Cover Story: Your Intervention, U.S. data get upstaged at ESC; even the AMERICA trial is French | By Rick McGuire and Debra L. Beck
CardioSource WorldNews Interventions | An interesting European Society of Cardiology meeting in Rome. (In terms of special guests, the Pope will indeed be hard to top.) Yes, the United States was well-represented, but in terms of interventional stories here (rushed to print, as you can tell by the date you’re holding this in your hands), America barely makes it to the page. Even the AMERICA trial was done in France! Sigh. It’s truly the World of Cardiology in the 21st Century.
Bolstering the Role of Aggressive Interventions Even after a non-ST elevation myocardial infarction (NSTEMI), aggressive use of percutaneous coronary intervention (PCI) and stenting makes a big difference in achieving positive outcomes, according to the results of an analysis of nearly 400,000 NSTEMI patients living in England and Wales.
Marlous Hall, PhD, from the University of Leeds, England, and colleagues analyzed data from the Myocardial Ischemia National Audit Project (MINAP) from 2003-2004 to 2012-2013. Over this period, fewer patients had intermediate-to-high GRACE risk scores (decreasing from 87.2% to 82.0%) and the proportion of patients at the lowest risk increased (4.2% to 7.6%; p = 0.01 for trend). As you remember, the GRACE score incorporates age, cardiac arrest, ST-segment deviation, biomarker elevation, blood pressure, heart rate, heart failure, and renal function.
Improvements in baseline GRACE risk scores through the years had a strong opposing force: the prevalence of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, a previous invasive coronary strategy, and current or ex-smoking status all increased (all p < 0.001 for all).
During the study period, use of guideline-indicated care increased, as did increased use of an invasive coronary strategy (even after adjusting for changes in clinical risk and pharmacological therapies), and patients experienced a significant decrease in 180-day all-cause mortality (10.8% to 7.6%).
In analyzing the reasons for the improved outcomes, investigators found that the reduction in baseline acute coronary syndrome (ACS) risk, increase in comorbidities, and use of guideline-indicated therapies did not fully explain the relative 3.2% year-by-year increase in 6-month survival rate throughout the study period.
As seen in international registries, these improvements were significantly and independently associated with use of an invasive coronary strategy. Specifically, an invasive coronary strategy, defined as coronary angiography, PCI, or coronary artery bypass graft (CABG) surgery, increased from 42.7% to 78.6% over the course of the study (p < 0.001).
In an accompanying commentary, Erin Bohula, MD, DPhil, and Elliott Antman, MD, MACC, of the TIMI study group and Brigham and Women’s Hospital, Boston, wrote, “Hall and colleagues have demonstrated that under optimal conditions with universal access to health care in a high-income region, the use of guideline-directed invasive coronary strategies and pharmacotherapy is associated with improved outcomes. It is time to translate the success of MINAP to low- and middle-income countries and health care systems, where the resources are limited but the needs are the greatest.” – Journal of the American Medical Association
A Comeback for BMS?
While some observers argue there is little role for bare metal stents (BMS) today, the Norwegian Coronary Stent Trial (NORSTENT) contends that BMS should not be retired yet. It is the largest single randomized trial evaluating second-generation drug-eluting stentsc (DES) versus newer BMS in a pragmatic, broadly inclusive, properly-powered, and inexpensive trial that (perhaps most importantly) was not industry sponsored.
Between Sept. 15, 2008, and Feb. 14, 2011, all patients undergoing PCI in Norway were evaluated for enrollment. Eligible patients were mostly defined as having stable angina or ACS and lesions amenable for either DES or BMS. Of 12,425 adults who met the eligibility criteria, 9,013 (72.5%) were randomly assigned to either BMS or DES implantation. After a median of 5 years of follow-up, there were no significant between-group differences in the primary composite outcome of death from any cause or nonfatal spontaneous myocardial infarction (MI), nor were there differences in the individual endpoints of death, MI, stroke, or hospitalization for unstable angina.
In an accompanying commentary to the concurrently published online results, Eric R. Bates, MD, FACC, of the University of Michigan Medical Center, Ann Arbor, noted that this confirmed historical evidence that coronary stenting has never shown a reduction in these clinical events on the basis of stent type. He did note, “… event rates with latest-generation bare-metal stents were lower than may be appreciated by most interventional cardiologists and that rates of stent thrombosis were low in both stent groups.”
Still, also as expected, second-generation DES performed better than the latest generation of BMS for target-lesion revascularization (5.3% vs. 10.3%, respectively; p < 0.001), any revascularization, and definite stent thrombosis.
Yet, Kaare Harald Bonaa, MD, PhD, Norwegian University of Science and Technology, Trondheim, Norway, who presented the data, said while DES patients did have less need for a second revascularization procedure, it was not to the level interventionalists might have expected. In fact, he said, “Thirty patients would need to be treated with DES rather than with BMS to prevent one repeat revascularization.” Dr. Bonaa added, “Patients treated with DES do not live longer and they do not live better than patients treated with BMS.”
Where are we? Dr. Bates noted that second-generation DES are preferred in most clinical situations. Nevertheless, he wrote, BMS use remains an important option in some patients, including those with a large vessel diameter in whom restenosis rates are low, those who cannot complete the longer duration dual-antiplatelet therapy (DAPT) recommended for DES because of noncompliance or need for noncardiac surgery, those who cannot pay for DES or a longer duration of DAPT, and those at increased risk for bleeding (e.g., patients with recent bleeding or a need for concomitant anticoagulation therapy). – New England Journal of Medicine
Single Imaging Good, Hybrids Less So
For patients presenting with what might be coronary artery disease (CAD), a new study tackled the tough topic of which noninvasive test is better? Investigators conducted a head-to-head comparison of the most commonly used noninvasive techniques in the single-center PACIFIC trial, which stands for (deep breath): Prospective Head-to-Head Comparison of Coronary CT Angiography, Myocardial Perfusion SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease using Fractional Flow Reserve as Index for Functional Severity of Coronary Stenoses. Just in case you were wondering which tests were tested….
The first lesson: hybrid approaches don’t help: diagnostic accuracy was not enhanced by either hybrid coronary computed tomography (CCTA)/single photon emission CT (SPECT) or CCTA/positron emission tomography (PET). The combos resulted in an increase in false negatives although there was a decrease in false positive results (p < 0.001). This was disappointing news to the presenters who have previously promoted two as being better than one: specifically, CCTA/SPECT.1
Comparing these noninvasive tests to the gold standard results, investigators showed that PET was significantly more accurate (85%) for diagnosing coronary ischemia compared to CCTA (74%; p < 0.01) and SPECT (77%; p < 0.01). Sensitivity of the noninvasive approaches was 87% for PET, 90% for CCTA, and 57% for SPECT, whereas specificity was 60%, 94%, and 84%, respectively.
“At present, there is little consensus about the choice of noninvasive imaging modality, and European and U.S. guidelines do not advocate for any one over another,” according to Ibrahim Danad, MD, from VU University Medical Center, Amsterdam, the Netherlands who presented the findings. “The vast majority of studies used invasive coronary angiography as a reference standard, which may lead to erroneous interpretations. These data represent the first comprehensive evaluation of coronary artery disease and will help to guide the clinician to choose the appropriate non-invasive test for his or her patients.”
Consider Procedural Complexity When Determining DAPT
Alongside other established clinical risk factors, procedural complexity looms as an important parameter to take into account in tailoring upfront duration of DAPT.
This comes from an interesting study of almost 9,600 patients, using pooled patient-level data from 6 randomized controlled trials. (Investigators spanned the globe: United States, Italy, Spain, the Netherlands, South Korea, and France.) Of the pooled population, 1,680 (17.5%) patients underwent complex PCI, defined as at least one of the following features: 3 vessels treated, > 3 stents implanted, > 3 lesions treated, bifurcation with 2 stents implanted, total stent length > 60 mm, or chronic total occlusion. The primary efficacy endpoint was major adverse cardiac events (MACE), defined as the composite of cardiac death, MI, or stent thrombosis. The primary safety endpoint was major bleeding.
Patients who underwent complex PCI were at a substantially higher risk of ischemic events, in a graded fashion, with increased procedural complexity (hazard ratio [HR]: 1.98; p < 0.0001) (FIGURE). The risk was similar in magnitude to that of other well-established clinical risk factors and tended to be greater for progressively higher degrees of procedural complexity.
In patients who underwent complex PCI, compared with a short period of DAPT (3 or 6 months), long-term DAPT (>1 year) significantly reduced the risk of cardiac ischemic events with a magnitude that, again, was greater for higher procedural complexity (adjusted HR: 0.56 for longer DAPT). Compared to the noncomplex PCI group, the p value for interaction was 0.01.
The benefits of prolonged DAPT appeared to be uniform across complex PCI components, DES generations, and clinical presentation. And, of course, long-term DAPT was associated with an increased risk of major bleeding that was irrespective of procedural complexity.
Currently, clinical decision making on upfront DAPT intensity and duration after coronary stenting is predominantly made on the basis of clinical ischemic and bleeding risk factors. Gennaro Giustino, MD, and colleagues are arguing that degree of procedural complexity “substantially influences future ischemic risk and identifies patients who may benefit from longer or more intense antithrombotic therapies.” – Journal of the American College of Cardiology
Time to Rethink ICDs in HF?
For primary prevention, implantable cardioverter–defibrillators (ICDs) reduce the risk of premature death among patients with left ventricular systolic dysfunction after MI and among patients with heart failure (HF) and reduced ejection fraction. What about patients with HF who do not have CAD?
The guidelines support ICDs in this setting, although based on less robust evidence, for sure; specifically, a meta-analysis of small trials involving patients with nonischemic cardiomyopathy, as well as subgroup analysis of patients with nonischemic cardiomyopathy from larger trials.
A new study – more than twice the size as the largest previous study – questions this approach. The Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH – conducted in Denmark, of course), randomly assigned 1,116 patients with nonischemic HF to conventional therapy or an ICD plus conventional therapy. After a median of 5.6 years, ICD therapy was associated with a risk of sudden cardiac death that was half that of conventional therapy, but the effect on overall mortality, the primary endpoint of the trial, was not significant.
Importantly, background therapy was really optimized ion this trial, with almost universal use of angiotensin-converting enzyme inhibitors and beta-blockers. Also, patients with nonischemic cardiomyopathy have lower rates of sudden cardiac death and of death from any cause than do patients with ischemic HF. Moreover (and unlike previous ICD trials), 58% of patients received cardiac resynchronization therapy (CRT).
There was a suggestion of a differential response according to age in the DANISH trial, with a possible benefit of ICD therapy with regard to death from any cause among younger patients (< 68 years of age). In an accompanying commentary, John J.V. McMurray, MD, FACC, noted that ICDs are expensive and not without adverse effects, meaning they should be avoided in patients who are unlikely to obtain a worthwhile benefit.
Dr. McMurray wrote: “These considerations highlight the need to target ICDs to the patients most likely to benefit — that is, those who remain at high absolute risk for sudden cardiac death despite receiving the best available pharmacologic and device therapy. The results of the DANISH trial, coupled with the generally infrequent use of ICDs globally, should open a debate about whether it is ethical to conduct new ICD trials involving the highest-risk patients. The challenge is how to identify such patients.”
In a press conference, Mariell Jessup, MD, FACC, of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia, said “This is the first trial looking at the use of ICDs in the setting of modern therapy so I think this was really an appropriate trial.” However, she said the big problem we have today is this: not enough ICDs are being used in patients with reasonable life expectancy. She said, “No country is putting in enough ICDs for patients who can expect to live more than 1 year.” – New England Journal of Medicine
AMERICA (The Study) Fails
Guidelines were recently updated upgrading multivessel primary PCI in hemodynamically stable patients with STEMI from Class III (Harm) to a Class IIb recommendation. The writing committee did not endorse routine PCI of non-culprit lesions but instead supported it as an option for patients based on clinical data, lesion severity/complexity, and risk of contrast nephropathy.2
What about high-risk patients, in general? At ESC, investigators presented – let’s call it a French-AMERICA study. Jean-Philippe Collet, MD, PhD, FACC, from the Institut de Cardiologie Hopital Pitié-Salpetrière (Paris, France), presented the results of the AMERICA (Active detection and Management of the Extension of atherothrombosis in high Risk coronary patients In comparison with standard of Care for coronary Atherosclerosis).
Patients were randomized to a proactive prevention program including revascularization of asymptomatic multisite artery disease when appropriate, lifestyle changes, and an aggressive pharmacological approach (n = 263), or to a more conventional strategy based on treatment of CAD and only symptomatic extra-coronary lesions (n = 258).
These patients were considered high risk based on either recently diagnosed 3-vessel disease (within the past 6 months) or ACS in the past month (in patients ≥75 years old). Nevertheless, detecting and treating the asymptomatic sites of stenosis did not improve 2-year outcomes compared to a more traditional approach of managing only symptomatic lesions.
Professor Collet said an aggressive secondary prevention strategy is probably best in these high-risk patients, which appears to be the standard of care already. He added, “We do not need to systematically identify asymptomatic multi-site artery disease in these high risk patients.”
The Culotte (Stent) Becomes Fashionable
For provisional side-branch stenting, T-and-protrusion (TAP) stenting and culotte stenting are both compatible with current recommendations, although a recent European consensus statement3 gave first place to some form of T-stenting (such as TAP stenting).
Not sure how it won top billing given there has been no randomized study comparing TAP stenting with culotte stenting in patients requiring side-branch stenting, but to fill this gap in evidence Miroslaw Ferenc, MD, PhD, FACC, and colleagues (University Heart Center Freiburg, Bad Krozingen, Germany) performed the randomized ‘Bifurcations Bad Krozingen’ (BBK) II trial.
During the procedure, if a side-branch stent was needed and the lesion was deemed amenable for both stenting techniques, patients were randomized to either TAP stenting (n = 150) or culotte stenting (n = 150). The primary endpoint was maximal in-stent percent diameter stenosis of the bifurcation lesion based on follow-up quantitative coronary angiography at 9 months.
Compared with TAP stenting, culotte stenting was associated with a significantly lower incidence of angiographic restenosis, although there was only a trend showing an advantage for culotte stenting based on 1-year target-lesion revascularization and target-lesion failure.
This difference in the primary endpoint was driven almost entirely by differences in the side branch, where the mean percent diameter stenosis was 16% in the culotte arm versus 22% in the TAP arm (p = 0.029). In contrast, there were no differences between techniques in the percent diameter stenosis in the main branch.
Said Dr. Ferenc: “Doctors working in the catheter lab should now consider this approach if they have patients with suitable anatomy for both techniques. Cardiologists can use culotte stenting with more confidence, knowing that this technique is associated with a very low angiographic restenosis rate and lower rate of TLR as compared with TAP stenting – even though it is slightly more challenging and requires appropriate training.” – European Heart Journal
DOCTORS: “Modest” Success with OCT
In a trial comparing optical coherence tomography (OCT)-guided versus standard angiography-guided coronary intervention in ACS patients, the addition of OCT impacted directly on physician decision-making in half the cases and was associated with higher post-procedure blood flow.
“This is the first randomized trial showing a potential positive effect on fractional flow reserve in ACS patients undergoing PCI and the higher the fractional flow reserve, the lower the event rate,” according to Nicolas Meneveau, MD, PhD, University Hospital Jean Minjoz, Besançon, France.
The procedure – which involves introducing an imaging catheter into the coronary artery to identify plaque morphology, check vessel size, lesion characteristics, and stent positioning and expansion – did significantly increase both procedural time and the use of contrast medium, but it did so without an increase in periprocedural complications or kidney injury.
The DOCTORS (Does Optical Coherence Tomography Optimize Results of Stenting) trial randomly assigned 240 patients with NSTEMI to either OCT-guided PCI or to fluoroscopy-guided PCI. The trial was conducted at 9 hospitals in France.
Most of the benefit of OCT seemed to be in the form of more information on top of that obtained by angiography, leading to a change in procedural strategy in 50% of cases. Post-procedure fractional flow reserve, the primary endpoint, was significantly higher in those who had OCT (0.94 versus 0.92 for angiography alone; p = 0.005). In the study arm, 82.5% of patients had a post-PCI FFR > 0.90, compared to 64.2% in the control arm (p = 0.0001).
OCT was performed after the initial angiography and repeated after stent implantation. The operators were encouraged to adjust their procedural strategy according to the data immediately available on the OCT images. The addition of pre-PCI OCT imaging did not appear to change the procedural strategy compared to angiography alone, but the first OCT run performed immediately after stent implantation showed stent malapposition in 32% of patients and stent underexpansion in 42%. Post-stent overdilation was performed in all patients with stent underexpansion, and in 22 out of 38 of those (58%) with stent malapposition (of whom 20 also had stent underexpansion).
The trial discussant, Stephen Windecker, MD, of Bern University Hospital in Switzerland, noted that OCT is recognized as a diagnostic modality in select patients to optimize stent implantation in the current ESC guidelines, but the recommendation class (IIb) and level of evidence (C) reflect the lack of randomized trial evidence guiding current clinical practice.
Whether the “modest” improvement seen in postprocedural FFR will translate into improved long-term clinical outcomes and whether the procedure is cost effective will need to be tested in future trials, said Dr. Windecker, but there are already some data indicating an inverse relationship between post-PCI FFR and the occurrence of MACE. Also to be determined: whether the findings can be extrapolated to other clinical settings, such as ST-segment MI populations. – Circulation
CE-MARC 2: Cardiac MR reduces unnecessary angiography
What’s better than guideline-directed care? In this case, maybe cardiac magnetic resonance (CMR) in symptomatic patients with suspected CHD. Investigators found that noninvasive CMR resulted in a lower probability of unnecessary angiography within 1 year compared to UK National Institute for Health and Care Excellence [NICE] guideline-directed care.
CMR and myocardial perfusion scintigraphy (MPS) strategies were similar in their ability to prevent unnecessary angiography, and there were no statistically significant differences in major cardiovascular adverse events at 1 year for all three strategies.
Current guidelines recommend angiography for patients with stable chest pain based on their pre-test likelihood for CHD. However, most of the risk prediction models used have been around for more than 3 decades and tend to overestimate risk, thereby increasing the probability of invasive coronary angiography. Add to this the fact that most patients who undergo elective coronary angiography – fully 60% in a recent large US study – are found to have no obstructive CAD, and this makes reducing unnecessary angiograms a good target for reducing both patient procedural risk and costs.
The Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) trial included 1,202 patients with suspected CHD from 6 United Kingdom centers. Patients were randomized to functional imaging-based investigation with either CMR (n = 481) or MPS (n = 481), or to NICE guideline-directed investigation (n = 240), where only those with a high pre-test likelihood of CHD are sent directly to angiography. Those with a pre-test likelihood between 10% and 29% were scheduled for cardiac computed tomography (CCT), and those with a pre-test likelihood between 30% to 60% (intermediate risk) were scheduled for MPS.
Unnecessary angiography, defined by the absence of significant stenosis measured by FFR or quantitative coronary angiography, was seen in 28.8% of the group managed according to NICE guidelines, compared to 7.5% of the CMR group, and 7.1% of the MPS group (p < 0.001 for CMR vs. NICE guidelines and p = 0.32 for CMR vs. MPS). Overall, 22% of the study population underwent coronary angiography within 12 months.
The CE-MARC 2 authors concluded, “Noninvasive functional imaging strategies reduced unnecessary angiography compared with guidelines-directed care.”
The investigators noted that MPS is the most commonly used test worldwide for the assessment of myocardial ischemia, with robust evidence supporting its prognostic value. However, their original CE-MARC trial showed that CMR had a higher diagnostic accuracy compared to MPS4 and was also a stronger predictor of risk for MACE.5 – JAMA
- Danard I, et al. J Nucl Med. 2013;54:55-63.
- Levine GN, et al. J Am Coll Cardiol. 2016;67:1235-50.
- Lassen JF, et al. EuroIntervention. 2016;12:38-46
- Greenwood JP. Lancet. 2012;379:453-60.
- Greenwood JP. Annals of Internal Medicine. 2016 May 10. [Epub ahead of print]
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