41; 95% CI, 1.23-1.62), chronic renal failure (aHR = 1.37; 95% CI, 1.23-1.53), anticoagulation at discharge (aHR = 1.18; 95% CI, 1.04-1.35), TAVR performed via non-femoral access (aHR = 1.18; 95% CI, 1.04-1.35) and moderate to severe prosthetic regurgitation (aHR = 1.28; 95% CI, 1.11-1.4).

The mortality associations at 3 years were of less interest than the questions surrounding anticoagulation. DAPT was not associated with mortality and did not prevent biologic valve dysfunction. Oral anticoagulation therapy, on the other hand, was associated with mortality and did prevent biologic valve dysfunction.

With the current identification of and interest in early biologic valve dysfunction in TAVR, there is renewed interest in identifying the best anticoagulation therapy. Studies have shown that oral anticoagulation is both preventative and can reverse early structural valve deterioration when it occurs in most cases. This has led to discussion at some centers of oral anticoagulation for all or selected TAVR patients to prevent early structural valve deterioration.

The association of oral anticoagulation with mortality in this study is difficult to fully assess. Sorting out comorbidities in this type of registry and the fact that most receiving oral anticoagulation in the trial had AF, a known association with mortality, complicates this relationship. Even with this limitation, it still gives one pause about the unbridled use of oral anticoagulation. The bottom line is that for TAVR, randomized trials will be needed to obtain a better answer to the question of anticoagulation, and those trials are coming.

EWOLUTION

Pershad: Two-year data from the EWOLUTION registry of a left atrial appendage closure device (Watchman, Boston Scientific) showed it conferred a reduction in adverse events in 1,025 patients with a history of stroke. Compared with historical data on vitamin K antagonist use, the device was associated with an 83% reduction in ischemic stroke. It also produced a 46% reduction in oral anticoagulant use. Bleeding was reduced by 67% in patients with prior hemorrhagic stroke and by 30% in patients with prior major bleeding.

This provided us with some important real-world data, which is great because randomized trials do not often tell you what happens when the therapy is rolled out outside the confines of that trial. This registry, which essentially excluded all patients who would have been enrolled in the randomized trial, allows us to do that. Having 2-year data is also important because 1 year is often not enough time to tell us what happens after patients stop taking their anticoagulants.

Having said that, these data are not adjudicated, which can raise concerns about their validity. But that is less of a concern for descriptive data, such as presence or absence of an anticoagulant, readmission to the hospital or presence of recurrent stroke. This increases the believability of the follow-up data.

Aspirin Trials

Bhatt: The question of whether aspirin has a role in primary prevention in the contemporary era is probably one of the hottest questions in CV medicine. There were two very relevant trials presented at the ESC Congress.

ASCEND examined aspirin vs. placebo in 15,480 diabetic patients without any obvious atherosclerosis over a median of 7.4 years. ARRIVE examined a much broader primary prevention population of 12,546 patients that was meant to be high risk, but the patients enrolled did not have particularly high event rates.

I thought the ASCEND trial was rather easy to interpret. It met its overall primary endpoint of a significant reduction in ischemic events, defined as MI, ischemic stroke, transient ischemic attack or CV death excluding intracranial hemorrhage (rate ratio = 0.88; 95% CI, 0.79-0.97). There was, as expected, an excess in nonfatal bleeding (rate ratio = 1.29; 95% CI, 1.09-1.52). The magnitude of the decrease in ischemic events was rather similar to that of the increase in bleeding. The researchers concluded — and it was reported in the media — that it was a negative trial because the benefits equaled the risks, therefore the net clinical benefit was null. But I think that is a very unsophisticated and incorrect way of interpreting the trial. It is not a surprise to have more bleeding with an antithrombotic vs. placebo. But if the reduction in irrevocable permanent ischemic events such as ischemic stroke and MI is greater than the increase in severe bleeding events, to me, that’s a good net clinical benefit. You can’t equate ischemic stroke and MI with transfusions. To me, ASCEND was a positive study, but that does not mean every patient with diabetes in the primary prevention world should be started on aspirin. You must use good clinical judgment.

ARRIVE examined patients requiring primary prevention, and it ended up enrolling, as often happens in trials, patients who were much lower risk than intended. That limited the power of the trial. The overall intention-to-treat primary endpoint of time to first occurrence of CV death, MI, unstable angina, stroke or TIA at a median of 5 years was neutral (HR = 0.96; 95% CI, 0.81-1.13), so the conservative interpretation is that the trial was neutral and aspirin offered no benefit. However, if one looks at the on-treatment and per-protocol analyses, there were significant reductions in ischemic events, and rates of intracranial hemorrhage were extremely low in this low-risk, carefully selected, carefully monitored population. So, there is a kernel of positivity within the trial.

This does not mean patients should be taking aspirin for primary prevention on their own. The broad use of aspirin on a population level is not supported, but I never believed that was a good strategy. There may be a role for aspirin in high-risk primary prevention, but its use should always involve a discussion between the physician and the patient.

Mehran: The role of aspirin in primary prevention has been well-established in prior studies, but the ASCEND and ARRIVE trials bring back into question whether aspirin is really preventing CV events. The previous studies that supported the role of aspirin were much older and were in patients not on therapies such as statins and BP medications, and we have made huge strides in medical therapy for BP control and other risk-factor modifications. If aspirin is relegated to sloughing the gastrointestinal tract and not really providing the ischemic protection we’re looking for, we need to question that. What’s great about science is that we constantly question ourselves to try to do the best for our patients.

Disclosures: Bhatt reports he has financial ties with multiple pharmaceutical and device companies. Kern reports he has spoken for Abbott/St. Jude Medical, Acist, CathWorks, HeartFlow, Opsens and Philips/Volcano and he was a member of the clinical events committee for FAME 2. Mehran reports she receives research grants from Abbott, AstraZeneca, Bayer, Boston Scientific, Daiichi Sankyo and Janssen and consultant fees or royalties from Abbott, Bayer, Boston Scientific and CSL Behring. Montalescot and Pershad report no relevant financial disclosures. Reardon reports he is a consultant/advisory board member for Medtronic. Thiele reports he receives grant and research support from the European Union and German Cardiac Society German Heart Research Foundation. Valgimigli reports he received grants from Terumo and The Medicines Company during the conduct of MATRIX; grants and personal fees from AstraZeneca; personal fees and nonfinancial support from The Medicines Company; and personal fees from Abbott Vascular, Alvimedica, Correvio, St. Jude Vascular and The Medicines Company outside the context of MATRIX.