Introduction
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

Although the American Heart Association Scientific Sessions 2018 (AHA 2018) was not an interventional-focused meeting, AHA 2018 had a strong selection of late-breaking science that impacted interventional cardiology. The following summarizes of some of the most impactful studies presented at AHA 2018. Our authors have done a commendable job succinctly summarizing the trials and offering brief commentary for your rapid reading and understanding. As always, your comments are appreciated.

FREEDOM Follow-On Study (Long-Term Survival Following Multivessel Revascularization in Patients with Diabetes)
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The Freedom (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial was a first-generation randomized trial of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in patients with diabetes mellitus. An earlier report showed that CABG was preferable at a 3.8-year follow-up, but the p value was borderline. The goal of the FREEDOM Follow-On Study was to provide longer-term follow-up. The late results (mean = 4.9 years; median = 7.5 years) were reported at AHA 2018. The original cohort included 1,900 patients. The follow-up cohort included 943 patients from 25 centers. There were no differences in patient demographics between the original cohort and the extended, follow-up group. Total mortality was 24.31% in the PCI group compared with 18.30% in the CABG group (hazard ratio 1.36; 95% confidence interval; 1.07-1.74; p = 0.01). Thus, the risk of mortality was significantly higher in the PCI group over total follow-up.

This trial continues to document worse outcomes for patient with diabetes and was not different for insulin-dependent versus non-insulin-dependent diabetics, which is consistent with current guidelines recommending CABG as the preferred revascularization approach in patients with diabetes mellitus.

A few comments are important relative to PCI in 2019:

• Current-generation stents demonstrate improved outcomes, which would have a benefit only for PCI patients.
• In addition, decisions regarding lesions to treat in this multivessel cohort could potentially be limited to only hemodynamically significant lesions if fractional flow reserve were employed. This likewise could improve results if this study were repeated today.
• With better technology for chronic total occlusion PCI, more complete revascularization may be possible today, likely improving late outcome.
• More stringent lipid management is possible today.
• Newer diabetic medications, particularly SGLT2 agents, likely would improve outcomes.

Surgery has potentially improved, with greater emphasis on all arterial revascularization. And the newer, add-on lipid and diabetes medications can apply to surgery patients as well. Thus, it is not easy to definitively challenge applicability of these late results to current clinical outcomes for PCI alone. In reality, many patients are not ideal operable candidates or are patients who desire PCI despite its limitations because of early stroke risk, which was higher with CABG. Thus, PCI will continue as a relatively frequent revascularization modality for diabetic patients.

It will be imperative to assess the impact of the newer therapeutic approaches in these diabetic patients to look for signals of improved outcomes. If outcomes significantly improve in smaller subgroups related to later-generation stents, revascularization strategies, and/or better medications, then it may become important to consider a new randomized trial of CABG versus PCI in diabetic patients. Until such time, CABG remains the preferred strategy for revascularization in diabetic patients provided the patients have the anatomic and clinical features consistent with expected optimal surgical outcomes.

T-TIME (Trial of Low-Dose Adjunctive Alteplase During Primary PCI)
By Angela Taylor, MD, MS
University of Virginia Children's Heart Center
Charlottesville, VA

Multiple studies have assessed the use of adjunctive therapies during primary PCI for ST-segment elevation myocardial infarction (STEMI) with the objective of reducing microvascular obstruction and, thus, infarct size. These have included the use of distal protection devices, catheter-based aspiration thrombectomy, half-dose lytics in combination with glycoprotein IIb/IIIa receptor blockade, adenosine, hypothermia, stem cell injection, magnesium, pexelizumab, and glucose/insulin/potassium infusion. Although many of these methodologies demonstrated promising preliminary data, none proved beneficial in large clinical trials.

T-TIME assessed the use of adjunctive low-dose alteplase at the time of primary PCI for STEMI given as an intracoronary infusion after reperfusion but prior to stenting in a small group of 440 subjects. Randomization was in a 1:1:1 fashion to alteplase 10 mg, alteplase 20 mg, or placebo. Microvascular obstruction was assessed with contrast-enhanced magnetic resonance imaging (MRI) as percent of left ventricular (LV) mass, and patients were followed for 3 months. Perhaps not surprisingly, there was no difference in the primary outcome of microvascular obstruction (2.3% vs. 2.6% vs. 3.5%, respectively). Perhaps somewhat unexpected was the statistically significant increase in troponin seen in the alteplase arms compared with placebo. Although not powered for these secondary endpoints, there were no differences in major cardiac events, Thrombolysis in Myocardial Infarction perfusion grade, or major bleeding.

T-TIME was not the first study to investigate the use of half-dose lytics in primary PCI. Previous studies, ASSENT-3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen)1 and GUSTO-V (Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial Infarction),2 assessed the use of half-dose lytics in combination with glycoprotein IIb/IIIa inhibitors in over 28,000 patients combined. Although they did demonstrate a reduction in recurrent ischemia, there was no survival benefit and a cost of higher bleeding rates. Earlier data have suggested that in order to improve mortality by 1%, a 20% improvement in Thrombolysis in Myocardial Infarction flow is needed.3 None of the earlier trials, nor T-TIME, accomplished this with the addition of half-dose lytics. Trials such as ASSENT-3 and GUSTO-V were equivocal at best, but T-TIME actually suggests potential harm with no improvement in microvascular obstruction and a potential increase in infarct size suggested by higher troponin elevations. Given the totality of data, the idea that low-dose adjunctive thrombolytic therapy will be of any benefit in primary PCI for STEMI can now be soundly put to bed.

Cardiac Remodeling Following Ligation of Arteriovenous Fistula in Stable Renal Transplant Recipients
By James A. Goldstein, MD, FACC
William Beaumont Hospital, Division of Cardiology
Royal Oak, MI

This randomized controlled study demonstrated that ligation of a functioning arteriovenous fistula (AVF) post-renal transplant reduced myocardial mass 15% assessed at 6 months by cardiac MRI, whereas there was no change in controls. Secondarily, significant decreases in bi-ventricular and bi-atrial volumes were also observed.

The authors should be congratulated for a provocative study that has potentially important clinical implications. AVF flows in the forearm reach 500-900 mL/min and in the upper arm range 900-1,500 mL/min. The presence of an AVF lowers systemic vascular resistance, resulting in increased stroke volume and cardiac output, which may lead to LV volume overload and eccentric LV hypertrophy. AVF has been associated with hemodynamic complications, including high-output cardiac failure and pulmonary hypertension. Further, LV hypertrophy is common (near universal) in patients with end‐stage renal failure and contributes to their morbidity and mortality (i.e., heart failure with preserved ejection fraction). Prior reports of AVF closure have described improvement in selected patients with high-output failure. Previous echocardiographic studies also suggest rapid and sustained LV mass reduction after AVF ligation. However, concern has been raised that routine closure might not obtain the expected benefits in cardiac remodeling owing to elevation of diastolic blood pressure and arterial stiffness caused by AVF ligation. The present findings documenting marked reduction in LV mass after AVF ligation (and the lack of any in the control group) are striking and support the need for future studies to delineate the long-term morphological, hemodynamic, and clinical effects of a strategy of routine AVF ligation.

EARLY (Optimal Timing of Intervention in NSTE-ACS Without Pretreatment With P2Y12-ADP Receptor Antagonists)
By Jose E. Exaire, MD, FACC
VCU Health
Richmond, VA

The EARLY trial randomized 709 patients with moderate to severe non-ST-segment elevation myocardial infarction (NSTEMI)/unstable angina (Grace mean score of 122) to very early (within 2 hours of randomization) versus delayed invasive strategy (12-24 hours after randomization). Of the total number of patients, 70% were troponin-positive on admission. The EARLY trial mandated no pre-treatment with P2Y12 inhibitors on hospital admission based on the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial that showed negative results when using upstream prasugrel pre-treatment (no change in ischemic events while increasing the risk of major bleeding). Nevertheless, 21% of the patients in the EARLY trial received an upstream dose of oral antiplatelets. In total, 78% of patients in the delayed arm underwent PCI, 3.0% underwent CABG surgery, and 19.0% were treated with medical therapy. Conversely, 71.7% of those in the very-early invasive strategy underwent PCI, 2.8% were treated surgically, and 25.5% received medical therapy. The primary outcome of cardiovascular (CV) death or recurrent ischemia at 30 days was 4.5% versus 21.3% (p < 0.001) in favor of very early strategy. The outcome was driven entirely by recurrent ischemia (4.1% vs. 20.7%, p < 0.001), and CV death was similar in both groups (0.6% vs. 1.1%, p = 0.69). Likewise, myocardial infarction (1.2% vs. 0.8%, p = 0.72), bleeding defined as BARC score >3 (0.3% vs. 0.8%), and length of stay (7.5 vs. 5.8 days, p = 0.046) were similar in both groups.

The 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes concur with the avoidance of upstream prasugrel use (Class III recommendation); however, it gives a Class IIa endorsement for upstream use of clopidogrel or ticagrelor when an early invasive strategy is planned.4 Therefore, at least 50-70% of the patients are routinely loaded with P2Y12 inhibitors, making it hard to apply the findings of this trial to daily practice. Likewise, the guidelines define early invasive strategy as PCI within the first 24 hours of presentation, making the 2-hour window used in the EARLY trial relatively out of the ordinary for practice. Due to the relatively high upstream use of P2Y12 inhibitors in the trial and the loose definition of recurrent ischemia, it is hard to associate the reduction in recurrent ischemia neatly to the pure effect of the very early revascularization. The major weakness of the trial was the mandate to delay P2Y12 inhibition for up to 24 hours because this is not often done in clinical practice, and it could partially explain the higher rate of clinical recurrent ischemia in patients with NSTEMI/unstable angina. More studies are needed to clarify the use of very early revascularization strategies in patients who are receiving optimal medical treatment.

Ten-Year Results From the ISAR-TEST 4 Randomized Trial
By Michael P. Savage, MD, FACC
Sidney Kimmel Medical College at Thomas Jefferson University
Thomas Jefferson University Hospital
Philadelphia, PA

The ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4) trial compared the safety and efficacy of a bioresorbable polymer sirolimus-eluting stent (BP-SES), Yukon Choice PC (Translumina Therapeutics; New Delhi, India); a new-generation permanent polymer everolimus-eluting stent (PP-EES), Xience (Abbott Vascular; Green Oaks, IL); and a first-generation permanent polymer sirolimus-eluting stent (PP-SES), Cypher (Cordis Corporation; Baar, Switzerland). The extended 10-year follow-up results of the trial were presented as a late-breaking presentation at AHA 2018. The primary endpoint was major adverse cardiac events (MACE) defined as death, myocardial infarction, or target lesion revascularization. The 10-year follow-up results were available in 83% of the patients. The incidence of MACE at 10 years was significantly higher in the PP-SES group (54.9%) than in the PP-EES (46.0%) or BP-SES (47.7%) groups. All-cause mortality was also significantly higher with PP-SES (37.2%) than with PP-EES (30.3%) or BP-SES (31.8%). There were no significant differences between PP-EES and BP-SES.

Newer-generation DES have been shown to have superior clinical outcomes compared with first-generation DES for the initial few years after implantation. However, there is a paucity of extended longer-term data on these devices. This analysis from the ISAR-TEST 4 trial helps to fill this important data gap. Compared with the Cypher PP-SES, the newer generation Xience PP-EES demonstrated truly long-term clinical superiority with lower rates of MACE, definite stent thrombosis, and mortality. Not only was there no evidence of a late catch-up phenomenon with the newer-generation PP-EES, but the event curves continue to separate from 5 to 10 years.

It is notable that the sirolimus-eluting stent with a biodegradable polymer was superior to the first generation sirolimus-eluting Cypher stent. These results suggest that the "problem" leading to more late clinical events with the first-generation Cypher DES was due to the thicker stent struts or the specific permanent polymer rather than the sirolimus drug per se. On the other hand, the biodegradable-polymer stent offered no clinical advantage over the newer-generation Xience everolimus-eluting stent, which has a permanent polymer. Most importantly, these results are reassuring in that they demonstrate the favorable long-term clinical durability of everolimus-eluting stents in contemporary use.

Neuroprotect Trial (Early Goal-directed Hemodynamic Optimization in Comatose Survivors After Out-of-hospital Cardiac Arrest)
By Kapildeo Lotun, MD, FACC
Sarver Heart Center, University of Arizona
Tucson, AZ
George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The Neuroprotect trial reported the results of 112 survivors of out-of-hospital cardiac arrest who remained unconscious at the time of hospital admission who were randomized to early, goal-directed hemodynamic optimization to achieve a mean arterial blood pressure of 85-100 mmHg during the first 36 hours of hospital care versus usual care. Early, goal-directed hemodynamic optimization is safe and improved cerebral blood flow versus standard care but did not reduce the extent of ischemic brain damage on diffusion-weighted MRI. Likewise, functional outcome was not significantly changed. Thus, the study demonstrated that the early, goal-directed hemodynamic optimization concept increased cerebral perfusion and oxygenation but failed to impact outcomes.

The outcome is disappointing because the interventions were safe and met their prescribed goals. The aim was good, but it was a little broad in scope. Although the endpoint was not reached, subset analysis will look for signals and also risk stratify patients who can benefit with this strategy. However, the results again emphasize that the outcome following cardiac arrest is complex with multiple intersecting factors related to time to return of spontaneous circulation and inflammatory mechanisms.

The Door to Unload (DTU) STEMI Safety & Feasibility Pilot Trial
By Perwaiz M. Meraj, MD, FACC
Cohen Children's Medical Center of New York
Queens, NY
George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

Door-to-balloon strategies to reduce hospital mortality over the past 10+ years have been highly effective. However, despite lower in-hospital mortality, late post hospital heart failure and consequent heart failure mortality have increased significantly related to the residual size of the myocardial damage. These consequences have increased research into reducing infarct size during myocardial infarction in addition to mortality. An important finding has been that LV unloading before is associated with reduced infarct size based on greater muscle salvage. Based on these non-human studies, unloading with a delay of 30 minutes before reperfusion is optimal.

To test this hypothesis, the DTU feasibility pilot trial was designed to test the ability to safely perform such a trial. The pilot trial randomized 50 patients with an anterior myocardial infarction to immediate reperfusion versus delayed reperfusion (30-minute delay) All patients were unloaded with an Impella CP (Abiomed, Inc.; Danvers, MA) before either reperfusion strategy. Safety and feasibility were determined by composite risk of major adverse CV and cerebral vascular events at 30 days. An assessment of efficacy was based on MRI-defined infarct size at 30 days.

There were 25 patients in each arm with mean door-to-balloon of 72 minutes in the immediate reperfusion group and 97 minutes in the delayed reperfusion group. Importantly, there were 2 crossover patients from the delayed group to the immediate group because of concerning instability in the delayed group. No differences in major adverse events were seen for either group at 30 days (8% vs. 12%, p = 0.99). MRI measures of infarct size as a percent of myocardial mass showed no significant difference between groups at 30 days (15 ± 12% vs. 13 ± 11%, p = 0.53). Thus, the feasibility of the concept was proven.

A tantalizing secondary analysis (the trial was not powered to demonstrate efficacy) showed that patients with the largest predicted infarct size based on total ST-segment sums showed a benefit at the greatest infarct size.

With this background investigators can now plan and proceed with a pivotal trial to determine if a strategy of immediate unloading with a delayed strategy of reperfusion can reduce infarct size and thus ultimately reduce post-infarct mortality and heart failure complications, leading to improved late outcomes.

References

1. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-13.
2. Topol EJ, GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001;357:1905-14.
3. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Eng J Med 1993;329:1615-22.
4. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-e228.

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