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

This year's European Society of Cardiology 2019 Congress (ESC Congress 2019) in Paris offered a significant number of trials of interest to interventional cardiology. The COMPLETE (Complete Versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early PCI for STEM) trail offers insight into issues surrounding benefits of complete versus incomplete revascularization surrounding ST-segment elevation myocardial infarction (STEMI) management as well as timing. The SYNTAXES trial provides late outcome results for percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in patients with three-vessel with or without left main disease. These and other important trials are discussed below. I trust these data and opinion comments will quickly provide you, the reader, with important findings and varied perspectives of these significant trials.

Many thanks to our contributors. As always, any comments are appreciated.

THEMIS-PCI
By John A. Bittl, MD, FACC
AdventHealth Ocala
Ocala, FL

The THEMIS-PCI (Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention) report in Lancet¹ found that the primary efficacy outcome (a composite of cardiovascular death, myocardial infarction [MI], or stroke) was lower in patients randomized to ticagrelor than to placebo (404 [7.3%] of 5,558 vs. 480 [8.6%] of 5,596; hazard ratio [HR] 0.85; 95% confidence interval [CI], 0.74-0.97; p = 0.013) in the subgroup of patients with a history of PCI.² However, THEMIS-PCI has major statistical flaws that limit its generalizability:

1. This was a subgroup analysis. The lay press understands that subdividing a main trial into subgroups is limiting because it introduces spurious results.³
2. The p-value describing the interaction between PCI and non-PCI patients for the primary outcome was not significant (p = 0.16).
3. There were no statistical penalties for multiple comparisons. Not specified in the clinicaltrials.gov file for the THEMIS-PCI trial is that multiple subgroup analyses were planned by the authors,⁴ who revealed that¹ "No adjustments were made for multiple comparisons, and therefore the p values presented are nominal." The term nominal is trial-speak for specious. Thus, the statistical value is unclear.
4. The number needed to treat (NNT) presented by the authors was an exaggeration. Although only 6,766 of 11,154 (62%) of patients completed 3 years of follow-up, the authors stated that 84 patients would require ticagrelor for 3 years to prevent a primary efficacy event,¹ but reporting the NNT for 3 years is a clinical-trial artifice that takes advantage of a threefold higher event rate after 3 years than after 1 year. It would have been more informative for the authors to calculate the average NNT each year and report a value of 254 (95% CI, 144-2,324). If they used this approach, they would have found that for every 1000 patients treated with ticagrelor each year, only 4 (95% CI, 1-7) would have avoided the primary efficacy endpoint. That is, for every 1,000 patients treated with ticagrelor, 996 would not have benefited; that is consistent with an unfavorable risk-benefit ratio.

Temporal Trends in Incidence and Outcome of ACS
By Cindy L. Grines, MD, FACC, MSCAI
Northside Cardiovascular Institute
Atlanta, GA

Johannes Neumann utilized a large national database to determine temporal trends in incidence and outcome of 3.8 million patients with acute coronary syndromes (ACS) who were hospitalized between 2005 and 2015 in Germany. Over this 10-year interval, there were fewer ACS admissions (due primarily to decreases in STEMI and unstable angina populations), but the incidence of non-STEMI (NSTEMI) increased. Over time, hospitalized patients were older, but mortality improved with increased utilization of angiography and PCI.

Of note, female patients were older (73 vs. 66 years of age), less likely to receive angiography or PCI, and had longer hospital stays and substantially higher mortality compared with men despite adjusting for age.

This report is important because it highlights the improvement in overall health resulting in reduced ACS admissions and, importantly, reduction in the incidence of STEMI. Although admitted patients are now older, the prognosis is better, likely due to increased utilization of angiography and revascularization procedures (medical therapies were not tracked). The increased incidence of NSTEMI follows use of high-sensitivity troponin testing. Although we can be proud of improvements overall, there is a glaring need for better diagnosis and treatment of women. Women continue to have a strikingly higher mortality and less utilization of angiography and PCI compared with men. We know that women have atypical symptoms, which causes delay in seeking medical attention and delay in treatment. However, the diagnosis should no longer be in question with rapid cardiac biomarkers. Perhaps it is time for physicians to accept responsibility for undertreatment of women!

The SWEDEHEART Registry
By Annunziata Nusca, MD, PhD
Cardiovascular Sciences Unit, Campus Bio-Medico of Rome
Rome, Italy

In the last decade, several studies have demonstrated the negative prognostic impact of bleeding complications in patients with ACS, regardless of treatment strategy (conservative or invasive). Thus, bleeding prevention is critical to further improve the outcomes of these patients as well as to avoid recurrent thrombotic events. In this setting, the SWEDEHEART Registry (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies), presented at ESC Congress 2019,⁵ adds some important information. This prospective national registry reported the occurrence of in-hospital and long-term (at 1 year from the acute event) bleeding complications in a large cohort of patients (n = 371.431) with acute MI in Sweden from 1995 until 2018. Importantly, time trends of bleeding complications were correlated with the introduction and cessation of new and more aggressive antithrombotic and invasive strategies in order to evaluate their impact on bleeding risk. In addition, the incidence of recurrent thrombotic events was also described during the same time interval.

About 40% of the enrolled patients had a STEMI. Furthermore, a progressive increase in the number of patients with previous PCI (from 2.5% in 1995-1996 to 20.7% in 2017-2018) and a greater use of oral anticoagulation (warfarin or novel anticoagulants) (from 4.5% in 1995-1996 to 9.8% in 2017-2018) was observed during the study time.

Data from this registry showed that the incidence of in-hospital bleeding (defined as fatal bleeding, intracranial bleeding, or bleeding requiring transfusion or intervention) significantly changed over the last 2 decades, increasing from 0.5% in 1995 to 2% in 2006/2007, with a following decrease to around 1.3% in 2011-2016. Importantly, examining pharmacological and procedural features affecting bleeding risk, a simultaneous greater use of invasive strategies, dual antiplatelet therapy, and GpIIb/IIIa inhibitors was recorded from 1995 to 2006/2007, whereas an increase in radial access and bivalirudin use was described from 2006/2007 until 2011.

Similarly, a progressive and significant increase in the incidence of 1-year out-of-hospital bleeding (defined as rehospitalisation after the index acute MI due to bleeding from the gastrointestinal tract, urogenitalia, airways, eyes, ear, or cerebral bleeding) was observed from 1995 to 2016; this was in parallel with an increased administration of more intensive antithrombotic therapies for at least 1 year after the acute coronary event, such as the use of new, more potent P2Y12 receptor antagonists.

Of note, adjustment for patients' clinical features did not change the temporal patterns of in- and out-of-hospital bleeding risk. Furthermore, similar bleeding trends were described in patients with both STEMI and NSTEMI.

Interesting findings were observed when bleeding and ischemic events were combined. Indeed, notwithstanding an overall absolute increase in in-hospital bleeding of 0.8% (from 0.5% to 1.3%), in the same time interval (from 1995 until 2018), in-hospital re-infarction progressively decreased from 2.8% to 0.6%, with an absolute reduction of 2.2%. Comparably, an absolute 2.3% rise in out-of-hospital bleeding was reported over the last 2 decades, with a meaningful concomitant 9.3% reduction in the rate of out-of-hospital cardiovascular death, MI, or stroke, resulting in a significant and steady decrease in total adverse events. In other words, the absolute reduction in the risk of ischemic events was substantially greater than the absolute increase in bleeding, confirming the substantial net benefit of new antiplatelet strategies on the long-term outcome of patients with ACS.

The observational design with unmeasured residual confounders may surely affect the quality of data coming from this registry. However, the main strengths of this study are the wide cohort of patients from a single national registry and the large temporal interval—over a 20-year span—considered. Furthermore, the authors did not use standardized in- and out-of-hospital bleeding definitions; despite that, a slight similarity was observed with moderate and severe GUSTO bleeding criteria. Furthermore, there was not a blinded adjudication of bleeding events, but International Classification of Diseases codes were used.

Regarding clinical implications, bleeding complications necessarily represent the "dark side of the moon" of our efforts to reduce the risk of recurrent ischemic events in patients with ACS patients through the use of increasingly aggressive antithrombotic strategies. Therefore, the identification of pharmacological or procedural features that are associated with a higher bleeding risk is crucial to prevent these complications and decrease mortality. The results of the SWEDEHEART Registry underline the clinical impact of antithrombotic strategies on bleeding complications in a real-world setting and over a long time period including the last 20 years. A cause-and-effect relationship between the use of antiplatelet/antithrombotic therapies and bleeding may only be assumed from the results of this registry; however, SWEDEHEART provides important information that may be used to effectively balance bleeding and ischemic risk in the tailored management of acute high-risk patients.

COMPLETE
By Bonnie H. Weiner, MD, FACC
Saint Vincent Hospital at Worcester Medical Center
Worcester, MA

This trial was designed to assess whether complete revascularization after successful primary PCI was beneficial compared with guideline-driven medical therapy after successful treatment of the culprit lesion. The trial also attempted to determine if the timing of complete revascularization was a factor in the complete revascularization group.

This was a large trial, and the investigators should be commended on accomplishing the goal for recruitment. However, during the 4 years of recruitment, clinical practice may have changed, and some bias may have crept in regarding patients who were included or excluded. The inclusion criteria included angiographic or functional assessments. We are well aware now that even 70% stenoses may not be functionally significant, particularly when assessed in the setting of acute MI where vasomotor tone is increased; therefore, some lesions may have been treated that were unnecessary. Of more concern, however, is that in the culprit-lesion-only group, lesions were not revascularized even if there was evidence of ischemia. That would likely bias the results in favor of the complete revascularization group, particularly for the second co-primary endpoint where ischemia-driven revascularization was a component.

When subsequent new MI were considered, the analysis provided demonstrated a lower rate for both STEMI and NSTEMI in the complete revascularization group. But whether the events were related to the culprit or non-culprit lesions is not addressed in either the paper itself or in the supplemental data. Understanding this might change the interpretation of the follow-up event rates.

Finally, the good news is that it doesn't seem to matter when the non-culprit revascularization occurs. This has practical implications, particularly in the United States where there may be reimbursement advantages under some payment models to waiting 30 days for the non-culprit revascularization. On the other hand, patients would likely prefer additional procedures to be performed during the same hospitalization or soon thereafter. This approach can therefore be individualized without risk.

The SYNTAX Extended Survival Study
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The SYNTAXES (SYNTAX Extended Survival Study) presented at ESC Congress 2019⁶ describes the 10-year survival rates from the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial, which randomized 1,800 patients with left main and/or three-vessel coronary disease that was deemed acceptable for either PCI or CABG after evaluation by both an interventional cardiologist and a cardiac surgeon. The stent utilized in the PCI arm was the first-generation TAXUS (Boston Scientific Corporation; Marlborough, MA), and the CABG was performed either on or off pump at the surgeon's discretion. The outcomes have been reported at 1, 3, 5, and now 10 years.

Follow-up was excellent. Overall, outcomes were complete for 94% of patients at 10 years: 93% for PCI and 95% for CABG. All-cause mortality at 10-year follow-up demonstrated the following:

• Complete cohort (PCI + CABG)- No significant differences between CABG and PCI using first-generation stents.
• Left-main cohort: No significant difference in mortality.
• Three-vessel disease cohort: Significantly worse outcomes for PCI favoring CABG.
• Medically treated diabetic patients: No significant difference.
• SYNTAX score >33 significantly favored CABG.

The SYNTAXES study affirms the importance of late follow-up for revascularization studies.

This is undoubtedly a landmark study with impressive 10-year follow-up. The results generally are favorable for equipoise between therapies with several caveats. First, the patient population overall had preserved left ventricular (LV) function, with only 2% of patients having an LV ejection fraction <30%, so one can argue that the results do not cover the full range of patients, like those with severe LV dysfunction. The diabetic group represents about a quarter of the patients, which maybe low considering the 10% of the US population who require insulin.

Though not provided in this report, prior studies have shown that three-vessel patients have less-optimal outcomes for PCI, which is driven by a higher percentage of patients receiving incomplete revascularization.⁷ However, the fact that patients with a SYNTAX score of >33% had less-optimal results suggests that completeness of revascularization remains an important marker for the most complex and extensive patients because of the risk of adverse PCI results. The good news is that in SYNTAX II,⁸ a "proof of concept" PCI-only study with inclusion criteria similar to SYNTAX I, lesions were treated based only on fractional flow reserve identification of hemodynamically significant lesions, there was high intravascular ultrasound use for vessel sizing and post-procedure confirmation of optimal results, and there was more emphasis on complete revascularization.

The result of this strategy yielded major adverse cardiac and cerebrovascular events at 2 years that was equivalent to the SYNTAX I surgical results. But it must be emphasized that the comparison was not randomized.⁸ None the less, there is growing belief that complete revascularization of major areas of myocardium subtended by ischemia-promoting lesions is important to get optimal late results that are comparable to CABG (except for off-pump CABG). In the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, patients having off-pump CABG had significantly lower survival compared with on-pump surgery, which seemed to track with less-complete major vessel revascularization in the off-pump group. To what extent the use of off-pump CABG potentially adversely affected the CABG results in SYNTAX I is unknown. There seems to be no doubt that incomplete PCI revascularization in patients with complex coronary artery disease is an issue that must be addressed in developing equipoise to CABG.

Lastly, the use of first-generation stents remains a potential limit for PCI outcomes, which should be improved with current stent designs. This will continue to be an evolving technical effect that will challenge long-term studies. However, a major strength of SYNTAXES is the value of presenting late outcomes that emphasize to interventionalist that PCI success is not just getting out of the lab without an acute complication.

16-Year Follow-Up of the DANAMI-2 Trial
By Rajesh M. Dave, MD, FACC
Geisinger HolySpirit Hospital
Camp Hill, PA

Thrombolysis remains the primary modality of treatment for patients with STEMI in a large part of developing world. DANAMI-2 (Danish Trial in Acute Myocardial Infarction-2) evaluated thrombolysis versus primary PCI in the treatment of patients with STEMI. A very long-term follow-up of these patients (16.7 years) shed light on effect of primary PCI on long-term outcomes of these patients. DANAMI-2 enrolled 1,572 patients who were randomized to tissue plasminogen activator versus primary PCI. If the randomizing center was not equipped for PCI, patients were transferred to PCI-capable centers. The primary endpoint of study was death from any cause, clinical reinfarction, or disabling stroke at 30 days. The trial was stopped early due to striking benefit in favor of primary PCI. The composite endpoint occurred in 8% of PCI patients versus 13.7% of fibrinolysis patients. This difference was maintained even when analysis was stratified by type of enrolling hospital (referral vs. onsite PCI). The composite endpoint was driven by reduction in recurrent MI; however, death rate was no different. At 16-year follow-up, this difference was maintained with 58.7% in PCI group versus 62.3% in fibrinolysis group.

Needless to say, primary PCI has revolutionized the treatment of STEMI. There are many ongoing efforts to equip more and more centers to be PCI capable, as well as infrastructure development to allow for increased availability of PCI in developing countries. DANAMI-2, however, does not address the concept of facilitated PCI, which is being increasingly practiced in developing countries.

BIOSTEMI
By Mirvat A. Alasnag, MD
King Fahd Armed Forces Hospital
Jeddah, Saudi Arabia

Stent technology has evolved since the first drug-eluting stents were released in 2002. Many subsequent generations of stents addressed the design of the stent cells: the number of links, the drug, the polymer, and the strut thickness. Any refinement in the technology is usually evaluated against the contemporary platforms with respect to safety, deliverability, and outcomes. The latest of these is the biodegradable polymer sirolimus-eluting stent. This stent was studied in the BIOSTEMI (Biodegradable Polymer Sirolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents in Patients With STEMI) trial, published September 2, 2019. This was a randomized, controlled prospective, single-blind study that compared the biodegradable polymer sirolimus-eluting Orsiro (Biotronik; Berlin, Germany) to the durable polymer everolimus-eluting stent Xience Xpedition/Alpine (Abbott Vascular; Chicago, IL) undergoing primary percutaneous revascularization in the setting of STEMI. The total number enrolled was 1,300, with 649 in the biodegradable polymer sirolimus-eluting stent arm and 651 in the durable polymer everolimus-eluting stent arm. The follow-up was 1 year. Results demonstrated superior performance of the biodegradable polymer stent with respect to the primary endpoint of target lesion failure (4% with the biodegradable polymer stent and 6% with the durable polymer stent). This was driven by a reduction in the ischemia-driven revascularization. As for the secondary endpoints, the results were similar for MI and probable or definite stent thrombosis (2% for both arms). Cardiovascular death, however, was 3% for the biodegradable polymer stent versus 6% for the durable polymer stent.

This study indicates that the ultrathin stents with a biodegradable polymer are safe and perform well in STEMI. The investigators preferred a superiority design, which was impressively met in this study. Whether these results are attributable to the ultrathin design or the biodegradable polymer cannot be discerned from this trial. A comparison with other stents with a biodegradable polymer such as the everolimus platinum chromium biodegradable polymer stent (SYNERGY [Boston Scientific Corporation; Marlborough, MA]) may shed light on this point. It is important to note that this was a low-risk population with a mean age of 62 years. Of the total population, only 11% had diabetes, and women constituted only 21%. Complicated MI or shock were excluded. Whether these results can be reproduced in a trial using the latest-generation durable polymer drug-eluting stent (Xience Sierra [Abbott Vascular; Chicago, IL]) as a comparator remains a question. Finally, the follow-up duration was only 1 year. With the recent 10-year outcome data from the SYNTAXES trial, we as a community will be anticipating longer follow-up in trials addressing novel stent technologies.

The EORP ACCA EAPCI Registry
By Mary C. Shields, MD, and Angela M. Taylor, MD, MS
University of Virginia Medical Center
Charlottesville, VA

The EurObservational Programme, Acute Cardiac Care Association, European Association of Percutaneous Coronary Intervention Registry on STEMI is an analysis of data collected from January 2015 to March 2017 evaluating the current treatments and outcomes of 11,155 patients with STEMI at 1 year. Data were collected from 193 hospitals across Europe and North Africa and affiliated hospitals (143 of the hospitals were part of a STEMI network). A cardiac catheterization laboratory and cardiac surgery backup was available in 86% and 57% of the hospitals, respectively. Inclusion criteria included chest pain or equivalent symptoms of more than 20 minutes within the prior 24 hours and ST-segment elevation or left bundle branch block on electrocardiography. Of the enrolled patients, 76.6% underwent primary PCI, 16% underwent fibrinolysis, and 7.4% did not receive acute reperfusion. Patients who did not receive reperfusion therapy were more commonly over age 75, female, and diabetic and had a previous history of MI. Reasons for no reperfusion included late presentation, spontaneous reperfusion, clinical inappropriateness, patient refusal, and wrong diagnosis.

The overall mortality rate at 1 year was 8.1%, which was almost double compared with the in-hospital mortality. The increase in mortality rate at 1 year was seen in all groups, with lowest mortality observed in patients who received primary PCI (5.9%) compared with patients receiving fibrinolysis (9.1%) and those who did not receive acute reperfusion (25.2%). Other clinical events at 1 year were rehospitalization (22.6%), heart failure (7.4%), recurrent MI (2.4%), and stroke (1%). The rates of rehospitalization ranged from 21.9% (reperfusion with PCI) to 27% (no reperfusion). At 1 year, 3.7% of patients had a Canadian Cardiovascular Society grading of more than 2, and 5% had a New York Heart Association Class greater than 2. Implantable cardioverter defibrillators were placed in 1.2% of patients, and 0.1% underwent cardiac resynchronization therapy. At 1 year, there was good adherence to beta-blocker (>80%) and statin therapy (>90%).

In comparison, in the United States, 97.5% of patients presenting to PCI-capable centers underwent primary PCI. Lytic therapy is still utilized in 7.02% of patients, and 3.26% of patients received neither lytic or PCI therapy in a contemporary US registry.¹⁰ The 1-year mortality rate for patients with STEMI undergoing primary PCI was 7.3%.¹¹ and adherence to guideline-directed medical therapy was similar.

The 1-year mortality in this study for patients with STEMI receiving PCI was 5.9%, which is comparable to 2 earlier European studies. These registries demonstrated a 1-year mortality of 9.4% in Sweden¹² and 11.4% in Denmark¹³ in patients presenting with STEMI. This current registry provides an encouraging evaluation of the increasing use of primary PCI for STEMI and the decreased mortality rate for patients receiving primary PCI compared with fibrinolysis. Some questions, however, remain unanswered:

• What accounts for the increased mortality in the year following STEMI, and can this be modified?
• Does the adherence to guideline-directed therapy have an effect on 1-year mortality?

ISAR-REACT 5: Time to Reassess Prasugrel in our Daily Practice?
By Michael Lipinski, MD, PhD
Cardiovascular Associates of Charlottesville
Charlottesville, VA

Prasugrel and ticagrelor were both found to be superior regarding ischemic outcomes in patients presenting with ACS compared with clopidogrel.^14,15 However, differences between the two medications became apparent early on and have played a major part in guiding physician practice patterns regarding utilization of either medication. Although very effective at reducing major adverse cardiac events (MACE) and providing rapid platelet inhibition, prasugrel was associated with increased bleeding risk, especially in the elderly and those with prior stroke or low body weight. Prasugrel was also associated with significantly increased bleeding at the time of surgery. This was particularly problematic if patients were pre-loaded prior to coronary angiography in the setting of ACS and found to have surgical coronary anatomy such as multivessel or left main disease. Ticagrelor also provided rapid platelet inhibition and improved MACE following ACS but does have adenosine-mediated side-effects, including dyspnea and bradycardia in a small subset of patients. This increased surgical bleeding risk and inability to use prasugrel in certain patient subsets has led to the trend for many institutions to utilize ticagrelor as their P2Y12 inhibitor of choice in the setting of STEMI. Furthermore, use of cangrelor, the intravenous P2Y12 inhibitor, represents another hurdle for prasugrel because ticagrelor and cangrelor can be utilized concomitantly, and interventionalists need to wait to administer prasugrel until after completion of cangrelor infusion. Delaying loading with prasugrel to the time of PCI in patients with NSTEMI was later shown to help decrease procedural bleeding without adversely impacting MACE.¹⁶ However, the damage may have been done because many interventionalists have established their practice patterns.

The ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen 5) trial recently presented at ESC Congress 2019 and published in the New England Journal of Medicine¹⁷ challenges many of our current practice patterns. Schupke and colleagues randomized 4,018 patients presenting with ACS to either ticagrelor (n = 2,012) or prasugrel (n = 2,006). The ticagrelor group was loaded with ticagrelor 180 mg immediately upon randomization and continued on ticagrelor 90 mg twice daily. Patients randomized to the prasugrel group were loaded with prasugrel 60 mg after randomization if they presented with STEMI, and loading with prasugrel was deferred until the time of PCI if patients presented with non-ST-segment elevation ACS and continued on prasugrel 10 mg daily or 5 mg daily in the elderly or patients with lower body mass. Following randomization, 84.1% of patients in the study underwent PCI while only 2.1% of patients proceeded to CABG. It is important to note that the number of patients undergoing CABG was much lower than previously seen. For example, 10.2% of patients in the PLATO (Platelet Inhibition and Patient Outcomes) trial were referred for CABG.¹⁵ The study demonstrated that patients randomized to prasugrel had significantly less death, MI, or stroke at 1 year compared with those randomized to ticagrelor (6.9% vs. 9.3%, HR 1.36; 95% CI, 1.09-1.70; p = 0.006).¹⁷ Importantly, major bleeding was not significantly different between the ticagrelor group at 5.4% and the prasugrel group at 4.8% (p = 0.46). MI was 63% more likely during follow-up in the ticagrelor group compared with the prasugrel group (96 vs. 60; HR 1.63; 95% CI, 1.18-2.25).¹⁷ These results are striking and raise the question of whether prasugrel use needs to be revisited. Prasugrel is currently generic and provides a cost-effective treatment for patients with ACS. There was no difference in mortality or bleeding in ISAR-REACT 5, suggesting that our concerns of subsequent need for urgent surgery and bleeding after PCI are unfounded. Although the study is provocative, it is unclear to me whether these findings will be able to overcome the inertia that has developed regarding use of ticagrelor. Time will tell whether ISAR-REACT 5 leads to changes in practice and an uptick in prasugrel use.

POPular AGE Trial
By Barbara D. Lawson, MD
VCU Health
Richmond, VA

In the current ESC guidelines, patients presenting with NSTE-ACS should be treated with a P2Y12 inhibitor, with ticagrelor and prasugrel being preferred over clopidogrel. In fact, clopidogrel is recommended only for patients who cannot receive ticagrelor or prasugrel or who need concomitant oral anticoagulation. These recommendations are based on the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) and PLATO trials, which demonstrated the superiority of prasugrel and ticagrelor over clopidogrel, respectively. In both of these trials, prasugrel and ticagrelor were associated with a higher incidence of Thrombolysis in Myocardial Infarction major bleeding, which is known to be associated with higher mortality. Given the higher bleeding risk in the elderly population, the POPular AGE (Randomized Comparison of Clopidogrel Versus Ticagrelor or Prasugrel in Patients of 70 years or Older With Non-ST-Elevation Acute Coronary Syndrome) trial aimed to demonstrate non-inferiority of clopidogrel in clinical outcomes with superiority in reducing bleeding risk compared with ticagrelor or prasugrel. In the study, approximately 1,000 patients (age ≥70 years) presenting with NSTE-ACS were randomized 1:1 to receive clopidogrel (75 mg) or either ticagrelor (90 mg twice daily) or prasugrel (5 mg or 10 mg). Regarding the primary safety endpoint of PLATO major and minor bleeding, there were significantly fewer events in the clopidogrel group versus the ticagrelor/prasugrel group (17.6% vs. 23.1%, HR 0.74). The co-primary endpoint of net clinical benefit (all-cause death, MI, stroke, and PLATO major and minor bleeding) was similar between the two groups, occurring in 27.3% of the clopidogrel group and 30.7% of the ticagrelor/prasugrel group (absolute risk difference -3.4%), meeting the non-inferiority threshold. When looking at the secondary efficacy outcome (death, MI, and stroke), there was no difference in adverse events between groups (12.8% clopidogrel, 12.5% ticagrelor/prasugrel, HR 1.02). The study concludes that clopidogrel is associated with significantly less bleeding and similar efficacy in preventing thrombotic events when compared with ticagrelor or prasugrel and that clopidogrel should be the preferred treatment in patients ≥70 years presenting with NSTE-ACS.

The decision of which P2Y12 inhibitor to use in ACS (and stable coronary disease) has been an ongoing area of research for many years. The TRITON-TIMI 38 and PLATO trials did show superiority for prasugrel and ticagrelor over clopidogrel, but the elderly population was underrepresented in these trials (13-15% of patients ≥75 years), despite composing ~35% of NSTE-ACS patients. Because of the higher bleeding risk, prasugrel is contraindicated in patients with prior stroke or transient ischemic attack and is cautioned against in patients ≥75 years or ≤60 kg. Ticagrelor is associated with dyspnea in 15-20% of patients and is cautioned against in patients with pre-existing conduction disease due to its association with bradyarrhythmias. These warnings are particularly salient in the elderly population, many of whom are frail, have concomitant lung or cerebrovascular disease, or have age-related conduction abnormalities. Thus, despite their proven superiority in the overall population, there are many potential reasons that ticagrelor or prasugrel may not be ideal agents in the elderly. The POPular AGE trial addresses these concerns, demonstrating a relatively safer bleeding profile with similar ischemic endpoints, and makes a strong argument for the use of clopidogrel in patients ≥70 years with NSTE-ACS. The findings of this study should promote confidence among clinicians to prescribe clopidogrel to this patient population unless there is a compelling reason not to, such as recurrent ischemic events or clopidogrel failure.

An Analysis From the Randomized Placebo-Controlled SEAS Trial
By Andrew W. Panakos, MD, and Mauricio G. Cohen, MD, FACC
University of Miami Miller School of Medicine
Miami, FL

At an ESC Congress 2019 late-breaking science session in aortic valve disease, the SEAS (Simvastatin and Ezetemibe in Aortic Stenosis) investigators, led by Olav Nielsen, presented an observational sub-analysis investigating the role for N-terminal pro-B-type natriuretic peptide (NT-proBNP) in predicting outcomes in patients with asymptomatic, non-severe aortic stenosis (AS). SEAS was a multicenter study that enrolled 1,873 patients between the ages of 45 and 85 with mild-to-moderate, asymptomatic AS (peak aortic-jet velocity of 2.5-4 meters per second on echocardiography) and without known coronary or cerebrovascular disease or diabetes mellitus. The main study results showed that simvastatin 40 mg combined with ezetimibe 10 mg lowered low-density lipoprotein levels but did not affect the progression of AS compared with placebo.

For the NT-proBNP sub-analysis, the authors chose a pragmatic endpoint of aortic valve events, defined as a composite of aortic valve replacement surgery, congestive heart failure due to AS, or death from cardiovascular causes. The secondary endpoints included the aforementioned aortic valve replacement surgery and cardiovascular death, as well as non-cardiovascular death. Of note, all endpoints were prespecified. Their sample consisted of the 1,644 patients who survived the first year without an aortic valve event and had their NT-proBNP levels assessed at 1 year. The normalized ratio between measured serum NT-proBNP level and maximal normal NT-proBNP level for age and sex was calculated for each patient. Patients were then stratified into normal (≤1), intermediate (1.01-2.99), and high (≥3) NT-proBNP ratios, based on blood samples drawn on a yearly basis. They also examined annual NT-proBNP relative change. The length of follow up was 2 years. NT-proBNP ratios increased by 10% in patients with mild AS and 21% in patients with moderate AS.

Patients with intermediate and high NT-proBNP values had an adjusted HR (95% CI) for aortic valve events of 2.0 (1.6-3.4) and 3.7 (2.8-4.8) compared to those with normal NT-proBNP values, respectively. Patients with a relative change of NT-proBNP levels ≥1.5 had an HR of 1.4 (1.2-1.7) for aortic valve events. Incidence rates for cardiovascular and non-cardiovascular death for patients with normal NT-proBNP levels (approximately 70% of the overall sample) were 1.1 and 9.8 per 100 persons per year in the mild and moderate AS subsets, respectively.

Surveillance of the rate of progression of AS has been a long-standing challenge, calling into question the optimal follow-up strategy, including serial echocardiography. Most clinicians still rely on patients' symptoms as the best indicators for aortic valve replacement, despite their variability and subjectivity. Yet a proportion of patients with AS develops asymptomatic LV dysfunction. The findings of this SEAS sub-study are relevant and support the use of NT-proBNP, an inexpensive laboratory test, as a risk stratification tool for patients with asymptomatic, non-severe AS (by echocardiography). A normal NT-proBNP level (adjusted for age and sex) appears to be a substantial favorable prognostic marker for aortic valve events. This may allow clinicians to offer reassurance and reduce the frequency of unnecessary ancillary tests (i.e., echocardiograms) for patients with AS who are at low risk for aortic valve events. Notable exclusions from this study were those with atherosclerotic cardiovascular disease and diabetes, which may affect NT-proBNP levels. Longer-term follow-up would be enlightening, particularly in those patients who have intermediate or high NT-proBNP levels and/or those who display a relative change over time. Despite these limitations, the SEAS results in aggregate with prior studies strongly suggest that NT-proBNP levels should be part of the routine evaluation and risk stratification of patients with AS.

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Keywords: ESC Congress, ESC 19, Acute Coronary Syndrome, Angina, Unstable, Aortic Valve, Aortic Valve Stenosis, Anticoagulants, Angiography, Coronary Angiography, Adenosine, Biomarkers, Blood Platelets, Bundle-Branch Block, Bradycardia, Body Weight, Cardiac Catheterization, Cardiac Resynchronization Therapy, Cardiac Surgical Procedures, Chest Pain, Chromium, Confidence Intervals, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Coronary Disease, Defibrillators, Implantable, Developing Countries, Diabetes Mellitus, Drug-Eluting Stents, Dyspnea, Echocardiography, Electrocardiography, Fibrinolysis, Follow-Up Studies, Gastrointestinal Tract, Heart Defects, Congenital, Heart Failure, Heart Valve Diseases, Hemorrhage, Hirudins, Hospital Mortality, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myocardial Infarction, Infarction, Incidence, Insulin, International Classification of Diseases, Length of Stay, Ischemic Attack, Transient, Myocardium, Natriuretic Peptide, Brain, Lipoproteins, LDL, Percutaneous Coronary Intervention, Peptide Fragments, Platinum, Platelet Aggregation Inhibitors, Polyethylene Glycols, Practice Patterns, Physicians', Polymers, Prognosis, Random Allocation, Purinergic P2Y Receptor Antagonists, Referral and Consultation, Registries, Risk Factors, Research Personnel, Prospective Studies, Simvastatin, Stents, Sirolimus, Single-Blind Method, Stroke, Stroke Volume, Surgeons, Survival Rate, Thrombosis, Ticlopidine, Taxus, Tissue Plasminogen Activator, Troponin, Warfarin

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