Shifting Focus
Stents Re-take Interventional Spotlight, TAVR Takes a Rare Hit

Cover Story | The stars aligned to unleash a slightly different TCT this year. For several years, much of the breaking news at the Transcatheter Cardiovascular Therapeutics meeting (not surprisingly) centered around TAVR (and TAVI for the European presenters). Sure, TCT.15 still had plenty of transcatheter aortic valve sessions, but they did not take up nearly the amount of prime time space at the convention as years past. Stents regained star status, with a best supporting role for the peripherals, and a special guest star. No, not Arnold Schwarzenegger, who indeed did appear as a special guest speaker; we’re talking about a truly late-breaking story that earned its own last-minute, add-on press conference—relating to TAVR. I guess you can’t keep a good story down.

TCT Highlights

High Bleeding Risk Patients
Among patients undergoing percutaneous coronary intervention (PCI), about 15% to 20% are at high risk for bleeding—and those percentages will climb higher given the aging population. These patients represent a clinical quandary because they are at both high ischemic and bleeding risk—and have largely been excluded from device and antiplatelet clinical trials.

For these patients, current guideline recommendations suggest either use of a bare-metal stent (BMS) plus 1 month of dual antiplatelet therapy (DAPT) or a drug-eluting stent (DES) plus “shortened” DAPT.

In an effort to find a better way of managing these patients, investigators conducted the LEADERS FREE trial (which, believe it or not, stands for the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent vs. the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk).1,2 BA9 is an mTOR inhibitor, like sirolimus and everolimus, but BA9 is 10 times more lipophilic than sirolimus and about five times more than everolimus.

There are several reasons why a polymer-free drug-coated stent (DCS) might be superior in this setting to a BMS. A DCS avoids any possible polymer-related adverse effects and the rapid drug transfer to the vessel wall (98% within 1 month) means it might be safe to shorten DAPT duration.

Urban et al. randomized high bleeding risk patients to either DCS (n = 1,221) or BMS (n = 1,211) followed by 1 month of DAPT. According to lead investigator Philip M. Urban, MD, FACC, director of interventional cardiology, La Tour Hospital, Geneva, Switzerland, “The LEADERS FREE trial clearly showed that a drug-eluting stent combined with a 1-month-only DAPT course was both significantly safer and more effective than a bare-metal stent in this subset of patients.” In terms of the primary safety endpoint (composite of cardiac death, myocardial infarction [MI], and definite/probable stent thrombosis at 1 year post-procedure), it occurred in 112 (9.4%) patients receiving the DCS versus 154 (12.9%) with BMS (p < 0.0001 for noninferiority and p = 0.005 for superiority).

For the primary efficacy endpoint of clinically-driven target lesion revascularization (TLR) at 1 year, results also were superior for DCS: 5.1% vs. 9.8% for BMS (p < 0.001 for superiority).

Among subtypes of MI, based on the third version of the universal definition of myocardial infarction, type 1 (spontaneous myocardial infarction) and type 4c (myocardial infarction related to in-stent restenosis) MIs occurred significantly less frequently in the DES group. Bernard Gersh, CHB, DPhil, MB, MACC, professor of medicine at Mayo Medical School, Rochester, MN, who was not involved with the study, told reporters at TCT.15: “Spontaneous MI is a really important endpoint. We did a study with Gregg W. Stone, MD, FACC, using the ACUITY trial (data) and showed that spontaneous MI had a powerful prognostic impact. I think that’s a hard endpoint and important that it was reduced (in LEADERS FREE).”

The BA9-DCS already is CE (Conformitė Europe) marked and, in the United States, Biosensors International has received conditional investigational device exemption approval to conduct a U.S.-based clinical trial of its BioFreedom stent.

Trying to Absorb ABSORB III

The future of bioresorbable stents may be a little murkier after ABSORB III.3 In this large-scale, randomized trial, treatment of noncomplex obstructive coronary artery disease using an everolimus-eluting bioresorbable vascular scaffold (BVS, Abbott Vascular, Santa Clara, CA) was noninferior to an everolimus-eluting cobalt–chromium stent (Xience, also from Abbott) at 1 year. That lack of difference held true for target lesion failure at 1 year, rates of cardiac death, target vessel MI or ischemia-driven TLR, and device thrombosis in the intention-to-treat analysis.

Dean J. Kereiakes, MD, FACC, medical director of Christ Hospital Heart & Vascular Center/The Lindner Research Center in Cincinnati, OH, presented the trial results and spoke to the press. “What is undeniable is that there is a durable hazard of device-related adverse events after the very best metal-platform (stent) we have today.” No matter the device, he said, that risk amounts to about 2% to 3% per year. The whole purpose of the bioresorbable stent, he added, was to improve late outcomes by removing this metal cage. “There is only one way for a metallic scaffold to change over time and that is for the artery to become more narrow,” said Dr. Kereiakes. “It can’t become larger.”

The remarkable thing is that a first-generation device with a 150-micron strut thickness went to toe-to-toe with the current “gold standard, best-in-class” device. Dr. Kereiakes said, “That’s what makes me comfortable as an interventionalist and as a clinician in putting it in one of my patients.”

Excellent, however… While demonstrating equivalency at 1 year, ABSORB III missed all three secondary endpoints—target-lesion failure, angina, or ischemia-driven TLR—all designed for superiority. Indeed, in most cases, the BVS looks numerically (albeit not statistically) worse than Xience.

Dr. Kereiakes understands “the optics” but added, “These are small, insignificant, not statistically significant differences in low-frequency events that are grossly under-powered. So, for many of these, it could be play of chance.”

What’s next? ABSORB IV will add 3,000 patients, leaving investigators to analyze a total of 5,000 patients (adding in the ABSORB III population) for a landmark analysis of 1 to 5 years. Difference in target lesion events will be the primary endpoint that will be “the money shot,” as Dr. Kereiakes put it, to show significant differences between these two devices. But he noted it will be 6 to 7 years before we see those results. He asked how long should we go without having this device available.

Daniel I. Simon, MD, FACC, a professor of medicine at Case Western Reserve University School of Medicine, Cleveland, OH, said in a press conference, “It is really important to understand the unmet need here. If you look at the 5-year results from the best-in-class Resolute DES, there is a target lesion failure rate of about 17%, about half of which are device-related and the other half is something else. We are trying to do better for our patients. This is another approach to try to improve upon those 5-year numbers and, as Dean says, we need time.”

But why pay more for a device that is just noninferior to the current best-in-class stent? Dr. Simon also is president of the Harrington Heart and Vascular Institute, University Hospitals in Cleveland, OH. When asked about costs, he noted that his centers do 13,000 cases a year in six angioplasty hospitals. “So, we are going to face questions like this pretty soon. In general, when you have new technologies or new iterations, one tends to pay more, but the question is why pay more? What is the advantage of the (bioresorbable) device? I think we are just learning what those advantages might be. Clearly, this trial does not suggest a patient-centered outcome benefit but it’s early on. In general, I think we’ll (be willing to) pay a little more for a device that patients are asking for because, as Dean pointed out, they are concerned about rigid cages in their heart arteries and access to the stented area down the line.” Yet he made it clear that what hospitals like his would be willing to pay for a BVS is an incremental increase in price, and not a lot more.

In reality, assuming eventual approval, will U.S. pricing be more like France or Germany? Marie-Claude Morice, MD, director of interventional cardiology, Institut Cardiovasculaire Paris Sud in Massy, France, said, in her country, the device is not yet reimbursed, but is expected to be soon at the same price as currently available DES. Michael Haude, MD, Lukaskrankenhaus Neuss, said Germany adopted this technology very early but the problem is the “really remarkable” price difference—the BVS is eight times more expensive than a standard drug-eluting stent. He added, “We need to find something that is not just noninferior but rather something that is superior.”

Bursting Balloons: Not All DCBs Alike
Charles T. Dotter, MD, first reported targeting a superficial femoral artery (SFA) lesion with an endovascular approach, but, 50 years later, there is still little consensus on the best treatment algorithm for these patients. Two drug-coated balloons (DCBs) recently were approved in the United States based on 12-month safety and efficacy data.

However, there has been concern that DCBs might be associated with late restenosis after angioplasty. This was based on 2-year data from LEVANT II (the second Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis trial), where there appeared to be a late catch-up phenomenon between 1 and 2 years. Primary patency was not stellar: 58.6% with the DCB vs. 53% with standard angioplasty.

At TCT, investigators presented the 2-year results of IN.PACT SFA (using the IN.PACT® Admiral DCB, Medtronic, Santa Rosa, CA). At 24 months, patients treated with DCB showed significantly higher primary patency compared to standard angioplasty (Figure; p < 0.001). The rates of clinically-driven TLR were 9.1% and 28.3% (p < 0.001) for the DCB and plain angioplasty groups, respectively. In their JACC paper, published simultaneously with the presentation at TCT,6 the authors noted that the 12-month clinically-driven TLR rate of 2.4% for the DCB group was the lowest reported in the medical literature for a femoropopliteal endovascular therapy and, while the rate was higher at 2 years, it remained much lower than seen with standard angioplasty.

John R. Laird, MD, FACC, professor of medicine and medical director of the University of California Davis Vascular Center, said, “In IN.PACT SFA, we did not detect any late catch-up and the patency benefit at 1 year was durable at 2 years. This answers an important question and may suggest not all drug-coated balloons are the same.” He added, “We think the excellent and durable results of this trial will drive a paradigm change in regards to SFA interventions.”

The discussant for the trial, David J. Cohen, MD, director of cardiovascular research, Saint Luke’s Mid America Heart Institute, Kansas City, MO, said during a press conference, “The strategy of leaving nothing behind, the strategy of no permanent implant, like a stent, is very attractive to endovascular specialists around the world—where (drug-coated balloons) are being used much more frequently—but patterns and practice are definitely shifting in the U.S. towards drug-coated balloons.”

Commenting on the trial, Upendra Kaul, MD, FACC, executive director and dean of cardiology, Fortis Escorts Heart Institute (New Delhi, India), said: “It is clear that the drug-coated balloons work much better than the non-drug-coated balloon in terms of recurrence in these small vessels and long lesions. Mortality probably won’t be affected but patient symptoms and claudication distance and everything else is more durable, certainly.”

One important aside: on October 29, about 2 weeks after TCT, a letter was published in the New England Journal of Medicine regarding LEVANT II.7 Mohamad A. Hussain, MD, and Mohammed Al-Omran, MD, both of Toronto, Canada, wrote, “Although these results are encouraging, it is unclear whether superior vessel patency translates into improvements in more clinically appropriate endpoints such as ambulatory function and quality of life.”

The LEVANT II authors responded, noting that their study was designed as a pivotal trial and was not powered to compare intergroup differences in such secondary endpoints. Nevertheless, LEVANT II did actually show significant improvement in favor of the DCB group in the walking-distance component of the Walking Impairment Questionnaire at 12 months. Similarly, a post hoc analysis evaluating sustained improvement in Rutherford class without re-intervention showed a benefit in favor of the DCB group compared to the standard-angioplasty group (76.2% vs. 66.6%; p = 0.04). In the IM.PACT SFA trial, as reported in JACC, patients treated with DCBs achieved similar levels of quality of life improvement versus standard therapy despite 58% fewer re-interventions than with standard angioplasty.

More TCT Highlights

TOTAL Failure, but is Anyone Paying Attention?
The TOTAL trial has been the world’s largest study of routine manual thrombectomy in ST-segment elevation MI (STEMI) patients, randomizing more than 10,000 patients worldwide to routine upfront manual thrombectomy versus bailout thrombectomy only. Despite a number of pathophysiological improvements, there was no difference in the primary outcome or its components.

According to Sanjit S. Jolly, MD, MSc, FACC, associate professor, McMaster University in Hamilton, Ontario, Canada, “We performed an updated meta-analysis including all randomized trials of thrombectomy versus PCI alone and now have more than 20,000 patients randomized and we found no difference in all-cause mortality between thrombectomy and PCI alone after STEMI. However, we observed a significant increase in stroke in this updated meta-analysis: 0.9% in the thrombectomy group vs. 0.6% in the PCI alone group.”8

The TOTAL trial results were presented at ACC.15 in March but little has changed. Dr. Jolly said it just takes time for information to make its way into clinical practice: “A number of colleagues have said they are using less thrombus aspiration based on the results. It is causing them to pause. As interventional cardiologists, we are very visually driven and when we see something we want to take it out. It may take more time for practice to shift.”

He added, “Personally, I have taken the strategy of the control arm in the trial: first approach, use a balloon and many times, with modern pharmacotherapy, if you have a large thrombus, you balloon it and things seem to break up, go downstream, and disappear. However, based on the approach of the trial, if you are unsuccessful with your balloon—you still don’t have flow, you can’t size the vessel, you have large thrombus—then I use thrombectomy as a sort of back-up therapy. It is more cost effective and, based on the trial results, a better approach.”

Thrombus Aspiration: Timing Isn’t Everything

What about STEMI patients presenting 12 to 48 hours after symptom onset?
“Many people thought if aspiration thrombectomy was going to be useful, this is the population who would benefit. PCI in this setting is challenging because the clot is fairly organized because if you have an organized clot and are using a balloon, all you are doing is just moving it up and down in the vessel. It’s disappointing, but for many of these patients the damage is already done, the horse is out of the barn, so it is often times harder to show a benefit with anything in this population,” said Steffen Desch, MD, professor at the University of Schleswig-Holstein, Campus Lübeck (Lübeck, Germany).

Second opinion: “Even if you extract thrombus, you are leaving a thrombogenic surface behind so microscopic thrombi will be formed. What it clearly shows is that after a few initial studies showing benefits of thrombectomy, we have so many studies now showing it has absolutely no benefit that we should no longer be using thrombectomy anymore with an exception for very, very few cases,” said Nico H.J. Pijls, MD, PhD, professor at Catharina Hospital (Eindhoven, The Netherlands)


Preventive Antianginal Therapy Fails Post-PCI
Incomplete revascularization is common in patients undergoing PCI and is associated with increased mortality and adverse cardiovascular events. Investigators randomly assigned patients to ranolazine (n = 1,332) or placebo (n = 1,319) to see if the anti-ischemic agent would improve the prognosis of these patients. After a median follow-up of 643 days, there was no significant difference in the composite primary endpoint or its constituent outcomes of incidence of ischemia-driven revascularization and ischemia-driven hospitalization in patients with a history of chronic angina and incomplete revascularization after PCI.10

“RIVER-PCI is the first study to prospectively study patients with incomplete revascularization after PCI, and what we have shown is the number of events is very, very high: 27% rate of the primary endpoint of time to first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization (without revascularization) and confirms what we have seen in retrospective studies,” Giora Weisz, MD, FACC, chairman of cardiology, Shaare Zedek Medical Center (Jerusalem, Israel) and associate professor of medicine, Columbia University Medical Center, New York City, NY.


Early CTO-PCI after MI: Maybe
In the setting of primary PCI (PPCI), about 10% of patients have a concurrent chronic total occlusion (CTO) in a non-infarct related artery (IRA) and this was recently identified as a high-risk subgroup. Would these patients with STEMI benefit from an additional intervention to open that CTO?

Currently, in the United States, managing such CTOs is highly variable and often dependent on the expertise of the center and limited to patients who are highly symptomatic or have a large area of myocardium at risk. While success rates are in the range of 70% to 80%, they are prolonged procedures associated with a high radiation dose, so operators do not take on such cases lightly.

“EXPLORE is the first randomized controlled trial of PCI of a non-IRA vessel within 1 week (average: 5 days) after primary PCI. Early CTO-PCI was not associated with higher left ventricular ejection fraction nor lower LV end-diastolic volume at 4 months. However, there was a clear signal of benefit in patients with a chronic total occlusion of the LAD because there was a highly statistically significant difference (p = 0.002) in ejection fraction in favor of CTO-PCI in this group. We believe PCI of chronic total occlusions after primary PCI may actually raise ejection fractions and may impact long-term clinical outcomes,” said Jose P.S. Henriques, MD, head of the catheterization laboratory, Academic Medical Center (Amsterdam, The Netherlands).

Yes, but Marco Valgimigli, MD, PhD, professor of cardiology, Thoraxcenter (Rotterdam, The Netherlands) argued, “It’s an important study, but I am not sure I buy in 100% to the conclusion of establishing the safety and feasibility of this approach. The four fatal MI events in the CTO-PCI group vs. zero on the other side is a matter of big concern to me.”


FFRCT: A Solid Foundation or Thin Ice?
Can fractional flow reserve (FFR) be estimated without coronary catheterization at a level of accuracy and reliability appropriate for individual patient level decision-making?

“In this nonrandomized study, we found that in symptomatic patients with intermittent probability of coronary artery disease, the evaluation strategy based on FFRCT had lower costs than invasive angiography and greater improvement in quality of life than usual noninvasive testing.11 The effect here is so big that I do not think this was by chance. If you do a CT angiogram and it’s normal, because it is so sensitive, people are happy with that result. But if you see something you are not sure if it’s significant, then the estimated FFR, if normal, is extremely reassuring that what you are seeing is not obstructing flow. This would be best tested using a randomized trial but I think it is going to show the same thing,” said Mark Hlatky, MD, FACC, professor of health research and policy and medicineat the Stanford University School of Medicine, Stanford, CA.

Second opinion, from Bernard De Bruyne, MD, PhD, associate director at the Cardiovascular Center Aalst (Aalst, Belgium): “I believe if these data can be confirmed by outcome data, this kind of an approach will probably largely replace the presently available noninvasive approach: stress testing. It is really a game changer, which we are already seeing used in practice in Europe; you get anatomy and physiology at the same time and same place; it is a very important paradigm change.”

From an Editorial Comment accompanying study publication in JACC12: “To routinely consider FFRCT, clinicians should be confident that sending patient data to a data processing center for a 1- to 2-day wait and additional significant cost has some value beyond what could be accomplished by conventional CCTA or combining CCTA with functional testing, such as exercise testing or stress imaging,” said Edward Hulten, MD, MPH, FACC, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, and Marcelo F. Di Carli, MD, FACC, Walter Reed National Military Medical Center, Bethesda, MD.

Subclinical Leaflet Thrombosis Post-TAVR: Way Too Early to Panic

One last-minute addition to TCT.15 was an entire press conference based not on data presented at the meeting but rather a paper published online the previous week in the New England Journal of Medicine.13 In brief, blood clots may complicate aortic valve replacements previously thought not to require the use of blood thinners. That’s actually the headline on the press release issued by the center where the research was conducted—leading to some early, let’s be polite and say ‘misleading,’ press coverage.

Investigators used four-dimensional, volume-rendered CT and detected reduced leaflet motion in 22 of 55 patients in a TAVR clinical trial and in 17 of 132 patients in a pair of registries that included both transcatheter and surgical AVR patients.

“About 13% of patients have reduced leaflet motion. Through a series of investigators we discovered that some of this is related to formation of blood clot, although there is no histologic or pathologic evidence of clot, but it is suggested by the fact that it did not occur in patients on blood thinners and it resolved in patients after taking blood-thinning medications. This is what suggested it is related to clot. Our findings related to neurologic events were preliminary and inconclusive. More investigations need to be done,” said Raj Makkar, MD, FACC, director, interventional cardiology and cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles, CA.

Dr. Makkar continued: “Clinical decisions need to be made on the basis of clinical outcomes and not images. What we would like is to learn from this study and then do further research. We should not make the leap from this study that all patients undergoing TAVR should be on blood-thinning medications, which have risks themselves. However, as we move away from the highest-risk patients and start considering TAVR on lower-risk patients, we need a good clinical trial to evaluate the effect of blood thinners on outcomes post-TAVR.”

“It is excellent and important work. We did CTs at our site back in 2011 and we looked back on those images and we cannot find leaflet thickening. However, our diagnostic confidence is much, much lower because there were simply far too many cases that were uninterpretable because we lacked the technological advances afforded those doing this new study at Cedars. CT is maybe giving us a way not to see mechanisms of stroke but rather early signals of valve degeneration that may lead to stroke down the road. While there is sensationalism that can come from these findings, if we take a step back it is a really exciting opportunity for the field to improve upon what are already excellent clinical outcomes. And it’s important that we include surgical valves in these studies because there is no reason to think this wouldn’t be occurring too with surgical valves. But it was previously occult and now Pandora’s box is open [with] a very interesting imaging finding,” said Jonathon Leipsic, MD, chair of radiology at Providence Health Care in Vancouver, Canada.

Jeffrey J. Popma, MD, FACC, director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston, MA, added: “This is not late stent thrombosis. That was a clinical presentation of a blood clot on a stent that was associated with myocardial infarction and death. This is an imaging observation of uncertain clinical significance that needs to be evaluated and studied further.”


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Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and VHD, Interventions and Structural Heart Disease

Keywords: CardioSource WorldNews Interventions, Aortic Valve, Aortic Valve Stenosis, Heart Valve Prosthesis Implantation, Stents

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