NEJM Letters Take on PARTNER Trial

Transcatheter aortic valve implantation (TAVI) has been met with much enthusiasm in the wake of the PARTNER trial, which backed the novel approach as an alternative to standard therapy in patients who are not candidates for surgical valve replacement. New correspondence published in the January 13, 2011, issue of the New England Journal of Medicine, however, question the appropriateness of aortic valvuloplasty in the trial’s control group. Other letters ask about disparities in baseline characteristics and request additional information about cost effectiveness and quality of life.

Outside experts Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY); Morton J. Kern, MD, of the University of California, Irvine (Irvine, CA); and Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), all told TCTMD that the PARTNER investigators responded well to the criticisms.

“It's very hard to poke holes in this trial,” Dr. Kirtane said in a telephone interview, crediting both the mortality and quality-of-life benefits observed in conjunction with TAVI.

Alternative to Surgery

Originally published in the October 21, 2010, issue of NEJM, the PARTNER (Placement of AoRTic traNscatheterER valves) trial randomized 358 patients who had severe aortic stenosis and cardiac symptoms but were ineligible for surgery to undergo TAVI or receive standard therapy.

At 1 year, the primary endpoint of all-cause mortality showed a significant advantage for TAVI over standard therapy, as did the co-primary endpoint, the composite of death/repeat hospitalization. Six-minute walking distance improved in both treatment arms from baseline to 1 year, but the difference was only significant for patients in the TAVI group. On the downside, TAVI was associated with higher rates of major vascular complications and bleeding episodes as well as a trend toward increased stroke incidence at 30 days.

Lack of Control?

Rita F. Redberg, MD, of the University of California at San Francisco Medical Center (San Francisco, CA), leads off the criticism with a letter that takes issue with the fact that 84% of patients in PARTNER’s standard therapy group underwent aortic valvuloplasty. She writes that the “wholly discredited procedure” was discontinued years ago, having been relegated since 1998 by American College of Cardiology/American Heart Association (ACC/AHA) guidelines to a class III recommendation. According to the 1998 guidelines, valvuloplasty is class III—not useful and in some cases possibly harmful—when used as an alternative to surgical valve replacement.

“The standard therapy in patients with aortic stenosis who are not surgical candidates is medical therapy alone,” she comments. “Unfortunately, the PARTNER study did not include a valid control group, and thus we do not know how TAVI compares with standard therapy.”

Valvuloplasty Can Be Suitable for Sickest Patients

PARTNER investigators Martin B. Leon, MD, and Craig R. Smith, MD, both of Columbia University Medical Center (New York, NY), and E. Murat Tuzcu, MD, of the Cleveland Clinic Foundation (Cleveland, OH), respond by pointing out that patients enrolled in the trial had aortic stenosis, severe cardiac symptoms, and multiple comorbidities considered “inoperable” by surgeons and cardiologists.

“In these ‘sickest of the sick’ patients with inoperable aortic stenosis, balloon aortic valvuloplasty is entirely appropriate as an important component of standard therapy,” they write. In fact, the procedure has a class IIb recommendation in the most recent ACC/AHA (2008) and European Society of Cardiology (2007) guidelines, the investigators note, and “is considered reasonable therapy in patients with aortic stenosis as a bridge to aortic-valve replacement or as palliation in patients who cannot undergo aortic-valve replacement because of coexisting conditions.”

Because valvuloplasty was safe in most patients who received it and also acted as a successful bridge to valve replacement in 12 patients who eventually underwent surgery, Drs. Leon, Smith, and Tuzcu conclude that PARTNER did contain an “entirely valid control group.”

In a telephone interview, Dr. Kern characterized the tone of Dr. Redberg's letter as “really kind of hostile,” but acknowledged she “made a good point.” In turn, the PARTNER investigators “responded in a good way,” he said.

Dr. Kirtane had a similar take on the situation, saying, “Her argument is well refuted by the response.”

The fact that outcomes related to valvuloplasty were so good—1 death and 2 strokes occurred within 1 week of treatment in 150 patients—is reassuring, he said. “The valvuloplasty doesn't make the aortic stenosis worse,” he pointed out. “The only thing it would do is cause a periprocedural stroke or death. And if you see the outcomes, they're great. That fear was not realized.”

Dr. Kirtane explained that it is possible that balloon aortic valvuloplasty outcomes have improved over the years. “The problem is that we don't want to say that, because we don't want people to get valvuloplasty in lieu of definitive therapy,” he commented. “But clearly, from a palliation standpoint, it's useful and at least in this population not only was it not harmful but it facilitated [surgical replacement] in a not insignificant portion of patients.”

Dr. Kern agreed that valvuloplasty has specific uses, including as a bridge to treatment. “It's not an effective treatment [in the long term], but it may provide some benefit for a short time,” he said, adding that in PARTNER, “the benefit didn't last as long as a year but it was better than nothing.”

In an e-mail communication with TCTMD, Dr. Ellis also concurred. “While valvuloplasty has significant limitations, it can provide short/intermediate-term symptomatic improvement for patients with aortic stenosis who are doing poorly on medical treatment alone. Further, medical therapy does little to alter the dismal prognosis in patients with severe aortic stenosis,” he commented. “To state the ‘unexpectedly high rate of death in the control group was undoubtedly due to [valvuloplasty] . . .’ suggests that the writer neither takes care of these patients frequently nor is fully versed in the literature.”

Imbalance at Issue

In another letter, Sabrina Trippoli, PharmD, of the Laboratory of Pharmacoeconomics (Florence, Italy), and Andrea Messori, PharmD, of Società Italiana Farmacia Ospedaliera (Florence, Italy), note that patients assigned to TAVI had significantly lower EuroScore values, indicating reduced surgical risk, compared with those randomized to standard therapy. “This difference raises the question of whether the better outcome (reduced rates of death from any cause) in the patients who underwent TAVI reflects the positive effect of the experimental treatment or better baseline conditions of this patient group,” they write.

The PARTNER investigators reassure that baseline characteristics in the trial were “generally well balanced,” although they acknowledge some additional differences including more frequent chronic obstructive pulmonary disease and atrial fibrillation in the standard therapy group and higher rates of calcified aorta in the TAVI group.

“Such baseline disparities are commonly observed” in small randomized trials, they note, but the mortality benefit with TAVI remained even after adjustment for these differences.

All 3 physicians interviewed by TCTMD agreed that the difference in EuroScore was unlikely to be clinically significant. Moreover, because the logistic EuroScore was derived from patients typically undergoing surgery, it is “unclear how well it performs in this patient population,” Dr. Kirtane said.

More Is Better

Jonathan Newman, MD, MPH, and Daichi Shimbo, MD, of Columbia University (New York, NY), say in their letter that the PARTNER trial represents a “tremendous advance” in patient care. “The decreases in mortality after TAVI reported by the authors are remarkable,” they write. “However, in the targeted population of elderly persons with multiple coexisting conditions, limited life expectancy, and disproportionate health care expenditures, a careful consideration of the cost-effectiveness and quality-of-life benefits of TAVI is warranted, especially in the context of recent domestic health care reform initiatives.”

Dr. Leon and colleagues agree that quality-of-life and cost-effectiveness analyses are “required to best determine the ultimate benefit of TAVI.” These were part of the original PARTNER trial design, they add. Quality-of-life data were reported in November 2010 at the American Heart Association Scientific Sessions in Chicago, IL, while cost-effectiveness analyses are ongoing.

“These quality-of-life outcomes suggest that in the PARTNER patient cohort, TAVI not only adds years to life, but also adds life to years,” the researchers conclude.

Note: Dr. Leon is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

---

Sources:
1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607.

2. Redberg RF. Transcatheter aortic-valve implantation for aortic stenosis [letter to the editor]. N Engl J Med. 2011;364:179.

3. Trippoli S, Messori A. Transcatheter aortic-valve implantation for aortic stenosis [letter to the editor]. N Engl J Med. 2011;364:179.

4. Newman J, Shimbo D. Transcatheter aortic-valve implantation for aortic stenosis [letter to the editor]. N Engl J Med. 2011;364:180.

5. Leon MB, Smith CR, Tuzcu EM. Transcatheter aortic-valve implantation for aortic stenosis [author reply]. N Engl J Med. 2011;364:180-181.

 

Related Stories:

• PARTNER: All-Cause, CV Mortality Lower in Patients Treated with TAVI vs. Standard Therapy at 1 Year
• PARTNER EU Registry Shows Promising TAVI Results at 1 Year
• PARTNER Analysis: TAVI Substantially Improves QOL vs. Standard Therapy