Important Trial Results for Interventional Cardiology From ACC.19

May 13, 2019   |  George W. Vetrovec, MD, MACC; Peter C. Block, MD, FACC; Tarek Helmy, MD, FACC; Karl B. Kern, MD, FACC; Barbara D Lawson, MD, FACC; Michael J. Lim, MD, FACC; Michael J. Lipinski, MD, PHD; Rajan Patel, MD, FACC; Alina M. Robert, MD, FACC; Barry F. Uretsky, MD, FACC

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

The American College of Cardiology's 68th Annual Scientific Session & Expo (ACC.19) offered a robust grouping of late-breaking clinical trials, from the extensive and favorable evolution of mitral and aortic valve therapies to the latest on extending the timing and optimal combinations of antiplatelet strategies to ensure maximum simplicity, efficacy, and safety. The continued evaluation of optimal radial application did not escape the trial list, and neither did the application of sonography (sonothrombolysis) to support earlier coronary reperfusion in ST-segment elevation myocardial infarction (STEMI), which potentially could improve outcomes for remote transport.

I believe this one of the most thorough collections we have published. I want to thank all the contributors for their excellent, succinct, and thoughtful commentary. We continue to balance academic commentary with physician practice perspectives.

I trust you, the readers, will find this a helpful summary of the new interventional science at ACC.19. As always, comments are welcome.

TAVR in Low Risk Patients: PARTNER 3 and Evolut Low Risk Trials
By Peter C. Block, MD, FACC
Emory University Hospital
Atlanta, GA

The randomized PARTNER 3 (Placement of Aortic Transcatheter Valves 3) (for patients with Society of Thoracic Surgeons (STS) scores <4%) and the Evolut Low Risk (Evolut Surgical Replacement and Transcatheter Aortic Valve Implantation in Low Risk Patients) (for patients with STS scores <3%) trials both studied whether TAVR (transcatheter aortic valve replacement), using the Edwards Lifesciences (Irvine, CA) balloon expandable valve in the former and the Medtronic (Dublin, Ireland) self-expanding valve in the latter, was non-inferior to surgical aortic valve replacement (SAVR). SAVR in both trials was superbly performed and set a high bar for TAVR outcomes.

PARTNER 3

The primary outcome, all-cause mortality, stroke, or cardiac rehospitalization at 1 year occurred in 8.5% of the TAVR group compared with 15.1% of the SAVR group (p < 0.001 for noninferiority; p = 0.001 for superiority). Secondary outcomes almost across the board also favored TAVR:

  • Stroke at 30 days was 0.6% for TAVR versus 2.4% for SAVR (p = 0.02)
  • New-onset atrial fibrillation at 30 days was 5.0% for TAVR versus 39.5% for SAVR (p < 0.001)
  • Death or disabling stroke at 1 year was 1.0% for TAVR versus 2.9% for SAVR (p < 0.05)
  • Length of stay was 3 days for TAVR versus 7 days for SAVR (p < 0.001)

However, SAVR had less mild paravalvular aortic regurgitation at 1 year: 29.4% for TAVR versus 2.1% for SAVR (p < 0.05).

Evolut Low Risk

All-cause mortality or disabling stroke at 30 days favored TAVR: 0.8% vs. 2.6% (p < 0.05), although all-cause mortality alone at 30 days was not significant (0.5% vs. 1.3% (p > 0.05). Other outcomes also favored TAVR: death, disabling stroke, life-threatening bleeding, major vascular complications, stage 2/3 kidney injury (5.3% vs. 10.7% [p < 0.05]) and all strokes at 30 days (3.4% vs. 5.6% [p < 0.05]). As in PARTNER 3, and as no surprise, atrial fibrillation at 30 days (7.7% vs. 35.4% [p < 0.05]) and life-threatening or disabling bleeding at 30 days (2.4% vs. 7.5% [p < 0.05]) favored TAVR. But new permanent pacemaker need at 30 days (17.4% vs. 6.1% [p < 0.05]) and moderate to severe paravalvular leak (3.5% vs. 0.5% [p < 0.05]) favored SAVR. Perhaps most importantly, if stroke were added to the combined endpoint of death and hospitalization at 2-year follow-up in Evolut Low Risk, TAVR also "beat" SAVR.

The outcomes of the two trials should be evaluated together. In short, even in low-risk patients in need of aortic valve replacement, TAVR needs to be included in any informed consent conversation because both trials showed non-inferiority of TAVR to SAVR. Should all patients with aortic stenosis have a TAVR? Absolutely not! Patients with a bicuspid valve, small aortic annuli, severe aortic or mitral regurgitation (MR), or low left ventricular ejection fraction (LVEF) <30% were excluded and might be better served with SAVR. Trials are underway evaluating TAVR in patients with bicuspid valves, but remember that congenital bicuspid valves are associated with proximal aortopathy that may need repair. There is still need for excellent cardiac surgery. Nonetheless, these two landmark trials support TAVR in most patients with aortic stenosis. As a final note, it is important to point out that both trials will continue to follow up patients in the long term—for 3-10 years in PARTNER 3. Those data will also help us understand the stability of TAVR valves over time and help address valve degeneration in TAVR patients.

One-Year Impact on Medical Practice and Clinical Outcomes of FFRCT: The ADVANCE Registry
By Tarek Helmy, MD, FACC
Center for Comprehensive Cardiovascular Care, Saint Louis University
St. Louis, MO

This is an analysis of 5,083 patients prospectively enrolled in multicenter international registry from July 15, 2015, to October 20, 2017. Patients with documented coronary artery disease on computed tomography coronary angiography (CTCA) had computed tomography-derived fractional flow reserve (FFRCT) evaluated for lesions between 30% and 90% stenosis. The treating physicians were asked to submit a management plan based on the CTCA results initially and then an updated plan based on the results of the FFRCT. Impacts of FFRCT on treatment strategy, as well as patient outcomes, are reported in this analysis.

The planned analysis included evaluation of the primary endpoint of major adverse cardiovascular events (MACE) at 1 year and downstream clinical management. The clinical endpoints included survival free from MACE inclusive of myocardial infarction (MI), all-cause mortality, or unplanned hospitalization for acute coronary syndrome (ACS) leading to revascularization. Furthermore, cardiovascular death in combination with MI was assessed at 1 year, as was the incidence of revascularization.

Patients with stenosis >50% and FFRCT <0.8 were more likely to get revascularization. At 1 year, in patients with FFRCT >0.8, there was a trend toward lower MACE but statistically significant lower rates of cardiovascular death and MI. There was good incorporation of FFRCT results in the management plan, and most patients recommended for medical therapy remained on medical therapy at 1 year with no significant adverse events.

These results, based on real-world observational data, support the potential application of CTCA enhanced with FFRCT for interventional revascularization decisions. This strategy should be considered for use in day-to-day practice.

COACT: Coronary Angiography After Cardiac Arrest Without ST-Segment Elevation
By Karl B. Kern, MD, FACC
Sarver Heart Center, University of Arizona
Tucson, AZ

The COACT trial (Coronary Angiography after Cardiac Arrest) is the first published randomized clinical trial evaluating the strategy of immediate coronary angiography versus delayed coronary angiography in patients successfully resuscitated after out-of-hospital cardiac arrest with an initial shockable rhythm and no ST-segment elevation on their electrocardiogram. A total of 552 patients was randomized. The primary endpoint was survival at 90 days, at which time 64.5% (176/273) of patients receiving immediate angiography and 67.2% (178/265) of patients in the delayed angiography group were alive (odds ratio 0.89; 95% confidence interval [CI], 0.62-1.27; p = 0.51).

This is the first report of 9 separate randomized clinical trials examining this issue in post-arrest patients without ST-segment elevation.1 Over the next decade when all of these trials are completed, more than 4,000 patients will have been studied. The COACT trial was well-done. No difference in the primary endpoint of 90-day survival was found. It should be appreciated that both arms of this trial had excellent survival rates, indeed much higher than the reported 25% post-resuscitation survival rate in the 1990s.2

A surprising finding was the low incidence of acute coronary thrombotic occlusion found among these resuscitated cardiac arrest patients: only 5% among all those undergoing coronary angiography and just 3.4% among those randomized to immediate angiography. Multiple non-randomized cohort studies involving 3,900 post-arrest patients without ST-segment elevation have found an acutely occluded coronary artery in 31%.3-8 This is the difference between only 1 in 25 patients having an acutely occluded coronary versus 1 in 3! Unquestionably, the cohort experience could include a significant selection bias, but the consistency among reports is striking. What is the actual incidence of acute coronary occlusion in the resuscitated patient without ST-segment elevation? That is the critical question we must answer before we can determine the optimal use of coronary angiography among those successfully resuscitated from out-of-hospital cardiac arrest but without associated STEMI. Of note, this group includes nearly 75% of resuscitated out-of-hospital cardiac arrest patients.6 If the incidence really is less than 5%, then immediate coronary angiography is not necessary. But if 1 in 3 patients has an occluded major coronary artery requiring timely reperfusion to preserve long-term myocardial function, then we need to provide such timely reperfusion even if immediate catheterization does not result in primary percutaneous coronary intervention (PCI) in 2 out of every 3 patients. As the other randomized clinical trials finish and report their findings, we should be able to determine the true incidence of acutely occluded coronaries in those resuscitated but without ST-segment elevation.

The real issue is about finding acutely occluded culprit vessels needing timely reperfusion and not just electrocardiographic findings. If timely reperfusion of such a thrombotic coronary is not achieved, heart muscle will be lost. Survival may or may not be significantly impacted, but that should not be the only goal. Quality of life, being able to return to meaningful physical activities without shortness of breath and heart failure (HF), is also an important goal.

GLASSY: Primary Results of the GLOBAL LEADERS Adjudication Sub-Study
By Barbara D. Lawson, MD
VCU Health
Richmond, VA

The goal of GLOBAL LEADERS was to determine whether P2Y12 monotherapy, rather than aspirin monotherapy, might sufficiently limit bleeding risk while retaining the ischemic benefits. In the study, nearly 16,000 patients with ACS or stable angina requiring PCI were randomized to aspirin plus ticagrelor for 1 month followed by ticagrelor alone for 23 months versus dual antiplatelet therapy (DAPT) for 1 year (clopidogrel if stable angina, ticagrelor if ACS) followed by aspirin alone for an extra year. In GLOBAL LEADERS, there was no significant decrease in all-cause mortality or new Q-wave MI in the ticagrelor monotherapy group, nor was there any significant difference in bleeding. The clinical endpoints for the study were investigator reported, however, and not centrally adjudicated. GLASSY (GLOBAL LEADERS Adjudication Sub-Study) used an independent central adjudication process to review not only the reported events from GLOBAL LEADERS but also potential unreported events. Regarding the primary efficacy endpoint of all-cause death, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization, ticagrelor monotherapy was noninferior to conventional therapy (8.41% vs. 7.14%; relative risk reduction 15%) but not superior. In addition, there was no difference in BARC 3 or 5 major bleeding between groups (2.46% in both groups). Among secondary endpoints, there was no difference in all-cause death, cardiac death, stroke, MI, or definite stent thrombosis at 2 years. Urgent target vessel revascularization was significantly reduced in the ticagrelor monotherapy group (1.87% vs. 2.72%; relative risk 0.69; 95% CI, 0.51-0.93). In a landmark analysis looking at the primary endpoint and most of the secondary endpoints at 1 versus 2 years, there was no sign of increased ischemic risk for ticagrelor monotherapy within the first year, but there was the suggestion of benefit in terms of MI (p for interaction = 0.062) and definite stent thrombosis (p for interaction = 0.007) after the first year. The study concludes that discontinuation of aspirin after 1 month while continuing of ticagrelor alone does not expose patients to a higher ischemic or bleeding risk and may decrease the risk of MI or stent thrombosis.

One of the major areas of investigation in interventional cardiology focuses on finding the ideal method and duration of DAPT that will balance the reduction in ischemic events with the increased bleeding risk. Longer DAPT duration appears to mitigate ischemic risk but increases bleeding risk. Current practice entails a period of DAPT, with the P2Y12 inhibitor typically being discontinued in favor of aspirin monotherapy after the prespecified duration of dual therapy. Most older studies have looked at shorter duration of DAPT before switching to aspirin monotherapy, but many recent studies are investigating brief DAPT followed by P2Y12 monotherapy. For example, the SMART-CHOICE (P2Y12 Inhibitor Monotherapy vs. Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention) trial stopped aspirin after 3 months and continued any of the P2Y12 inhibitors (clopidogrel, ticagrelor, or prasugrel), the STOPDAPT-2 (One-Month Dual Antiplatelet Therapy Followed by Clopidogrel Monotherapy vs. Standard 12-Month Dual Antiplatelet Therapy With Clopidogrel After Drug-Eluting Stent Implantation) trial stopped aspirin after 1 month and continued clopidogrel or prasugrel, and GLOBAL LEADERS/GLASSY stopped aspirin after 1 month and continued ticagrelor. In general, the results have consistently shown non-inferiority for ischemic events, with variable results on bleeding: some show no difference, and others show decreased bleeding. At this point, the data should not change clinical practice because the benefit of P2Y12 monotherapy over aspirin monotherapy in reducing ischemic events has not been definitively shown. What we now know is that P2Y12 monotherapy is non-inferior to a conventional treatment strategy, with some suggestions (in secondary endpoints and subset analyses) that there may be some ischemic benefits (MI and stent thrombosis). More data are needed before we can truly justify a change in practice. If studies don't show a convincing benefit to P2Y12 monotherapy over aspirin monotherapy, perhaps we should stick with conventional aspirin monotherapy after a period of DAPT. This is particularly relevant when considering patients who need non-cardiac surgery after PCI. Most surgeons are willing to operate on aspirin but prefer not to operate on a P2Y12 inhibitor due to increased bleeding risk. If clinical practice evolves to P2Y12 monotherapy after a short duration of DAPT, it should be with sound clinical evidence to support it.

COAPT Follow-Up Sub-Studies
By Michael J. Lim, MD, FACC
Center for Comprehensive Cardiovascular Care, Saint Louis University
St. Louis, MO

ACC.19 in New Orleans, LA, showcased more information on what promises to be a paradigm shift in therapy for many patients with HF. For years, patients with dilated left ventricles and resultant (secondary) MR have posed a clinical question: "Can elimination of MR effectively change the outcome for these patients?" Previously, we were given only limited data to address this ever-growing patient population because surgical mitral valve repair or replacement were our only options, and limited registry data as well as single center case series painted an unclear answer. Last fall, the MITRA-FR (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trials were both presented; the COAPT trial showed a marked benefit to MitraClip (Abbott; Abbott Park, IL) therapy, and the MITRA-FR trial showed no benefit. Two separate presentations on this topic from ACC.19 provided us with more insights to advance our knowledge given the seemingly paradoxical nature of the catheter transcatheter mitral valve replacement data.

The first, by Dr. Suzanne Arnold, described the improvement in quality of life as part of the COAPT trial. Utilizing two well-described and accepted tools (the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the SF-36), patients from the COAPT trial were evaluated on their overall change during the clinical trial period of 24 months, comparing MitraClip (n = 302) to standard care (n = 309). Changes in the KCCQ and the SF-36 showed significant improvements with transcatheter mitral valve replacement in this patient cohort that were seen immediately post-procedure and sustained during the follow-up period. The data showed that number needed to treat to have 1 patient alive and with a large improvement in KCCQ score was 5.7!

In the second, Dr. Federico Asch presented the echocardiographic data from the COAPT trial. With the COAPT trial showing a 43% relative risk reduction in all-cause mortality or HF hospitalization over standard care, the evolving thought for many clinicians has turned to trying to identify which patients should be referred for this therapy. From this presentation, the key to addressing this appears to be twofold:

  1. HF was rigorously managed in all patients within the COAPT trial prior to undergoing transcatheter mitral valve replacement.
  2. The echocardiographic selection criteria were specific in defining "a COAPT patient."

Specifically, almost 86% of the patients included in the study had an effective regurgitant orifice area ≥0.3 cm2 or pulmonary vein systolic flow reversal. With 84.1% of COAPT patients achieving ≥2 grades of reduction in MR, only the echocardiographic right ventricular systolic pressure was found to significantly predict poor mortality after MitraClip. In contrast, tricuspid regurgitation grade, LVEF, right ventricular systolic pressure, and effective regurgitant orifice area were all negatively correlated to worsened outcomes in the medical therapy patients.

Taken together, these data offer the following initial thoughts:

  1. The COAPT trial is the first trial that has shown that therapeutic reduction of secondary MR provides significant benefit to patients with HF, including marked improvement in quality of life, as well as mortality and HF hospitalization rates.
  2. We need to avoid the urge to rely on procedures alone to provide the benefits to our patients because COAPT patients were aggressively managed from a medical standpoint prior to undergoing therapy for MR reduction.
  3. We should aspire to duplicate the abilities of our echocardiography laboratory assessment of secondary MR as was performed in the COAPT trial, with careful understanding of the overall picture to find those patients in our practice who would fit into the trial as performed and thereby potentially receive benefits like those seen in the study.
  4. We eagerly await more of these types of data to further define the COAPT patient population in the future.

Ticagrelor Reversal: Think of the Possibilities
By Michael J. Lipinski, MD, PhD
Cardiovascular Associates of Charlottesville
Charlottesville, VA

Ticagrelor is an oral reversible P2Y12 inhibitor frequently utilized in combination with aspirin for the treatment of ACS and in patients undergoing PCI. Bleeding in the setting of DAPT can place patients at major risk of morbidity and mortality and may also significantly increase the risk of perioperative bleeding in both cardiac and non-cardiac surgery. The ability to reverse the antiplatelet effects of ticagrelor and restore normal platelet aggregation could pose a major advance in the treatment of acute hemorrhage of patients taking ticagrelor and also enable rapid reversal of its antiplatelet effects in patients requiring surgery. This may potentially obviate the need to discontinue ticagrelor several days prior to surgery, which potentially increases the risk of MACE during this time period. Similarly, interventional cardiologists even place coronary bare-metal stents in select patients that may necessitate early interruption of dual antiplatelet therapy when patients are in need of surgical treatment, such as in the setting of malignancy.

Dr. Deepak Bhatt and colleagues recently presented "First Randomized Human Experience With Ticagrelor Reversal Agent" at ACC.19 and simultaneously published their manuscript in the New England Journal of Medicine. The authors randomized 16 patients to placebo and 48 patients to different scenarios with ticagrelor treatment and different regimens of ticagrelor reversal agent. Importantly, the authors demonstrated that bolus and infusion of the ticagrelor reversal agent PB2452 resulted in immediate and sustained reversal of the antiplatelet effects of ticagrelor. This was confirmed with several assays of platelet function and aggregation, such as light transmission aggregometry, VerifyNow P2Y12 assay, and vasodilator stimulated phosphoprotein platelet reactivity index. Reversal occurred within 5 minutes after administration of the bolus, and the reversal of platelet inhibition was maintained during the duration of reversal agent PB2452 infusion, with restoration of platelet function for over 20 hours following a 16-hour infusion. There was no evidence of rebound in platelet activity after drug cessation, and there were no serious adverse events felt to be study related. It is important to note that this reversal agent was tested in healthy volunteers following up to 48 hours of ticagrelor administration and was not in patients taking ticagrelor for underlying cardiovascular disease or with prior coronary stent placement. Thus, the safety of ticagrelor reversal in the perioperative setting or in the case of acute reversal for patients with active bleeding remains to be studied. However, this study is extremely promising and raises the potential not only to reverse the antiplatelet effects of ticagrelor in the setting of acute bleeding but also to enable rapid reversal of ticagrelor immediately prior to surgery, with discontinuation of the reversal agent at an appropriate time following surgery. This may not minimize the amount of time patients who require DAPT are without adequate platelet inhibition, but it may make "bridging" with either cangrelor or a glycoprotein IIb/IIIa inhibitor a thing of the past because treatment with ticagrelor to the time of the surgery could be continued uninterrupted. We eagerly await further studies assessing the safety and efficacy of the ticagrelor reversal agent PB2452 in patients with underlying cardiovascular disease in the setting of clinical need for ticagrelor reversal.

DECLARE-TIMI 58: Dapagliflozin and Outcomes in Patients with Peripheral Artery Disease
By Rajan Patel, MD, FACC
Interventional Cardiology Fellowship Program, Ochsner Medical Center
New Orleans, LA

During ACC.19, Dr. Marc Bonaca presented data from the subset of patients with peripheral arterial disease (PAD) who participated in the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized controlled trial. Patients with type 2 diabetes who had atherosclerotic cardiovascular disease (ASCVD) or who were at high risk for ASCVD were randomized to either a selective inhibitor of sodium glucose co-transporter 2 (SGLT2) or placebo.9 SGLT2 is a protein found in the proximal tubule of glomeruli. It is partially responsible for glucose reabsorption from the glomerular filtrate. SGLT2 is located on the luminal membrane side of proximal tubule cells. This may explain the finding that SGLT2 inhibitors are more effective in patients with normal renal function as opposed to reduced renal function because the drug needs to access the tubule lumen. Furthermore, the mechanism of SGLT2 inhibitors appears to be independent of insulin, thus reducing the risk of hypoglycemia when used as a sole hypoglycemic agent.10

Three SGLT2 inhibitors are currently available in the United States: dapagliflozin, empagliflozin, and canaglifozin.11 These were individually evaluated in a series of large randomized controlled trials: DECLARE-TIMI 58,9 the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial,12 and CANVAS (Canagliflozin Cardiovascular Assessment Study). CANVAS comprised 2 trials: the original CANVAS study and the CANVAS-Renal study consisting of 10,142 patients together.13 Beyond the hypoglycemic effect of SGLT2 inhibitors, each of these trials has demonstrated, both individually and when considered together in a meta-analysis,14 a significant reduction in the relative risk of HF hospitalization and progression of renal disease. Additionally, among the subset of patients with ASCVD, these medications reduced MACE in a meta-analysis. However, all of these drugs carry an increased risk of fungal genital infections and diabetic ketoacidosis compared with placebo. CANVAS raised concerns after reporting an increased risk of amputation in the canagliflozin group compared with placebo (6.3 vs. 3.4 patients per 1000 patient-years; hazard ratio 1.97; 95% CI, 1.41-2.75). The risk of amputation was higher among patients with a history of PAD or previous amputation. The DECLARE-TIMI 58 and EMPA-REG OUTCOME trials did not detect an increase in amputations among the treatment groups in the overall study population. Therefore, a sub-study was performed among the DECLARE-TIMI 58 patients with PAD. These data were presented at the American College of Cardiology's 67th Annual Scientific Session and Expo.

In DECLARE-TIMI 58, a total of 1,025 patients of the 17,160 in study population had PAD. The PAD group was slightly younger, had more males, had less hypertension, had a longer duration of diabetes, had more insulin use, had more renal disease, and had more ischemic cardiomyopathy patients compared with the non-PAD group. In the PAD group, 49% had Fontaine 2a claudication, 21% had Fontaine 2b claudication, 6% had critical limb ischemia at baseline, and 25% were asymptomatic regarding PAD. Compared with the non-PAD group, patients with PAD had a higher incidence of any limb ischemic events, amputation, acute limb ischemia, critical limb ischemia, and limb infection. However, in both the overall study population and the PAD subgroup, there was no difference between the dapagliflozin group and the placebo group regarding overall amputation, amputation for acute limb ischemia, amputation for critical limb ischemia, or amputation for infection. Furthermore, there was no difference regarding any limb ischemic events or major adverse limb events or elective revascularization procedures.

The data presented at ACC.19 confirm previously published data that diabetics with PAD are at increased risk for amputation compared with those without PAD.15 However the DECLARE-TIMI 58 data also demonstrate a lack of any signal suggesting that the SGLT2 inhibitor dapagliflozin may lead to more amputations among diabetics with PAD. Therefore, the increased amputations reported in the CANVAS studies with canagliflozin do not appear to be a class effect of SGLT2 inhibitors. Only a head-to-head randomized controlled trial of the various SGLT2 inhibitors against each other and a placebo group in a diabetic PAD population could definitively confirm the absence of a class effect. Nonetheless, the high risk of amputation among diabetics with PAD necessitates that this vulnerable population receive frequent evaluation by vascular specialists and podiatrists and that careful clinical judgement is used when considering SGLT2 inhibitors for these patients.

Twelve-Month Results From the TREAT Trial
By Alina M. Robert, MD, MPH, FACC
St. Luke's Idaho Cardiology Associates
Boise, ID

The primary TREAT (Ticagrelor in Patients With ST-Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis) trial demonstrated safety of ticagrelor in comparison to clopidogrel at 30 days as an adjunctive antiplatelet agent in adult patients age 18-75 with STEMI treated with fibrinolytic therapy. The current report extends the safety analysis to 12 months and includes an underpowered, exploratory outcome analysis. There was no increase in major bleeding, although there were more frequent minor bleeding events. Two 12-month outcome analyses—death from vascular causes, MI, or stroke and death from vascular causes, MI, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events—failed to show an efficacy benefit.

Because many patients with STEMI in rural areas worldwide have limited access to primary PCI, the TREAT trial is important because it demonstrates the safety of using the more potent P2Y12 inhibitor in the setting of fibrinolytic therapy. Although major bleeding was also not significantly different between ticagrelor and clopidogrel in PLATO (Platelet Inhibition and Patient Outcomes), that trial excluded patients with STEMI who received fibrinolytics. The TREAT trial attempts to fill this evidence void. However, the efficacy of ticagrelor post lytic therapy was not confirmed because the study was underpowered for this analysis, with suggestion that composite outcome reduction was not observed with ticagrelor. Furthermore, the study excluded patients of advanced age, which is a growing population of patients who present with ACS and have a higher risk of bleeding.

This study contributes additional evidence to the field, but it is unlikely to significantly change practice because it does not confirm efficacy of ticagrelor compared with clopidogrel in patients with STEMI treated with fibrinolytics and excludes elderly patients. Additional studies would be important to evaluate the safety and efficacy of ticagrelor when given upfront with fibrinolytics in patients with STEMI and when administered to elderly patients along with an assessment of potential benefits of monotherapy and in combinations with low-dose oral anticoagulants.

DEFINE-PCI: Blinded Physiologic Assessment of Residual Ischemia After Successful Angiographic PCI
By Barry F. Uretsky, MD, FACC
University of Arkansas for Medical Sciences
Little Rock, AR

Angiographic optimization of PCI has been assumed to be synonymous with relief of ischemia to the treated myocardium. However, recent studies have demonstrated that as high as 20-30% of angiographically optimized PCI have a post-PCI fractional flow reserve value in the ischemic range.16-18 This finding is particularly important insofar as post-PCI ischemia (as defined by FFR) has been shown in several studies to be related to long-term clinical outcomes.16-22 Dr. Allen Jeremias and colleagues have evaluated the frequency of post-PCI ischemia using the resting pressure index, instantaneous wave-free ratio (iFR), with the post-PCI iFR measurement evaluated in a blinded fashion in the DEFINE PCI (Physiologic Assessment of Coronary Stenosis Following PCI) observational trial. Of 462 patients with angiographically successful iFR pullback (of 500 patients enrolled), there was a 24% incidence of a post-PCI ischemic iFR (≤0.89). Of these 24%, 81.6% of vessels showed a focal stenosis (defined by iFR as an abrupt ≥0.03 step-up) accounting for at least part of the observed low iFR. Of these focal stenoses, 38.4% were in-stent. Another 31.5% of focal lesions were said to be proximal to the stent and 30.1% distal to the stent.

The DEFINE PCI study adds to the evidence that ischemia persists in a relatively large number of vessels with angiographically optimized angiographic stenting. In the absence of imaging, the authors' claim of focal stenosis in large percentage of patients must be confirmed with imaging, as does their trans stenotic pressure gradient of >0.03 defining a "focal" (<15 mm) lesion. Further, the baseline iFR measurement did not include a pullback, which may have identified other vessel sites that required stenting, which would explain in part the high rate of residual ischemia. It is interesting that over a third of focal stenoses were in-stent, which suggests stent underexpansion and which may be an opportunity to improve outcomes by improving stent deployment technique. Additionally, the assumption that a majority of these persistent ischemic lesions (>80% as suggested by the authors) could be improved by further interventions needs confirmation because multiple previous studies have shown that diffuse segments, which are most often distal and in the left anterior descending artery, are a major contributor to persistent residual ischemia after angiographically successful PCI.

The DEFINE PCI study has added to the body of evidence to support a randomized trial to determine the value of post-PCI functional testing in improving acute and long-term outcomes. Further studies are needed to evaluate the role of post-PCI functional testing (with either FFR or non-hyperemic pressure indices, including iFR) to improve acute results and the effect on long-term outcomes.

SAFARI-STEMI: The Safety and Efficacy of Femoral Access Vs. Radial Access for Primary PCI in STEMI
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The SAFARI-STEMI (Safety and Efficacy of Femoral Access vs Radial Access in STEMI) trial is a Canadian investigator-initiated, randomized trial of radial versus femoral access in the setting of patients transferred for STEMI (symptoms ≤12 hours) with mortality as the primary outcome. Power calculations defined a total sample size of 4,884 patients randomized 1:1.

After 2,292 randomized patients, the Data and Safety Monitoring Board stopped the trial for futility because the event rates were too low to achieve significant differences after complete enrollment.

Results of the 2,292 randomized patients demonstrated 98% of patients received up to 4,000 units of heparin with maximum clotting times of 395 seconds radial versus 389 seconds femoral. During the procedure, 88.1% radial versus 92.4% femoral (p = NS). The 2 groups were similar in symptom onset to first inflation time. However, radial patients had significantly longer door-to-balloon times: 47 versus 44 minutes (p = 0.007). Fluoroscopy times were significantly longer for radial: 9.4 versus 8.2 minutes, (p = 0.0001). Thrombolysis in Myocardial Infarction flow rates were mildly but significantly lower at baseline for the radial group, while post-PCI they remained lower but appeared to be a smaller degree post-PCI.

At 30 days, the primary endpoint of mortality was not significantly different: 1.5% radial versus 1.3% femoral (p = 0.69). Secondary outcomes at 30 days showed no difference in reinfarction, stroke, and a composite of death, reinfarction, and stroke. Likewise, stent thrombosis was also not significantly different between the 2 groups. Finally, at 30 days there were no differences in the bleeding rate by multiple parameters.

The authors point out that comparing these results with other trials, SAFARI-STEMI is the largest next to the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) trial and the most dedicated specifically to STEMI. Trials driving the benefit of radial PCI are the RIVAL (Radial Vs Femoral Access for Coronary Intervention) and the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST Elevation Acute Coronary Syndrome) trials. RIVAL had only slightly lower enrollment, but RIFLE-STEACS was a smaller trial. The authors conclude that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI.

One point of interest is that the results do not include any information about the participating operators and/or the experience of the sites with each technique. Such information would be helpful to better understand any experience issues that may have contributed to the results given variable results across all studies of radial versus femoral PCI.

Given the variation in operator experience in the United States (44% performing <50 PCI procedures a year)23 and the continued need to perform safe, large bore femoral access in limited procedures, operators should be facile in both techniques. When experience is limited in a technique, forcing low-volume operators to perform STEMI PCI via an unfamiliar technique potentially may result in worse outcomes than might be achieved by more experienced operators. Part of clinical decision-making is considering an operator's individual skill sets and how they apply to the required procedure. In the case of STEMI, an operator may not have the luxury of deferring to another operator, in which case performing STEMI PCI by a technique consistent with their skills is likely to yield the best outcomes, and, at least according to the SAFARI-STEMI trial, radial versus femoral access should not make a difference.

Sonothrombolysis in STEMI Treated With Primary PCI: Final Results From the First Randomized Study in Humans
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

Sonothrombolysis is a technique that uses high-index mechanical impulses (sonothrombolysis) delivered by a standard ultrasound transducer during a microbubble intravenous infusion. Microbubble cavitation induced by the high mechanical impulses creates shear forces, dissolving coronary artery and microvascular thrombi. The generated shear forces also induce endothelial and red blood cell nitric oxide based on small animal studies, thus potentially further improving microvascular myocardial blood flow.

Dr. Wilson Mathias and colleagues presented this intriguing first-in-man study, MRUSMI (Microvascular Reperfusion Utilizing Sonothrombolysis in Acute Myocardial Infarction), demonstrating the impact of sonothrombolysis on primary STEMI management. They investigators randomized 100 patients with STEMI 1:1 to standard primary PCI versus sonothrombolysis plus primary PCI. Ultrasound impulses were delivered with ultrasound imaging during injection of standard echocardiography contrast infusion before PCI and following PCI.

The results showed significantly more frequent ST-segment elevation resolution in the sonothrombolysis group before PCI (32% vs. 4%), and recanalization on angiography was 48% in sonothrombolysis PCI versus 20% in PCI (p < 0.001). Furthermore, infarct size by magnetic resonance imaging was lower (40 ± 20 vs. 29 ± 22 grams; p = 0.026) and LVEF was increased in the first 48 hours and persisted for up to 6 months (47 ± 12 vs. 53 ± 10; p = 0.048) for the sonothrombolysis-treated patients.

Although the sample size is small and this is a first-in-man study, the results are certainly encouraging because the technology is not new, nor does it require expensive additional, specialized equipment. Presumably, a larger study will be forthcoming.

Outcomes for STEMI acutely are markedly improved with the ultimate use of rapid transfer and primary PCI in the United States. However, many issues remain for optimal STEMI management in the United States and worldwide. Rapid and immediate PCI is not universally available worldwide. Furthermore, even with the effective US strategy, there remains a major risk of late HF post-STEMI. Fortunately, several recent pilot studies have introduced conceptual additions to primary STEMI management, which may effectively address these issues, such as DTU-STEMI (Door-To-Unload in STEMI Pilot Trial) reported at the American Heart Association Scientific Sessions 2018,24 recent approval of supersaturated oxygen for left anterior descending STEMI,25 and now this study of sonothrombolysis. Results of larger trials of these techniques over the coming years will hopefully document real opportunities to further optimize STEMI results in the United States and worldwide, acutely and post-hospitalization.

References

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Keywords: ACC Annual Scientific Session, ACC19, Acute Coronary Syndrome, Adenosine, Angina, Stable, Anticoagulants, Coronary Angiography, Aortic Valve, Aortic Valve Stenosis, Aortic Valve Insufficiency, Aspirin, Atrial Fibrillation, Benzhydryl Compounds, Blood Platelets, Blood Pressure, Cardiomyopathies, Catheterization, Clinical Trials Data Monitoring Committees, Cohort Studies, Confidence Intervals, Constriction, Pathologic, Coronary Occlusion, Coronary Artery Disease, Coronary Stenosis, Diabetes Mellitus, Type 2, Coronary Vessels, Diabetic Ketoacidosis, Echocardiography, Electrocardiography, Drug-Eluting Stents, Dyspnea, Exercise, Erythrocytes, Follow-Up Studies, Fluoroscopy, Glucosides, Glucose, Healthy Volunteers, Goals, Heart Valve Prosthesis, Heart Failure, Heart Ventricles, Heparin, Hemorrhage, Hypertension, Hospitalization, Hypoglycemic Agents, Hypoglycemia, Infusions, Intravenous, Insulin, Ischemic Attack, Transient, Length of Stay, Longitudinal Studies, Medical Futility, Magnetic Resonance Imaging, Mitral Valve, Mitral Valve Insufficiency, Microbubbles, Myocardial Infarction, Neoplasms, Myocardium, Nitric Oxide, Odds Ratio, Outcome Assessment, Health Care, Pacemaker, Artificial, Patient Selection, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Phosphoproteins, Platelet Activation, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Aggregation Inhibitors, Pulmonary Veins, Registries, Research Personnel, Quality of Life, Sample Size, Selection Bias, Risk, Sodium, Sodium-Glucose Transporter 2, Stents, Stroke, Stroke Volume, Surgeons, Thrombolytic Therapy, Survival Rate, Thrombosis, Ticlopidine, Tomography, Transcatheter Aortic Valve Replacement, Tricuspid Valve Insufficiency, Ultrasonography, Vasodilator Agents, Vulnerable Populations


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