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

Below is a compilation of summaries of selected interventional trials from the spring cardiology meetings, Cardiovascular Research Technologies 2018 (CRT.18) and the American College of Cardiology 2018 Annual Scientific Session and Expo (ACC.18). In addition to the expert commentary, we've provided the ACC coverage of the trials where applicable. As always, these reviews represent the trials of most interest to interventional cardiology. Comments are welcome.

Transcatheter Aortic Valve Replacement for Patients with Severe Aortic Stenosis who are at Low Risk For Mortality: Interim results from the Prospective Multicenter LRT Clinical Trial
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Virginia Commonwealth University
Richmond, VA

This study, reported at CRT.18,¹ was an interim analysis of a multicenter trial of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients with aortic stenosis. The ultimate outcome comparator will be a propensity-matched group of patients from the same institutions having surgery. Generally, the sites were low volume, which perhaps represents a more realistic or "real world" study. The results presented were from only the TAVR cohort treated with commercially available valves. The goal of the study was to assess low-risk patients defined as by a Society of Thoracic Surgeons (STS) risk score of <3. The 125 patient TAVR arm had a baseline STS risk score of 1.9 +/- 0.5 with a mean age of 74 +/- 5.7 years.

The most impressive finding was no mortality at 30 days. Appropriate and favorable directional changes also occurred in valve gradient (12.3 ± 4.4 mmHg.) and valve area (1.64 ± 0.41 cm2) following TAVR at 30 days. As noted in Dr. Waxman's presentation, adverse outcomes through 30 days appear lower than other recent TAVR trials: major bleeding (4.0%), need for a permanent pacemaker (4.8%), stroke (0%), and moderate or greater paravalvular leak (0%).

Importantly, however, valve leaflet thrombosis was evident by 30 days with subclinical leaflet thrombosis evidenced by hypo-attenuating leaflet thickening in 9.3% of patients. Patients on oral anticoagulants as opposed to antiplatelet therapy were less likely to have subclinical leaflet thrombosis.

Late outcome results focusing on valve durability and complications related to valve leaflet thrombosis will be extremely important given the recognized early incidence of valve leaflet thrombosis. Although encouraging, these preliminary results clearly need late validation and comparison to surgical results, which in this study will be with a propensity matched cohort. Later follow-up regarding the type of anticoagulation (anticoagulants such as warfarin vs. antiplatelet agents) may also provide important insights into the best acute and long-term management strategies.

In summary, the significance of the data from the TAVR arm of the trial is limited by the modest sample size and no reported comparative surgical data. Despite these limitations, the trial provides some important insights on TAVR in general. The search for the "final answer" regarding the appropriateness of TAVR for low-risk patients is ongoing.

NOTION: Nordic Aortic Valve Intervention
By Giuseppe Biondi-Zoccai, MD
Sapienza University of Rome
Rome, Italy

At ACC.18, Dr. Thyregod and colleagues presented the 5-year results of the NOTION trial, which randomized 280 low-risk patients with severe aortic valve stenosis to transcatheter aortic valve implantation (TAVI) with Medtronic CoreValve (Medtronic, Dublin, Ireland) versus surgical aortic valve replacement (SAVR), reporting similar long-term rates of death, stroke, or myocardial infarction (MI). The study acronym was aptly chosen because this trial challenges the notion that low-risk patients must always be treated with SAVR. On top of similar rates for the primary endpoint (respectively 39.2 vs. 35.8%; p = 0.78), no significant differences were found for death, stroke, transient ischemic attack, MI, valve reintervention, and endocarditis. Significant differences were found, though, for atrial fibrillation (favoring TAVI), and pacemaker implantation, effective orifice area, mean gradient, and aortic regurgitation (all favoring SAVR). It is worth repeating that, despite such differences and the apparent significant association between pacemaker implantation and long-term death, the overall outlook was similar with TAVI and SAVR. Thus, this trial also suggests that pacemaker implantation and aortic regurgitation do not necessarily impact in an independent fashion on long-term clinical outcomes. Another important highlight was the substantial stability in valve performance parameters in both groups, despite concerns for degeneration and fatigue of TAVR in comparison with SAVR.

In conclusion, despite the relatively small sample, the NOTION trial surely calls for a paradigm shift and, pending larger randomized trials in low-risk patients, reinforces the favorably disrupting role of TAVI for severe aortic stenosis. The availability of new-generation devices, likely superior to CoreValve for pacemaker rates and aortic regurgitation severity, raises our optimism that TAVI performance versus SAVR will continue to maintain its ground even in the future.

TREAT: Ticagrelor in Patients With ST-Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis
By Rajesh M. Dave, MBBS, FACC
Holy Spirit Hospital
Camp Hill, PA

It is well established that primary percutaneous coronary intervention (PCI) performed in a timely fashion leads to the best outcomes in patients with ST-segment elevation MI (STEMI). However, in a large portion of the world, fibrinolytic therapy is the mainstay in treatment of STEMI. Moreover, the availability of PCI and optimal PCI techniques in STEMI varies greatly by region and operators. Therefore, pharmacotherapy-induced lysis has significant impact on the cardiovascular health of a large population globally. Antiplatelet therapy is a major component of management of acute MI. In certain studies, fibrinolysis has been shown to cause platelet activation. Ticagrelor is a more potent and faster P2Y12 inhibitor than clopidogrel and may have advantages in the setting of fibrinolysis.

In the PLATO (Platelet Inhibition and Patient Outcomes) study, which evaluated patients with STEMI as well as non-STEMI, immediate use of ticagrelor was shown to be superior to clopidogrel with a small increase in bleeding risk. The TREAT trial examined question of safety of ticagrelor in patients with STEMI who were treated with fibrinolysis. In nearly 90% of patients, converting to ticagrelor after initial exposure to clopidogrel is safe and not inferior for major bleeding. Major bleeding at 30 days, per thrombolysis in MI major bleeding criteria, occurred in 0.73% of patients receiving ticagrelor and 0.69% of those receiving clopidogrel (absolute difference 0.04%; 95% confidence interval, –0.49-0.58%; p < 0.001 for no inferiority). Fatal (0.16 vs. 0.11%; p = 0.67) and intracranial (0.42 vs. 0.37%; p = 0.82) bleeding events were not different between the study groups. Minor bleeding occurred in 3.24% of ticagrelor patients and 2.01% of clopidogrel patients (p = 0.02).

However, there are a few limitations of the study. First, large numbers of patients in this trial had clopidogrel pre-exposure. Second, only patients younger than age 75 were included. In my opinion, the most important question is whether initial loading of ticagrelor with fibrinolysis would lead to better outcomes without increasing bleeding. I am comforted that even patients with pre-exposure to clopidogrel did not have greater bleeding risk with conversion to ticagrelor in the TREAT trial, bringing us one step closer to the ultimate question about outcome as stated above. We will await future investigations for this important question.

SECURE-PCI: Statins Evaluation in Coronary Procedures and Revascularization
By Germano Di Sciascio, MD, FACC
Campus Bio-Medico University of Rome
Rome, Italy

This is a randomized multicenter trial investigating the administration of high-dose atorvastatin in patients with acute coronary syndromes (ACS). The study was conducted in Brazil and enrolled a large number of patients (4,191) with STEMI (25%), non-STEMI (60%), and unstable angina (15%) who were randomized to receive 80 mg atorvastatin versus placebo before and 24 hours after an invasive strategy consisting of diagnostic angiography followed by PCI (65%), coronary artery bypass grafting (8%), or medical management (27%). All patients received 40 mg atorvastatin for 1 month thereafter, and the primary endpoint was 30-day major adverse cardiovascular events. The study was negative in the overall population; no benefit was demonstrated in the treatment arm versus the placebo arm (6.2 vs. 7.1%). However, statistical benefit was observed in the two thirds of patients who underwent PCI versus those who were medically managed (6.0 vs. 8.2%) and in the STEMI group (p = 0.01). The study does not clarify why 27% of patients did not receive PCI, which would be unusual in the United States, but we presume it was due to "not enough disease."

Previous smaller trials have demonstrated a cardioprotective effect of high-dose atorvastatin given prior to PCI in patients with stable angina (ARMYDA [Atorvastatin for Reduction of Myocardial Damage During Angioplasty]) and ACS (ARMYDA-ACS [Atorvastatin for Reduction of Myocardial Damage During Angioplasty-Acute Coronary Syndromes]) and for patients who are statin-naïve or in the background of chronic therapy (ARMYDA-RECAPTURE [Atorvastatin for Reduction of Myocardial Damage During Angioplasty-RECAPTURE]). Those studies utilized different protocols in a variety of clinical syndromes, with a consistent benefit essentially due to reduction of periprocedural MI, in patients already scheduled for elective or urgent PCI. This evidence provoked a Class IIa recommendation for administration of high-dose statins before PCI already in the 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention,² with Level of Evidence A for statin-naïve patients and B for patients on chronic statin therapy, and a Class IIb Level of Evidence B in the 2011 ESC/EAS Guidelines for the management of dyslipidemias in the same year.³ ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation also recommended "to initiate or continue high dose statins early after admission in all STEMI patients without contraindication or history of intolerance, regardless of initial cholesterol values" (Class IA).⁴ Thus, the concept of statin treatment in patients with ACS is not new, particularly in the milieu of the heightened inflammatory state of PCI. The authors have the merit of having investigated this concept in a larger randomized trial, and had they enrolled only patients undergoing PCI, the results would have been more meaningful; the present study's results were driven by the almost 1/3 of patients who did not undergo PCI. The significant benefit observed in the subgroup of patients with STEMI undergoing primary PCI is intriguing and deserves further specifically designed studies. The concept of administering a high-dose statin "at the first medical contact" in a patient with evolving MI, if further tested and proven beneficial, may strengthen existing guidelines and influence practice patterns.

This paper also confirms hypotheses on the mechanisms involved in the beneficial effect of statins in this scenario: probably not low-density lipoprotein dependent (because of the short time in which benefit is evident), more likely pleiotropic, with a constellation of anti-inflammatory, anti-thrombotic, nitric oxide-producing effects that encourage their application in the acute interventional setting.

COMPASS: Cardiovascular Outcomes for People Using Anticoagulation Strategies
By Jad Omran, MD
Sulpizio Cardiovascular Center, University of California-San Diego
La Jolla, CA

The importance of antiplatelet/antithrombotic combination therapy was adequately addressed in the COMPASS study.⁵ This multicenter, double-blinded, randomized placebo-controlled trial enrolled 27,395 participants with coronary artery disease (CAD) and/or peripheral arterial disease (PAD). This study has shown that combination therapy between low-dose rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily) has reduced the composite of cardiovascular death, stroke, or MI by 24% in patients with stable CAD when compared with aspirin monotherapy. In patients with PAD, combination therapy had similar effects on major adverse cardiovascular events and remarkable decrease in major adverse limb events (MALE) by 46%. These results were under the expense of increased major bleeding events in the combination group without significant difference in fatal or intracranial bleeding.

Presented during ACC.18, a unique subgroup analysis from the COMPASS study has focused on patients with PAD.^6,7 In this analysis, researchers considered 6,391 patients with lower extremity PAD and studied the prognosis of patients who suffered MALE. MALE was defined as severe limb ischemia (acute or chronic) that led to therapeutic intervention (percutaneous or surgical). Researchers have identified independent predictors of MALE that included severe ischemia symptoms at baseline, prior limb or foot amputation at baseline, prior history of peripheral revascularization surgery or angioplasty, and randomization to the aspirin arm of trial. They noted that diabetes, smoking, female sex, and history of CAD were not independently predictive of MALE. Importantly, the cumulative incidence of 1-year risk after MALE for subsequent hospitalization was 95.4%, 22.9% for vascular amputations, and 8.7% for death. The study has also showed that combination therapy is superior to aspirin monotherapy in reducing MALE, total and major amputations, vascular interventions, and outcomes.

This study has several important implications. It reinforces the importance of MALE in patients with PAD given the threefold increase in death and 200-fold increase in the risk of subsequent vascular amputation. Because limb amputations are associated with 50% risk of mortality in the year following the procedure, MALE events should be taken seriously by providers to make aggressive therapeutic measures following these events. The study also adds up to the existing regimen in reducing vascular events in patients with PAD (avoidance of tobacco, use of statins and angiotensin-converting enzyme inhibitors). Other important observations from this study include the heterogeneity of medical therapy following MALE. Most patients (63%) remained on their randomized study drug, but 13% received single antiplatelet therapy, 10% dual antiplatelet therapy, 2% oral anticoagulation, and 12% with no therapy; this necessitates future studies in this area. The COMPASS study is a potentially practice-changing study given the consistent treatment benefit among all study subgroups; however, several unresolved issues exist. The exclusion of patients on dual antiplatelet therapy will leave the benefit of adding rivaroxaban to this group of patients unknown. The early termination of the study might have overestimated the treatment effect and underestimated the potential harm (bleeding) of the study drugs.⁸

Balancing the ischemic and bleeding risk in our patients would be paramount for patient selection because a high bleeding profile may prohibit such a regimen. Regardless of whether this study will lead to the approval of low-dose rivaroxaban by the US Food & Drug Administration (FDA), COMPASS represents a major milestone in treatment and prevention of CAD and PAD.

ANNEXA-4: Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding
By Michael P. Savage, MD, FACC
Sidney Kimmel Medical College at Thomas Jefferson University
Thomas Jefferson University Hospital
Philadelphia PA

An interim analysis of the ongoing ANNEXA-4 was presented at ACC.18 in Orlando. ANNEXA-4 is a prospective, single-arm, Phase IIIb/IV study of andexanet alfa in patients presenting with acute major bleeding within 18 hours of receiving a Factor Xa inhibitor. Andexanet, designed as a specific reversal agent, is a recombinant modified human Factor Xa molecule that acts as a decoy to bind with Factor Xa inhibitors, thus restoring native Factor Xa coagulant activity. The drug is administered as an intravenous bolus followed by a 2-hour infusion. The study presentation reported on 227 patients in the safety analysis and 132 patients in the efficacy analysis who were included in the study as of October 20, 2017. The mean age of the study population was 77 years; approximately 3/4 of the patients were treated for atrial fibrillation, and the remainder were treated for venous thromboembolic disease. Andexanet was effective in reversing the anticoagulated state regardless of which specific Factor Xa inhibitor had been used. The median reduction of Factor Xa inhibitor activity was 88% for patients taking rivaroxaban, 91% of patients taking apixaban, and 75% for patients taking enoxaparin. At 12 hours post-treatment, excellent or good hemostasis was achieved in 83% of patients. At 30 days, 12% of patients had died and 11% had a thrombotic event. The mortality rates were consistent with the high-risk nature of the patient population of whom 61% presented with intracranial bleeding and 27% presented with gastrointestinal bleeding.

The development of an effective antidote for Factor Xa inhibitors is a major therapeutic milestone because almost 3 million people in the United States alone currently take a Factor Xa inhibitor, and over 80,000 of these patients are hospitalized each year for major bleeding. The non-vitamin K antagonist oral anticoagulants appear to be generally safer and more effective than warfarin. However, one of the obstacles to wider use of non-vitamin K antagonist oral anticoagulants and especially Factor Xa inhibitors has been the inability to reverse their anticoagulant effect in the setting of acute major bleeding. In contrast, warfarin can be reversed by administration of vitamin K or fresh frozen plasma. Currently, there are no FDA-approved antidotes for Factor Xa inhibitors. The safety and efficacy results of andexanet in the ANNEXA-4 study compare favorably with those of idarucizumab, which received FDA approval in late 2016 as a reversal agent for the direct thrombin inhibitor dabigatran. The salutary effects of andexanet in ANNEXA-4 move the drug ever closer to the goal line as the first-in-class agent to be approved for the treatment of major bleeding associated with Factor Xa inhibitors. That would be an important and welcome advance.

References

1. Waksman R. Transcatheter Aortic Valve Replacement for Patients with Severe Aortic Stenosis who are at Low Risk For Mortality: Interim results from the Prospective Multicenter LRT Clinical Trial. Presented at CRT.18, March 2018. Available at http://www.crtonline.org/Assets/720cdbea-89b1-4f91-94fa-90776b299208/636559285145300000/def0e6f7-aaf4-4e60-a452-5abf9e67e801-pptx.
2. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
3. European Association for Cardiovascular Prevention & Rehabilitation1, Reiner Z, Catapano AL, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
4. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)1, Steg PG, James SK, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-619.
5. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30.
6. Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205-18.
7. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219-29.
8. Anand SS, Caron F, Eikelboom JW, et al. Major Adverse Limb Events in Lower Extremity Peripheral Artery Disease: COMPASS Trial. J Am Coll Cardiol 2018;Mar 11:[Epub ahead of print].

Keywords: ACC18, ACC Annual Scientific Session, Acute Coronary Syndrome, Adenosine, Aged, Amputation, Angina, Stable, Angina, Unstable, Angiography, Angioplasty, Angiotensin-Converting Enzyme Inhibitors, Antibodies, Monoclonal, Humanized, Anticoagulants, Antidotes, Aortic Valve, Aortic Valve Stenosis, Aortic Valve Insufficiency, Aspirin, Atrial Fibrillation, Blood Platelets, Cholesterol, Cohort Studies, Confidence Intervals, Coronary Artery Bypass, Coronary Artery Disease, Antithrombins, Diabetes Mellitus, Dyslipidemias, Endocarditis, Enoxaparin, Factor Xa, Factor Xa Inhibitors, Fibrinolysis, Heart Valve Prosthesis, Hemostasis, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ischemic Attack, Transient, Lipoproteins, Lower Extremity, Myocardial Infarction, Nitric Oxide, Pacemaker, Artificial, Patient Selection, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Platelet Activation, Platelet Aggregation Inhibitors, Prospective Studies, Pyrazoles, Pyridones, Random Allocation, Recombinant Proteins, Research Design, Smoking, Stroke, Surgeons, Thrombolytic Therapy, Thrombosis, Ticlopidine, Tobacco Use, Transcatheter Aortic Valve Replacement, Vitamin K, Warfarin

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