The Take Home: ACC

Issue: May/June 2016

In March, attendees from all over the world gathered in Chicago for the annual American College of Cardiology Scientific Session. In total, nearly 19,000 attendees took part in the 3-day meeting, which featured 2,400 posters and oral presentations and 24 late-breaking clinical trials.

Cardiology Today’s Intervention was onsite and spoke with several experts on some of the most anticipated and talked-about trials presented. Among them were David H. Adams, MD, of Mount Sinai Health System; Khaldoon Alaswad, MD, of Henry Ford Hospital, Detroit; Chandan Devireddy, MD, of Emory University; ACC Scientific Session Interventional Track Coordinator David E. Kandzari, MD, of Piedmont Heart Institute, Atlanta; Ajay J. Kirtane, MD, SM, FACC, of NewYork-Presbyterian Hospital/Columbia University Medical Center and Cardiology Today’s Intervention Editorial Board member; ACC Scientific Session program chair Athena Poppas, MD, FACC, of Rhode Island Hospital and Brown University; Michael J. Reardon, MD, of Houston Methodist DeBakey Heart and Vascular Center; Michael Rinaldi, MD, of Sanger Heart and Vascular Institute at Carolinas Medical Center, Charlotte, North Carolina; and Gregg W. Stone, MD, of NewYork-Presbyterian Hospital/Columbia Medical Center and Cardiology Today’s Intervention Editorial Board member.

PARTNER 2A and SAPIEN 3

Kirtane: The top-line results of the PARTNER 2A trial are pretty breathtaking. It really strikes home when you see the results: TAVR was noninferior (primary outcome of all-cause mortality or disabling stroke at 2 years: intention-to-treat population, 19.3% vs. 21.1% [HR = 0.89; 95% CI, 0.73-1.09; P for noninferiority = .001]; as-treated population, 19.8% vs. 21% [HR = 0.87; 95% CI, 0.71-1.07; P for noninferiority < .001]), and in some ways somewhat superior to surgery, particularly when assessed from a transfemoral approach. In the transfemoral-access cohort, TAVR was associated with reduced risk for the primary outcome compared with surgery (HR = 0.79; 95% CI, 0.62-1).

That’s big news for both patients and physicians because we are seeing increasingly lower-risk populations being able to be treated with TAVR. Now, this is not truly low risk, because these patients were still 80 years old and had Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) scores in the 5% range. But this is another randomized trial showing no worse outcomes with TAVR, which is less invasive and linked with fewer bleeding complications and less atrial fibrillation. TAVR is not only here to stay, but is going to be expanding rapidly.

In practice, we’re going to see the use of TAVR as an option to be considered for patients at lower risk than currently. In addition, there are going to be ongoing trials in low-risk patient populations and those with asymptomatic aortic stenosis. Over time, TAVR may become the dominant therapy by which patients with aortic stenosis are treated.

Rinaldi: PARTNER 2A was a well-conducted study at excellent centers, and was well thought-out. It found that TAVR seems to be as good as conventional survey for all outcomes in an intermediate-risk population. The complication rates were excellent in the TAVR arm. Stroke and death were equal in the two arms, and in the subset of patients with transfemoral access patients statistically did better with TAVR than surgery. There can be no criticisms of the surgical techniques. The STS PROM score was 5%, but the observed mortality was only 3%, even in the surgical arm. The study had excellent surgery and excellent TAVR, and TAVR looks like a reasonable alternative to conventional surgery. That doesn’t mean that surgery is bad, just that TAVR is complementary. Hopefully, this will open up options for patients who are not perfect surgical candidates, but not terrible ones either.

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The major implication is that TAVR has really caught on. At this point, the technique has advanced even from when this trial was conducted. The Sapien XT device (Edwards Lifesciences) used in this trial is a good device and better than the original Sapien device. But the new Sapien 3 device is even better, with a skirt that reduces paravalvular leak and a smaller profile to reduce vascular complications. In most centers, even the surgeons believe that TAVR is the best therapy for these patients. There had already been a lot of creep toward using TAVR in the intermediate-risk population. A lot of patients who are currently being called high risk by surgeons probably would have qualified for this trial.

There were concerns that TAVR is associated with a higher paravalvular leak rate. There were slightly higher, but not terrible, paravalvular leak rates with the Sapien XT device. Interestingly, only patients with moderate/severe paravalvular leak had worse outcomes. Mild paravalvular leak was not associated with poorer outcomes. With the Sapien 3 device, we are seeing almost no moderate/severe aortic insufficiency, just mild, which this study suggests is not important. There are also concerns about pacemaker rates being higher with TAVR. In this study, the pacemaker rates were slightly higher in the TAVR group, but not by a lot, approximately 2%. I find that reassuring, and it is important as we move the device to younger patients, in whom the implications of pacemakers are not insignificant. This is important as there remains concern that pacemaker rates are higher with TAVR, and these findings put that concern into question.

It is also important to note that in PARTNER 2A, the length of stay was shorter with TAVR and complications such as major life-threatening bleeding, kidney injury and new-onset AF were lower with TAVR than surgical AVR. TAVR appears, in moderate-risk patients, to have a quicker recovery and lower risk for certain important complications.

I believe this will lead to FDA approval and Medicare reimbursement for this indication. The TAVR market share is approximately 30%, and I think after this study it will move toward 50%. The PARTNER 3 trial of TAVR in low-risk patients is about to commence, as is a similar study with the CoreValve device (Medtronic), so the field is moving in the direction of TAVR. This is a win for TAVR and patients. It does not mean that surgical valve replacement is going to go away, but it opens more options for a larger number of patients.

Adams: This represents another landmark trial for the TAVR field. We now have evidence that we can move safely into an intermediate-risk patient group. This means we will see continued expansion of TAVR into a larger population of patients who require intervention for severe aortic stenosis. TAVR has become the standard of care for high-risk and extreme-risk patients, and we will now see a majority of intermediate-risk patients undergo TAVR instead of open surgical treatment. Less-invasive approaches are always preferred by patients when they can be done with similar efficacy and safety, and we now have the data to move the TAVR needle again. Particularly encouraging was the subanalysis indicating that patients suitable for transfemoral access actually had a lower rate of death or major stroke compared with an open surgical approach. The results of PARTNER 2A are a testament to how far we have traveled in the TAVR field, and certainly set the table for TAVR trials in low-risk patients.

Reardon: The 1-year data for the nonrandomized Sapien 3 valve registry showed excellent results. The 1-year all-cause mortality rate was 7.4% for TAVR vs. 13% for surgical AVR, with a low moderate or greater paravalvular leak rate of 1.5%. The researchers also did a propensity-matched analysis against the noncontemporaneous PARTNER 2A surgical arm. In this analysis, the primary endpoint of all-cause mortality, stroke or readmission was superior for TAVR. These results suggest TAVR performs well in the intermediate-risk category.

CARIN

Poppas: Preventing kidney injury from contrast dyes administered during PCI is a challenge that we have looked at in a number of different ways. Kidney disease has some interaction with MI and morbidity and length stay. We have hydration as a therapy, and we know prehydration is effective, but in this cohort only half the patients received adequate prehydration because of some of the constraints of moving patients through the system faster. The CARIN study assessed the safety and efficacy of CMX-2043 (Ischemix LLC), a novel derivative of alpha lipoic acid, in 361 patients who were scheduled for an angiogram and who had impaired kidney function and at least one other risk factor. Compared with placebo, three different doses of CMS-2043 showed no significant difference in the incidence of acute kidney injury or other secondary endpoints. To see the failure of an alternative therapy is frustrating. Inflammation in kidney injury is complex, and we keep trying to address it in different ways.

EARLY-BAMI

Devireddy: Early-BAMI was a novel study that looked at administration of IV beta-blockers (metoprolol) immediately after patients with STEMI were picked up by EMS and then a second bolus in the cath lab, 5 mg each. In this trial, there were no significant differences in infarct size as assessed by MRI at 30 days (metoprolol group, 15.3%; placebo group, 14.9%; P = .616), enzymatic infarct size (P = .88), left ventricular ejection fraction (P = .68) and adverse events. There was a slight signal in terms of a decrease in the rate of malignant arrhythmias with metoprolol (3.6% vs. 6.9%; P = .05). But the question remains: Is there any danger to early use of beta-blockers in this population? There were no safety signals that seem to indicate a problem. I think this trial could be tweaked to look at in the future whether intracoronary beta-blockers have an impact in this population.

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DANAMI 3-DEFER

Kandzari: Prior smaller studies have suggested improved angiographic outcomes and, in some instances, improved clinical outcome with a strategy of deferred stenting. The DANAMI 3-DEFER trial included 1,207 patients with STEMI and had a median follow-up of more than 3 years. The results presented showed no difference in the composite endpoint of all-cause mortality, hospitalization for HF, reinfarction and repeat target lesion revascularization between patients randomly assigned to standard primary PCI with stent implantation or delayed stenting for 48 hours (delayed group, 17%; standard group, 18%; HR = 0.99; 95% CI, 0.75-1.29; P = .92). Importantly, and I think this was understated in the presentation, there was a significantly greater likelihood of unplanned target vessel revascularization in the deferred group, and this was a difference that occurred early. Further, there were no subgroups identified that would benefit from the deferred strategy. There was, however, a modest but statistically significant difference in LVEF at 18 months (delayed group, 60%; standard group, 57%; P = .04). But overall, LVEF was preserved in both cohorts so, likely, this modest but statistically significant difference will not have a long-term impact. In many ways, DANAMI 3-DEFER was a study that will not change clinical practice.

Alaswad: There are a couple of important messages from this trial. First, for the current generation of cardiologists who have always stented immediately, it is important to see that there is not much penalty for delaying it when required. Second, while we always thought that we tended to oversize the stent, these findings show that the average diameter of the stents in both groups was 3.5 mm. Overall, the findings don’t give us a final answer. We still have work to do.

DANAMI 3-iPOST

Kandzari: A great deal of preclinical science has suggested that ischemic postconditioning can reduce infarct size, and this led to great interest in expanding that into human clinical trials and in real-world applications in STEMI. DANAMI 3-iPOST was a large study (n = 1,234) with long follow-up (median, 39 months) in patients with STEMI who were randomly assigned to receive standard angioplasty or ischemic postconditioning prior to stent implantation in the blocked artery. Approximately 40% of these patients had anterior MI. The primary composite endpoint, death from any cause and hospitalization for HF, was 10.5% in the postconditioning group vs. 11.2% in the standard PCI group (HR = 0.93; 95% CI, 0.66-1.3; P = .66). Mean LVEF was 52.7% in the postconditioning group vs. 50.8% in the standard PCI group (P < .05). Reminiscent of the DANAMI 3-DEFER study, there were modest but significant differences in LVEF, but overall the LVEF was fairly preserved in both groups.

Although both DANAMI studies may have scientific merit for further study, I think it may be unlikely given the practical challenges of funding and likely a waning investigator interest when such large randomized trials did not show any benefit. Both of these studies highlight many of the challenges that we currently have with performing and conducting STEMI trials and the challenges of demonstrating potential improvement upon current care.

ABSORB III

Stone: The Absorb bioresorbable vascular scaffold (BVS, Abbott Vascular) has been introduced as a competitive alternative technology to metallic drug-eluting stents, which has the potential to improve long-term outcomes. We previously presented results of the ABSORB III randomized trial, the pivotal U.S. approval study in 2,008 patients which showed that BVS was noninferior to Xience (Abbott Vascular) for the primary 1-year endpoint of target lesion failure. However, there were concerns about an increased rate of scaffold thrombosis with BVS vs. Xience. We performed a much more detailed analysis to try to determine which subgroup, if any, those events might cluster in. We found that the events did cluster in patients who had BVS implanted in very small vessels (< 2.5 mm), which weren’t really intended for the device. We analyzed outcomes by whether a lesion was treated with a reference vessel diameter < 2.25 mm by quantitative coronary angiography (QCA). Surprisingly, 19% of patients had those lesions treated with BVS, and these patients had an increased rate of TLF and device thrombosis compared with Xience. In contrast, in patients with good-sized vessels (81% with reference vessel diameter 2.5 mm) who were appropriately treated had similar rates of TLF, device thrombosis and other adverse events.

While the numbers were relatively small and the trends did not reach statistical significance, given the biologic and mechanistic plausibility of what happens when you implant a thick strut scaffold in a very small vessel, it seems that should be avoided. Recently, an FDA advisory panel voted 9-0 that the Absorb BVS is safe and effective for use as indicated, so it’s going to be important that we train people not to implant the Absorb BVS in very small coronary arteries.

Disclosures: Adams reports serving as national co-principal investigator of the CoreValve trial funded by Medtronic and that his institution receives royalties from Edwards Lifesciences and Medtronic. Devireddy reports consulting for Medtronic and his institution receives clinical trial support from Edwards Lifesciences and Medtronic. Kirtane reports that his institution receives research funding from Boston Scientific, Edwards Lifesciences, Medtronic and St. Jude Medical. Reardon reports that his institution receives compensation from Medtronic for his service on an advisory board. Rinaldi reports consulting for Boston Scientific and past unpaid consulting for Edwards Lifesciences. Alaswad, Kandzari, Poppas and Stone report no relevant financial disclosures.