The Take Home: ACC

In March, the American College of Cardiology held its Annual Scientific Sessions in San Diego. Cardiology Today’s Intervention was onsite and interviewed experts on breaking news presented. Interviewees include Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, with Harvard Medical School and Brigham and Women’s Hospital; William Bommer, MD, with University of California, Davis; Editorial Board member Howard C. Herrmann, MD, with University of Pennsylvania; Sanjit S. Jolly, MD, MSc, with McMaster University, Hamilton, Ontario, Canada; David E. Kandzari, MD, with Piedmont Heart Institute, Atlanta; Thomas J. Povsic, MD, PhD, with Duke Clinical Research Institute; Stephen Ramee, MD, MS, with Ochsner Medical Center; Editorial Board member Kenneth Rosenfield, MD, MHCDS, with Massachusetts General Hospital; James Slater, MD, with NYU Langone Medical Center; and Editorial Board member Gregg W. Stone, MD, with Columbia University Medical Center/New York-Presbyterian Hospital and Cardiovascular Research Foundation.

AFTER EIGHTY

Bommer: As the population ages, we are seeing an increasing number of older patients coming in with ACS. In the After Eighty study, researchers randomly assigned 457 older patients (mean age, 84 years) to early invasive therapy including PCI or to conservative therapy. For most 80-year-olds, the question is: Will an invasive procedure make a difference in their lifetime and lifespan? In this study, individuals who received early invasive therapy had a 47% reduction in the composite outcome of death, MI, stroke and urgent revascularization compared with optimal medical therapy (invasive, 41%; conservative, 61%; rate ratio = 0.19; 95% CI, 0.05-0.52), which was significant and remarkable. The good news is that bleeding side effects were not significantly increased. In the United States, this likely means it will now be recommended to send individuals older than 80 years for early invasive therapy if they have significant risk factors.

TOTAL

Bhatt: Previously, the thought had been that there might be a reduction in ischemic events with manual aspiration thrombectomy. Meta-analyses of smaller trials done in years past on this topic showed a reduction in all-cause mortality with manual thrombus aspiration and individually a number of the trials showed reductions in stent thrombosis and improvement in a variety of surrogate endpoints. However, TASTE, a large, registry-based, randomized clinical trial, did not find any benefit in the primary endpoint for manual aspiration thrombectomy.

The TOTAL trial was meant to be the tie-breaker to definitely determine whether manual aspiration thrombectomy reduces ischemic events. As it turns out, the trial found no hint of benefit (primary outcome of CV death, recurrent MI, cardiogenic shock or NYHA class IV HF within 180 days: 6.9% vs. 7%; HR = 0.99; 95% CI, 0.85-1.15) and indeed found a significant increase in the rate of stroke (0.7% vs. 0.3%; HR = 2.06; 95% CI, 1.13-3.75) in the patients randomly assigned to manual thrombus aspiration.

Those are not data that would be supportive of routine thrombus aspiration during STEMI, and for that reason I am going to change my practice. This shows that sometimes meta-analyses of small studies can be misleading. Alternatively, maybe times have changed since those studies were done, and now with low-profile, second-generation drug-eluting stents and quicker door-to-balloon times, perhaps the potential benefit of aspiration isn’t as great as it used to be. Also, this trial does not rule out the possibility that patients with large thrombus burden may still benefit from manual aspiration thrombectomy. So I wouldn’t go so far as to say it should never be done, but certainly on the basis of this trial and TASTE, it should not be part of routine primary PCI.

Kandzari: After the results of the two predicate trials, TAPAS and TASTE, many clinicians still continued, as evidenced by large databases from the ACC, to perform thrombectomy. However, now there is a potential suggestion of a safety hazard. In this large trial of 10,732 patients with STEMI undergoing primary PCI, we have the opportunity for statistical significance for low-frequency events, which is a good thing. However, the stroke event rates early on are 0.7% and 0.3%. Yet in TASTE, the event rate was 0.5% in both arms. If we can, in further analyses, truly translate the procedure of thrombectomy to a higher stroke rate, then I think the question of performing thrombectomy at all needs to be revisited. On the other hand, there is an opportunity to investigate potential differences in stroke and nonstroke patients. In further analyses, I think we will learn that there are many other comorbidities in the individuals who experience stroke, and if that seems to account for the differences rather than thrombectomy per se, then that would be an important consideration.

The lesson is that we cannot advocate thrombectomy as a routine procedure in every patient with STEMI, nor is that being performed today in clinical practice. In selected instances, in terms of bailout and when there is persistence of thrombus or no reflow in the coronary artery, there still may be clinical utility for thrombectomy.

PARTNER 1

Rosenfield: The 5-year results of the PARTNER 1 trial confirm the fact that transcatheter aortic valve replacement is a game-changing therapy.

PARTNER 1 enrolled 699 patients with severe aortic stenosis at high risk for surgery (348 to TAVR [Sapien, Edwards Lifesciences] and 351 to surgical AVR). At 5 years, risk for death was 67.8% in the TAVR group and 62.4% in the surgical AVR group (HR = 1.04; 95% CI, 0.86-1.24). It is remarkable how identical the curves look over time. It is also striking that the outcome in this very high-risk group who went on to surgery or TAVR was essentially the same. At 5 years, risk for stroke was also similar. The presence of paravalvular leak was associated with slightly poorer outcome; conversely, the subset who did not have paravalvular leak demonstrated slightly better outcomes than the surgically implanted valves. The good news is that these were first-generation devices studied. The newer generations — there are approximately 30 valve companies working on iterations — are lower profile with a better seal around the outskirts of the valve so there is less chance of paravalvular leak.

There were slight differences, but the important thing about this trial is that it shows percutaneously implanted valves are durable and the outcome at 5 years is no different than at 1 year. For high-risk patients, TAVR is an excellent alternative to surgery and clearly may be preferred.

PARTNER II S3

Herrmann: Overall, the Sapien 3 valve (Edwards Lifesciences) showed an impressive outcome in terms of 30-day all-cause mortality (high-risk cohort, 2.2%; intermediate-risk cohort, 1.1%), CV mortality (high-risk, 1.4%; intermediate-risk, 0.9%), stroke (high-risk, 1.5%; intermediate-risk, 2.6%) and vascular complication rates.

The results show that there has been considerable evolution in the devices for TAVR as well as in operator experience. I don’t think we should attribute the great outcomes only to the valve, but also to what we have learned about how to do TAVR better. I can’t wait to see the longer-term results, as 1 year was the primary endpoint. I also can’t wait to see the comparison of the intermediate-risk group with the surgical arm and the Sapien XT arm of PARTNER IIA, which is the approval cohort study for Sapien 3 in intermediate-risk patients.

U.S. COREVALVE HIGH RISK STUDY

Ramee: The biggest takeaway from the 2-year U.S. CoreValve High Risk Study (Medtronic) was the impressive survival data (22.2% vs. 28.6%; P = .04) and complication data (stroke, 10.9% vs. 16.6%; P = .05) in favor of TAVR vs. surgical AVR in a high-risk patient cohort. [As of press time], these data are not yet published or peer-reviewed, so we will have to wait to see any impact on the guidelines. But if the data are as the investigators have presented it, I think both intermediate-risk and high-risk are going to be TAVR indications. It is hard to compare the self-expandable and balloon-expandable valves against each other; we are going to need a randomized trial between the two.

MITRACLIP

Slater: This is our first look at real-world U.S. experience with the MitraClip transcatheter mitral valve repair system (Abbott Vascular; n = 564). This real-world experience has shown the procedure to be very effective: procedural success, 91.8%; complication rate, 7.8%; in-hospital mortality, 2.3%, 30-day mortality, 5.8%; cardiac surgery, 0.5%; stroke, 1.8%, MI, 0%; major bleeding, 3.9%; cardiac perforation, 0.7%; and device-related events, 2.7%. This was a high-risk population; the median STS-PROM score for repair was almost 8%. Most patients who received MitraClip had degenerative mitral regurgitation (MR), whereas in Europe MitraClip is targeted toward a population that has more functional MR. The FDA has not yet bought into the concept of treating functional MR with the MitraClip, so most operators were confining themselves to the population that the FDA intended them to be treating.

This is a refreshing look at the introduction of a major technology that I think has a niche application that is valuable and is being applied across the country. I don’t know whether these findings will prompt more doctors to try the procedure because it is difficult to learn. You have to be at a center where you see these patients with some frequency. Our center is doing four to five implants per month. That is enough to keep your skill set up and technically improve.

EMBRACE-STEMI

Rosenfield: The purpose of the phase 2 EMBRACE-STEMI trial was to see whether Bendavia, a cell-permeable and mitochondrial inner membrane-targeting peptide that theoretically acts by reducing reperfusion injury affecting myocardial function and other cellular functions, would reduce infarct size. It would make a huge impact to find an agent that does reduce infarct size by reducing reperfusion injury, the thought being that you would preserve myocardial function and decrease the long-term effects of acute MI. Obviously, this is a holy grail.

The composite endpoint of the trial (area under the curve for leakage of the creatinine kinase-MB enzyme within 72 hours of successful PCI) was not achieved, but there were signals that this agent may be effective in achieving this goal. Namely, ST-segment elevation was resolved more quickly in the Bendavia group than in the control group. The only difference in the patient demographics was hypertension (Bendavia, 37.9%; control, 60%). When the researchers did a subgroup analysis looking at hypertensive patients in both group and matched them, there was more of an effect in the Bendavia group. So for hypertensive patients, maybe the drug mitigates the effects of the hypertension.

I don’t know whether this drug will be effective in reducing infarct size, but it certainly is intriguing and should be pursued.

MATRIX

Stone: In the last year, there has been a lot of confusion regarding choice of the optimal anticoagulant during PCI in patients with ACS. MATRIX has put most of these issues to rest. Similar to what we saw in the HORIZONS-AMI trial of 3,600 randomized patients, in more than 7,200 randomized patients MATRIX also found a substantial reduction in all-cause mortality in patients treated with bivalirudin (Angiomax, The Medicines Company) rather than a heparin-based regimen (2.3% vs. 1.7%).

MATRIX should lead to increased use of bivalirudin once the results of this study are disseminated in the press and publication. All-cause mortality trumps all other endpoints. That, coupled with the large reduction in major bleeding, with similar preservation of ischemic MACE, makes bivalirudin the optimal choice for patients with STEMI and non-STEMI undergoing PCI. This held for both patients undergoing femoral and radial artery access.

Jolly: MATRIX is a very important trial. [Regarding the access analysis], it built upon the findings of RIVAL in that it took high-volume operators and exquisitely showed that radial access not only reduced bleeding (radial, 1.6%; femoral, 2.3%), but also reduced mortality (radial, 1.6%; femoral, 2.2%). This will be the study to perhaps change guidelines to make radial access the default approach. Our next step is physician training and translating this demonstrated benefit into clinical practice.

REGULATE-PCI

Povsic: REGULATE-PCI wanted to test two hypotheses. No. 1, is factor IX inhibition a useful target for anticoagulation during PCI? No. 2, is using an anticoagulation system that is completely reversible and controllable advantageous in this setting? Unfortunately, trial enrollment was stopped due to the rate of serious allergic reactions in patients treated with combination pegnivacogin and the reversal agent anivamersen (REG1), which was not counterbalanced by an efficacy signal, leaving the enrollment numbers insufficient to provide definitive answers.

However, we learned three things: Inhibiting factor IX appears to be an effective target for anticoagulation and suppression of ischemic events; reversible anticoagulation worked, but without complete reversal at the end of the procedure, and was associated with higher bleeding rates, but a trend toward lower rates of stent thrombosis; and REG1 as currently formulated is associated with severe allergic reactions at a low but unacceptable rate for this particular clinical setting. The exact mechanism is unknown and is being actively investigated.

I think reversible anticoagulation remains an attractive concept to proceduralists. This study ended up being too small to definitively answer whether this will translate into clinical benefit, so I would be cautious about overinterpretation and saying this would not work.