My Big 4 at ACC: EVEREST II, Partner Cohort A, RIVAL, and PROTECT II

The American College of Cardiology’s Annual Scientific Session is the time to hear about the most important advances in cardiology. These presentations are often summarized in the media and later published in the scientific journals. I thought I would take this editor’s page to give you my top 4 studies that reflect some of the biggest advances influencing the cath lab in the immediate future. 

EVEREST II — Mitral Valve Clip Study for Mitral Regurgitation

The EVEREST II trial results for 2 years showed that percutaneous repair of the mitral valve with the MitraClip device (Abbott Laboratories, Abbott Park, Ill.) was less effective at reducing mitral regurgitation (MR) than surgery (mitral valve repair or replacement, MVR), but the procedure was safer and had similar improvements in clinical outcomes.¹ The MitraClip was ‘not inferior’ to surgery for the primary endpoint of freedom from death or severe MR. For the end points of needing MVR after the initial procedure, the benefit of surgery over the clip was attributed exclusively to clip patients needing subsequent surgery. However, at 1 and 2 years, most (80% and 78%, respectively) of the clip patients did not need surgery and surgeries were almost always within the first 6 months after the procedure. The odds of avoiding surgery after that period were much better with the percutaneous procedure.

Both the clip and MVR reduced left ventricular (LV) diastolic volume in the EVEREST II study. New York Heart Association (NYHA) class heart failure was better with the clip. The left ventricle responded favorably to treatment with the clip. The results of the study are shown in Tables 1-2.

From this data, it appears that the clip will be a good option for some patients, especially if the valve anatomy is suitable, and the patient is at high risk during surgery. According to subgroup results, the clip may be better for older patients, those with functional rather than degenerative mitral regurgitation, and for patients with left ventricular dysfunction. I agreed with the comments of Dr. Ted Feldman, the principal investigator, that “This is a first-in-class catheter-based strategy for mitral regurgitation. It is a very big step.”

The Transaortic Valve Implant (TAVI) Study: The PARTNER Trial

The PARTNER trial presented the results for patients in cohort A. PARTNER cohort A consisted of high-risk aortic stenosis patients deemed eligible for surgery. The study compared transaortic valve implant (TAVI) with aortic valve replacement (AVR) surgery for severe aortic stenosis. The comparison showed that the TAVI procedure is as good as AVR in surgery-eligible patients for mortality (Table 3), with less bleeding, but more strokes (Table 4). At 30 days, deaths were numerically lower, but not statistically different in the TAVI group. By one year, deaths in both groups were the same (Table 3).

The secondary endpoint (major strokes) was higher in the TAVI-treated patients, both at 30 days and one year. In a combined endpoint of all stroke or transient ischemic attack (TIA), the difference between groups was statistically significant (Table 4).

It was important to note that compared to TAVI, both major bleeding (19.5% vs. 9.3%, p < 0.001) and new onset atrial fibrillation (8.6% vs. 16%, p < 0.001) was twice as common in AVR patients. In contrast, vascular complications were 4 times higher in the TAVI group (11% vs. 3.2%, p < 0.001). Symptom improvement (NYHA class and six-minute walk test) was greater in the TAVI group than the AVR patients at 30 days, but no different at one year.

The PARTNER Cohort A trial results emphasized that patients who are very high-risk candidates for surgery can be helped by TAVI, with the tradeoff of higher stroke and vascular complications for less bleeding and procedure-related atrial fibrillation, with the same mortality rate. Furthermore, it is equally important to note that not everybody is a candidate for TAVI. Some patients are too old, too frail, or too debilitated to benefit or even withstand a TAVI. Dr. Craig Smith, the principal investigator, stated, “Future randomized studies [will] focus on lower-risk patients who are candidates for operation.” My view is that TAVI, like the early days of balloon angioplasty and stenting, will undergo technological revolutions and that this procedure will take its place in the treatment of valvular heart disease, just like percutaneous coronary intervention has taken its place in coronary artery disease treatment.

Radial Versus Femoral Access for Acute Coronary Syndromes Treatment:  The RIVAL Trial

For patients with acute coronary syndromes (ACS), transradial access reduced the risk of vascular-access complications by 63% compared to femoral access. However, use of the radial access did not reduce death, myocardial infarction (MI), stroke, or non-coronary artery bypass graft (CABG)-related major bleeding at 30 days.^3,4 The RIVAL trial showed that procedural success rates were equivalent between the two approaches and that the large majority of patients preferred the radial approach if a repeat procedure were to be needed.

While disappointing to die-hard radialists, I agreed with Dr. Jolly, the principal investigator, that we can be assured that both radial and femoral procedures are safe and effective in the current era. While we have addressed the debate between access methods here before, this study again points to the advantage of radial access providing lower rates of vascular complications.

The RIVAL trial is the largest comparison to date of the transradial and transfemoral approaches and is notable for the fact that the patients had ACS with and without ST-segment elevation (those with the highest bleeding risks). It was also important that the interventional cardiologists were modestly experienced, as they were required to have performed a minimum of 50 radial procedures in the prior year.

The primary 30-day outcome, a composite of death, MI, stroke, or non-CABG-related major bleeding, was the same: 3.7% for radial patients and 4.0% for femoral patients (p = not significant). There was no significant difference between the two approaches for the secondary endpoint of death, MI, or stroke or non-CABG major bleeding at 30 days. Of interest, two-thirds of PCI bleeds were not at the access site. 

For ST-elevation MI (STEMI) patients treated transradially, there was a 40% relative reduction in the risk of death, MI, stroke, or non-CABG-related major bleeding, and a 61% relative reduction in the risk of death (both significant changes). In addition, experience was important, since there was a significant reduction in the risk of the primary outcome, a 51% reduction, among PCI centers that performed the highest volume of radial procedures.

The benefit for the radial approach to STEMIs raises some questions, but according to the comments of the investigators, this effect was due to more experienced operators and the use of more potent antithrombotic drugs with their associated bleeding side effects. My bottom line is that radial for STEMI patients is better, but my own experience and team must rise to meet the challenge.

Impella Versus Intra-Aortic Balloon Pump:  The PROTECT II Trial

The PROTECT II study was a prospective, multi-center, randomized trial in high-risk PCI patients requiring hemodynamic support comparing the Impella 2.5 to intra-aortic balloon pump (IABP) and measuring major adverse events at 30 days, with 90-day follow up. To be enrolled, patients needed non-emergent high-risk PCI of an unprotected left main coronary or the last patent conduit, with an left ventricular ejection fraction (LVEF) under 35% or three-vessel disease and a LVEF over 30%.

The overall outcome for the entire study cohort at 90 days showed a 21% reduction in major adverse events for Impella over the IABP (p = 0.029). However, the benefits were different in patients where a Rotoblator device (Boston Scientific, Natick, Mass.) was used. In the pre-specified high-risk PCI patients without atherectomy (88% of study), Impella had a significant benefit over the IABP at both 30 and 90 days (p = 0.003) with a 29% reduction of major adverse events. In the pre-specified atherectomy group (12% of study), there was no difference (p = 0.316) in major adverse events at 90 days. In this subgroup, the Impella arm demonstrated a significant increase in peri-procedural CK-MB release (p = 0.030) and decreased repeat revascularization at 90 days (p = 0.006) (Tables 5-6).

Curiously, the PROTECT II trial was stopped early for futility. I think this means that the safety committee felt that the endpoint differences would never be reached, but clarification was not forthcoming. The study designers predicted that patients randomized to hemodynamic support by Impella would have a 20% adverse event rate and that those randomized to IABP would have a 30% rate. However, the overall adverse event rates were not worse in the IABP group than in the Impella group in the interim analysis, and the study was stopped.

Dr. William O’Neill, the trial's lead investigator, nonetheless reported the per-protocol analysis of the trial. A total of 447 patients were enrolled in the intention-to-treat study, but only 426 met all the criteria to be included in the per-protocol analysis. The per-protocol analysis showed that the Impella patients had 21% fewer major adverse events at 90 days than the IABP patients (40.8% vs. 51.4%; p = 0.029).  From the presentation, it appears that the Impella device was superior to IABP support for a subset of high-risk coronary intervention patients (with the caveats noted).

One of the major confounders of this study was the unplanned use of rotational atherectomy, since 70% of patients treated with Impella and atherectomy had an adverse event, compared to only 35% of patients treated with an IABP and atherectomy. Controversy around this study suggests that further information is needed to reach a strong conclusion, but that in the patients needing the most support, the device that provides the highest level of support may be the one with the ability to provide the highest cardiac output with the lowest device-related risks. 

In summary, the ‘big 4’ studies provide an excellent view into the future of our interventional practices and should stimulate critical thinking about the best approaches to aortic and mitral valve disease, ACS and high-risk PCI patients. I look forward to seeing what is in store for us over the coming year.

References

1. Feldman T, Foster E, Glower DG, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011 Apr 14;364(15):1395-1406.
2. Otto CM, Verrier ED. Mitral regurgitation — what is best for my patient? N Engl J Med 2011 Apr 14;364(15):1462-1463.
3. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography in patients with acute coronary syndromes (RIVAL): A randomized, parallel group, multicenter trial. Lancet 2011 Apr 4 [Epub ahead of print]. doi:10.1016/S0140-6736(11)60404-2. 
4. Di Mario C, Viceconte N. Radial angioplasty: Worthy RIVAL, not undisputed winner. Lancet 2011 Apr 4 [Epub ahead of print]. doi:10.1016/S0140-6736(11)60469-8.

______________________________

Disclosure: Dr. Kern reports that he is a speaker for Volcano Therapeutics and St. Jude Medical, and is a consultant for Merit Medical and InfraReDx, Inc.