By Rick McGuire

The 2014 ACC Scientific Sessions were held in Washington, DC, and—as always—featured interventional cardiology sessions in the i2 Summit sections with close involvement of TCT. The annual meeting location allowed ACC.14 to host a series of special discussion sessions offering diverse panelist perspectives on the when, how, and why of FDA decision making and its status as a medical gatekeeper.

More than 13,000 cardiovascular team members came together to focus on the prevention, diagnosis, and treatment of cardiovascular disease. Here are some of the highlights of this year's Scientific Sessions.

SYMPLICITY Complicates Things
You don't see this often: about a month before the SYMPLICITY data were presented as a late-breaking clinical trial at ACC.14, speakers at the Cardiovascular Research Technologies (CRT) meeting were trying to explain what went wrong and figure out what to do with renal denervation for patients with treatment-resistant hypertension. The failure of SYMPLICITY HTN-3 to meet its primary endpoint was tipped in a news release from the study sponsor (Medtronic) on January 9, 2014. This led to an abrupt change in title for a positive editorial published less than 2 weeks later in EuroIntervention, which suddenly sprouted a question mark: The quickening path ahead for renal denervation therapies?¹

In perhaps the most widely anticipated presentation at ACC.14, renal denervation fell short of both primary and secondary efficacy endpoints in patients with severe resistant hypertension. This pivotal US trial demonstrated that the sham-controlled group experienced a nearly identical reduction in blood pressure as those who underwent the actual procedure.

The trial was presented by Deepak Bhatt, MD, executive director of Interventional Cardiovascular Programs at Brigham and Women's Hospital and professor at Harvard Medical School, and published simultaneously online by JACC.² The trial revealed important information: "We feel the results underscore the importance of blinding and sham controls in the evaluation of new devices. What we saw in this trial, and not evident in my presentation, is that a lot of the [resistant hypertension] patients who came into the screening process fell out because of excellent medical therapy. That is, with really attentive, good medical therapy, a portion of these patients can come under control—that is an important lesson from this trial."

At the CRT meeting, Robert S. Schwartz, MD, medical director at the Minnesota Cardiovascular Research Institute, reviewed the physiologic rationale for nonresponders in SYMPLICITY HTN-3. He told CSWN: Interventions, "New operators, for example, were brought into the HTN-3 trial that hadn't been used previously. There may be some questions with the device itself, because it has some new components to it. We have to be concerned about whether or not the energy actually got out to the nerves in the same way."

Just because SYMPLICITY may have under-performed doesn't mean renal denervation deserves no respect. Horst Sievert, MD, PhD, director of the CV Center Frankfurt, Germany, is principal investigator of the REDUCE-HTN trial presented at TCT.13. This post-marketing study suggests about 85% of patients treated with the Vessix™ Renal Denervation system (Boston Scientific; Natick, MA) experienced a clinically-meaningful decrease in blood pressure. In an interview at CRT, Dr. Sievert said, "It's a bipolar radiofrequency system that is balloon-based. This [design] has some advantages, at least in theory: bipolar energy allows very localized application of energy so there's less treatment variation than with the SYMPLICITY catheter. The results so far are looking really good with this device."

At ACC.14, Anthony DeMaria, MD, outgoing editor-in-chief of JACC and discussant for SYMPLICITY HTN-3, said he thinks it's time to hit the brakes on renal denervation and go back to the basics. He told the press, "It's clear we have only a minimal understanding of what is going on in terms of where the renal sympathetic nerves actually are and whether we really are accomplishing denervation. There is plenty of tantalizing evidence that [renal denervation] can be effective, but we need to go all the way back to anatomy and physiology, and even to pathophysiology, to ensure we are effectively denervating so we can measure the effects of the procedure."

Has the popularity of renal denervation taken a hit from the failure of SYMPLICITY HTN-3? Dr. Sievert said, "The impression I have in my practice is that referring physicians and patients are still looking for it and asking for it. There may be some issues for reimbursement—not yet but this may show up as soon as the insurance companies look at these study results. But overall the enthusiasm has not changed."

Feeling the HEAT
Selective "bailout" use of glycoprotein IIb/IIIa inhibitors (GPI) is increasingly the norm in routine practice for patients undergoing primary PCI (PPCI). It is recommended by international guidelines (including ACC/AHA and ESC guidelines), and bivalirudin + GPI ends up being used in 7–15% of patients. Bleeding is associated with less favorable outcomes and GPI use does result in increased bleeding, which has been observed for both bivalirudin and heparin.

HEAT-PPCI (How Effective are Antithrombotic Therapies in PPCI) used a "real-world" population of patients to evaluate bivalirudin + "bailout" GPI (n = 905) versus heparin + "bailout" GPI (n = 907). For the primary outcome of major acute coronary events at 28 days (a combined endpoint including death, stroke, reinfarction, and target lesion revascularization [TLR]), bivalirudin was associated with significantly more events (TABLE 1; 8.7% vs. 5.7%; RR = 1.52; p = 0.01). The difference was driven mostly by reinfarction and TLR, which favored heparin (2.7% vs. 0.9% and 2.7% vs 0.7%, respectively). Stent thrombosis was also higher with bivalirudin (3.4% vs. 0.9%; RR = 3.91; p = 0.001). There was no difference in the primary safety outcome of major bleeding: 3.5% with bivalirudin versus 3.1% with heparin (p = 0.59). There was also no difference in minor bleeding (p = 0.25) or the combination of major or minor bleeding (p = 0.54).

TABLE 1. HEAT-PPCI Primary Efficacy Outcome


While this was a single-center, open-label study, there was 100% recruitment of eligible patients and complete follow-up with no "lost" cases. Also, outcome measures were overt clinical events with independent blinded adjudication.

So, the use of heparin rather than bivalirudin reduced the rate of major adverse events with no increase in bleeding complications. The authors concluded that their results suggest substantial savings in drug costs with heparin plus selective (bailout) GPI.

Trolling Through More TAVR Trials
Investigators presented the first-ever randomized head-to-head comparison of two devices commonly used to treat aortic stenosis, and it turns out that balloon-expandable transcatheter valves produced more successful procedures and more frequent relief of symptoms than self-expanding valves.

The CHOICE trial tracked 241 TAVR procedures in five major hospitals in Germany. Half of the patients received a balloon-expandable valve (Edwards Sapien XT; Edwards Lifesciences Corporation; Irvine, CA) with the other half getting a self-expanding (Medtronic CoreValve®; Medtronic, Inc.; Minneapolis, MN) device. The balloon-expandable valve resulted in more successful procedures (the study's primary endpoint) and improved patient symptoms (a secondary endpoint). There was no significant difference between the groups for cardiovascular mortality at 30 days, bleeding and vascular complications, or stroke. Successful procedures were those in which the valve was implanted in the correct position and provided a tight enough seal to prevent blood from leaking across the valve.

FIGURE. CHOICE Primary Endpoint – Device Success


Procedures using a balloon-expandable valve had a success rate of 95.9% as compared to 77.5% for the self-expanding valve (FIGURE; RR = 1.24; p < 0.001). Investigators said the difference is due to two things: more valve regurgitation greater than mild in the self-expandable arm and less frequent need for more than one valve with the balloon-expandable device.

Commenting on the trial, Peter Libby, MD, chief, Division of Cardiovascular Medicine at Brigham and Women's Hospital, said, "This is an evolving technology and we are in the infancy of these approaches. I am very confident that as we gain more experience and continue this partnership between the device industry and physicians, we will have continued improvements so the problems of a first-generation valve with increased aortic regurgitation will be a distant memory in 5 to 10 years—and to the great benefit of our patients."

He noted to the media attending ACC.14 that one "remarkable thing" in the CHOICE trial flow chart was a little box labeled 'heart team.' One thing to emerge from the advent of transcatheter valve therapy, said Dr. Libby, is the idea of the valve team where people who might be considered competitors come together to determine what is best for the patient. "We're going to need more of this in the United States," he said, "as we move towards accountable care organizations where the goal is improved outcomes." Also, embedded in the CHOICE trial was an emphasis on the imager, who Dr. Libby called "the unsung heroes of the heart team who are absolutely essential for picking the patients and designing your protocols."

In another late-breaking clinical trial, investigators reported that TAVR with the self-expanding CoreValve was associated with significantly lower death rates at 1 year compared with conventional surgical valve replacement in high-risk patients with severe aortic stenosis.

The CoreValve US Pivotal High Risk Trial, published online simultaneously in the New England Journal of Medicine,³ enrolled patients with an assessed increased risk of death from aortic valve surgery. Of 795 patients randomly assigned to valve replacement by catheter or surgery, 747 patients underwent one of the procedures: 390 in the TAVR arm and 357 in the surgical aortic valve replacement (SAVR) arm. The average age was about 83 years in both groups. The results exceeded the initial noninferiority goal (p < 0.001 for noninferiority) and, by pre-design, then moved on to a superiority analysis.

Death rates at 30 days were not significantly different, with a 3.3% death rate for TAVR and 4.5% percent for SAVR. A significant difference emerged at the 1-year primary endpoint of all-cause mortality: 14.2% for TAVR compared to 19.1% for SAVR (p = 0.04 for superiority), a 26% survival benefit for TAVR.

Among their limitations, the study authors acknowledged that patients had a lower 30-day mortality rate than specified in their inclusion criteria, therefore the trial population may have been at lower risk than intended.

"This is the first prospective study of any device that suggests TAVR is superior to [surgery] in a predefined population of patients, and that's a provocative finding," said David H. Adams, MD, professor and chairman of the Department of Cardiothoracic Surgery at Mount Sinai Medical Center and co-principal investigator of the study. He emphasized the "outstanding outcomes" in the surgical arm: "The low mortality rates with conventional surgery far exceeded the predicted mortality according to the Society of Thoracic Surgeons predictive model. In order to pass a superiority threshold, transcatheter treatment with the CoreValve device had to exceed excellent surgical outcomes."

In addressing the press, Dr. Adams said the 2-year follow-up data have not been locked down yet but the data continue to be encouraging. He added, "Our 1-year major cardiovascular and cereobrovascular event rate in exploratory analysis was significantly lower in patients undergoing transcatheter therapy."

Valentin Fuster, MD, professor of cardiology at Mount Sinai Hospital, New York City, and incoming editor-in-chief of JACC, commented on the trial. "This is an extraordinary result with significant impact on patients." In the original PARTNER A trial, he noted, the mortality rates were similar for TAVR and SAVR but neurological events were higher in the TAVR arm. Thus, he said, the results from Dr. Adams and colleagues are "quite surprising," adding, "Here comes the issue: why? It may be technical issues with better follow-up and more sophisticated imaging. The type of catheters may be easier to introduce. Maybe the patients are a little lower risk than the PARTNER trial.

"Certainly this is a great result," he concluded, "but I would like to insert a word of caution." Dr. Fuster underscored the high-risk elderly population and emphasized that "we should not now move [TAVR] to a younger population with lower risk," rationalizing that it is so much easier to percutaneously deliver a valve than opening the chest. His concern relates to consistent data suggesting a greater risk of developing lacunar lesions in the brain following TAVR versus SAVR. "While the cognitive effects in an elderly population seem to be minimal," Dr. Fuster stressed, "we do not know what the cognitive effects might be in a younger population."

PCI-CAMPOS: Safer PCI—But Less Successful
In 2011, the ACC/AHA/SCAI PCI guidelines gave a class IIa recommendation for primary PCI at hospitals without on-site cardiac surgery and a class IIb recommendation for elective PCI.⁴ In an effort to evaluate the introduction of PCI care at hospitals without on-site cardiac surgery, the state of California instituted a pilot program comparing the results of 153,950 PCI procedures in six pilot (off-site) and 122 comparator (on-site) facilities.

California hospitals without surgical backup had a higher percentage of ST-elevation MI (32% vs. 17.9%) and emergent PCI (34.6% vs. 19.9%) than hospitals with on-site surgical backup. The patient risk-adjusted composite safety endpoint of in-hospital death, stroke, and emergency CABG was significantly lower in California hospitals (1.87%) without surgical backup, compared with those hospitals with surgical back-up on site (2.36%). On the other hand, the composite efficacy of <20% TIMI 3 was slightly lower in off-site hospitals compared with on-site hospitals (88.4% vs. 91%).

So, pilot off-site hospitals showed slightly better PCI composite safety but worse PCI composite efficacy endpoints than on-site hospitals. In presenting the data, William Bommer, MD, director of noninvasive services at the University of California, Davis, said one partial driver of the PCI-CAMPOS efforts was that heavily populated states, such as California, could potentially benefit from broader use of off-site PCI. The finding that the pilot facilities without on-site cardiac surgery performed proportionately more primary PCIs than on-site hospitals would underscore the fact that an important population of patients is being served by these centers.

It should be noted that shortly before ACC.14, the ACC, AHA, and SCAI released a consensus document outlining steps hospitals can take to provide the safest possible environment for PCI when the facility does not provide cardiac surgery as a backup should complications occur.⁵ The authors pointed out that while PCI use has increased significantly since the procedure was introduced more than 30 years ago, advances in drug-eluting stents, greater use of medication to treat some types of blockages, increased emphasis on heart disease prevention, and new technologies to help physicians better evaluate blockages have all contributed to a drop in PCI use since 2006. This has led to an increase in the number of facilities that are considered "low volume" (i.e., performing fewer than 200 PCIs per year) according to the consensus document. Overall, one-third of facilities performing PCI had no on-site cardiac surgery, and among those hospitals, about two-thirds were considered low volume.

While the evidence from randomized studies suggests that procedures can be performed safely without on-site surgery, Gregory J. Dehmer, MD, lead author of the consensus document, said, "At the same time, the number of low-volume centers is increasing, making it essential that those facilities without backup cardiac surgery have strict protocols in place to ensure the highest level of patient safety."

Not Poised for Greatness
Globally, 200 million adults undergo major noncardiac surgery every year and 10 million will suffer a major vascular complication in the first 30 days post-op, the most common being myocardial infarction. Surgery is associated with platelet activation and many point to coronary artery thrombosis as a mechanism of perioperative MI. Also, surgery leads to a marked activation of the sympathetic nervous system, which can cause a mismatch between the supply of and demand for myocardial oxygen and subsequent myocardial infarction.

Clonidine decreases central sympathetic outflow, while aspirin is an analgesic and anti-inflammatory agent. POISE-2 (the PeriOperative ISchemic Evaluation-2) trial had a 2 x 2 factorial design to look at both of these agents in patients undergoing noncardiac surgery. The earlier POISE-1 study found that beta-blockers greatly reduced risk of MI during and after noncardiac surgery, but increased risk of devastating strokes and mortality. In POISE-2, researchers used low-dose clonidine, which smaller studies had suggested would provide the heart-protecting benefits of beta-blockers without increasing stroke risk.

The results caught investigators off guard. Clonidine failed to improve the primary outcome of mortality and nonfatal MI at 30 days after randomization, with 365 events for clonidine versus 339 for placebo.⁶ The clonidine group had a nonsignificant increase in the number of MIs (325 clonidine vs. 293 placebo), but two secondary measures were significant: clinically important hypotension was seen in 2,385 clonidine patients (48%) versus 1,854 placebo patients (37%), and 16 clonidine patients had nonfatal cardiac arrest versus five in the placebo group. Patients will be followed for 1 year.

What about aspirin? The primary endpoint of death and nonfatal MI at 30 days was not significantly different between the two groups (7% in the aspirin group vs. 7.1% in the placebo group); however, major bleeding was significantly higher in aspirin-treated patients than in the placebo group (4.6% vs. 3.7%).⁷ They did find that the optimal time to restart aspirin was 8–10 days after surgery.

Thus, POISE-2 suggests:

• Clonidine increased nonfatal cardiac arrest and promoted clinically important hypotension.
• Aspirin increased the risk of major bleeding.

Trial discussant for the aspirin analysis, John Jarcho, MD, deputy editor of the New England Journal of Medicine said, "This is an issue that has concerned cardiologists and surgeons for a long time: what can we do medically to reduce (perioperative) risk of myocardial infarction in patients who undergo noncardiac surgery? Here is an intervention—aspirin—that is effective in all kinds of settings having to do with coronary artery disease and yet in this particular trial, it was not beneficial and patients had more bleeding." (Both the clonidine and aspirin results from POISE-2 were simultaneously published online in NEJM.)

As for the other side of the trial, Daniel I. Sessler, MD, chair of the Outcomes Research Department at the Cleveland Clinic and a study investigator, said, "Clonidine should not be given to patients having noncardiac surgery in an attempt to reduce perioperative mortality or heart attack. If anything, it worsens the outcome." He speculated that clonidine didn't perform as expected because it caused hypotension out of proportion to its protective effect on heart rate.

Dr. Jarcho added, one thing to know about the POISE-2 trial was that while most patients had coronary disease or risk factors for coronary disease, only a small percentage (4.3%) had coronary stents. "That's important because we know aspirin reduces the risk of stent occlusion. So, the question of whether aspirin should be continued in surgical patients was not evaluated in this trial."

Steroids Also Fail
Cardiopulmonary bypass results in an inflammatory response that correlates with adverse outcomes. Prophylactic steroids attenuate this response but clinical benefits are unclear. For many centers in North America, steroid use in this setting continues as standard practice—but should it? Richard Whitlock, MD, PhD, of McMaster University presented the results of the Steroids in Cardiac Surgery (SIRS) trial involving about 7,500 patients randomized to 500 mg of intravenous methylprednisone or placebo given intra-operatively.

The trial discussant, Amit Khera, MD, director of preventive cardiology at the University of Texas Southwestern Medical Center said, "We have a (previous) meta-analysis of 30 studies—although most had fewer than 100 patients—suggesting benefit of steroids and a trial of 4,500 patients with a strong trend towards benefit. In this definitive study, at least for methylprednisone in higher doses, there was no benefit. Previously there was a hint towards improvement of atrial fibrillation and respiratory complications (with steroids) but given the increased risk of myocardial infarction (p = 0.001) seen here (TABLE 2), that offsets those for sure. This should not be a strategy we pursue; we should not be giving higher-dose steroids in the perioperative period to improve outcomes."

TABLE 2. SIRS Co-Primary Outcomes at 30 Days

References

1. Kirtane AJ, Leon MB. EuroIntervention. 2014;9:1021-3.
2. Bhatt DL, Kandzari DE, O'Neill WW, et al. N Eng J Med. 2014 April 10. [Epub before print]
3. Adams DH, Popma JJ, Reardon MJ, et al. N Engl J Med. 2014;370:1790-8.
4. Levine GN, Bates ER, Blankenship JC, et al. J Am Coll Cardiol. 2011;58:e44-e122.
5. Dehmer GJ, Blankenship JC, Cilingiroglu M, et al. J Am Coll Cardiol. 2014 March 13. [Epub ahead of print]
6. Devereaux PJ, Sessler DI, Leslie K, et al. N Engl J Med. 2014;370:1504-13.
7. Devereaux PJ, Mrkobrada M, Sessler DI, et al. N Engl J Med. 2014;370:1494-503.