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Redberg sounds off on PARTNER trial

Rita F. Redberg, MD
Cardiovascular Business (CVB) speaks with Rita F. Redberg, MD, about a letter she sent to the editor of the New England Journal of Medicine.

To: Editor, New England Journal of Medicine
From: Rita F. Redberg, MD, University of California at San Francisco Medical Center
DATE: January 13, 2011
Subject: PARTNER Trial

Dear Editor,

Although Leon et al (N Engl J Med 2010;363:1597-1607) report that transcatheter aortic-valve implantation (TAVI) is better than standard therapy, a look at the Placement of Aortic Transcatheter Valves (PARTNER) trial shows that this conclusion is unfounded. What the authors call “standard therapy” was—in 84 percent of the patients—a wholly discredited procedure that was largely discontinued years ago. This discredited procedure, aortic valvuloplasty, has been relegated to class III—that is, “not useful and may be harmful”—since 1998 (J Am Coll Cardiol 1998;32:1486-1588). Aortic valvuloplasty fell out of favor years ago because of “dismal” (40 percent) event-free one-year survival (J Am Coll Cardiol 1995;26:1522-1528).

The unexpectedly high rate of death in the control group was undoubtedly due to the use of this outdated, dangerous procedure. It is notable that the lowest one-year rates of death (33 percent) in the PARTNER study were among the 12 patients in the standard-therapy group who underwent surgical aortic-valve replacement. The standard therapy in patients with aortic stenosis who are not surgical candidates is medical therapy alone. Unfortunately, the PARTNER study did not include a valid control group, and thus we do not know how TAVI compares with standard therapy.

Sincerely, Rita F. Redberg, MD

Redberg reports being a member of the [FDA's] Cardiovascular Device Expert Panel. No other potential conflict of interest relevant to this letter was reported. Reprinted with the permission of the New England Journal of Medicine.

CVB: Could you further explain why the choice of the control arm makes Leon et al’s conclusion "unfounded"?

Redberg: When a randomized trial is conducted, researchers typically compare a new technology or technique with the standard therapy. However, the standard therapy for patients who have severe aortic stenosis but are not surgical candidates is not a procedure, but instead, it is optimal medical therapy. In the PARTNER trial, Leon et al used an aortic balloon valvuloplasty in 84 percent of the patients in the standard therapy arm. Valvuloplasty was largely abandoned more than 10 years ago, because of negative patient outcomes—which is probably why the researchers saw a high mortality rate in this arm. Therefore, I was shocked to see that the PARTNER researchers used the technique as the standard therapy arm. If a procedure doesn’t prove better than doing nothing, then it is best to do nothing. In order to truly understand how the new TAVI technique will really compare with actual standard therapy, it needs to be compared with optimal medical therapy.

CVB: How do you think the European registry data have informed these questions?

Redberg: We need to pursue properly designed randomized, controlled trials before we can examine the registries because of the confounders associated with registries. For instance, the people who do not receive the TAVI procedure would generally be sicker than in the randomized trials. Therefore, registries are helpful only if you have a randomized trial first.

CVB: If the TAVI procedure were approved in the U.S., what would you currently recommend for these inoperable patients with severe aortic stenosis?

Redberg: First, many of my patients with this condition are faring well with optimal medical therapy. However, before recommending the TAVI technique—which has a high rate of stroke and vascular complications, only a randomized trial can elucidate its potential benefits. Before we recommend any procedure, we need to be certain that the benefits will outweigh the risks. We don’t currently have those data.

RE: PARTNER investigators respond

E. Murat Tuzcu, MD
Cardiovascular Business (CVB) speaks with E. Murat Tuzcu, MD, from the Cleveland Clinic, who was an investigator on the PARTNER trial, about the current role of balloon aortic valuloplasty in patients with severe aortic stenosis.

To: Editor, New England Journal of Medicine
From: Martin B. Leon, MD, and Craig R. Smith, MD, Columbia University Medical Center, New York City, and E. Murat Tuzcu, MD, Cleveland Clinic Foundation  
DATE: February 23, 2011  
Subject: Author Response to Redberg’s Letter to the Editor

Dear Editor,

[T]he 358 patients in the PARTNER trial had aortic stenosis, severe cardiac symptoms (93 percent of the patients had New York Heart Association class III or IV symptoms) and multiple coexisting conditions (mean Society of Thoracic Surgeons score, 11.6 percent). These conditions were considered “inoperable” by surgeons and cardiologists.

In these “sickest of the sick” patients with inoperable aortic stenosis, balloon aortic valvuloplasty [BAV] is entirely appropriate as an important component of standard therapy. [BAV] is a class IIb recommendation in the most recent guidelines of the American College of Cardiology and American Heart Association (Circulation 2008;118:e523-e661) and the European Society of Cardiology (Eur Heart J 2007;28:230-268), and it 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.

In the PARTNER study, [BAV] was safe (one death and two strokes occurred within seven days after [BAV] in 150 patients). [BAV] was a successful bridge to aortic-valve replacement in 11 of the 12 patients with initially inoperable aortic stenosis who subsequently underwent aortic-valve replacement. Among patients in the standard-therapy group in the PARTNER study, the rate of death from any cause at three months was 20 percentage points lower among patients who underwent [BAV] than among patients who did not undergo this procedure, and patients who underwent [BAV] had a significant mortality benefit over the course of the trial (P=0.04 by the log-rank test). Therefore, as compared with patients who underwent TAVI, the patients with inoperable aortic stenosis who underwent [BAV] and received optimal medical therapy composed an entirely valid control group in the randomized PARTNER trial.

Sincerely, Martin B. Leon, MD, Craig R. Smith, MD, and E. Murat Tuzcu, MD, on behalf of the PARTNER investigators.

Reprinted with the permission of the New England Journal of Medicine.

CVB: What is the current treatment strategy for inoperable patients with severe aortic stenosis?

Tuzcu: Symptomatic patients with severe aortic stenosis must undergo an operation for an aortic valve replacement. For symptomatic aortic stenosis patients who cannot undergo an operation, especially for those with advanced heart failure, there is no good solution because there is no effective medical treatment for these patients. The only medical treatment available is aimed at alleviating symptoms of heart failure. Unfortunately, many of these patients typically don’t tolerate standard heart failure therapy well, so we are limited by the drugs we can use. Moreover, medical therapy has no impact on the natural course of the disease, but just potentially alleviating symptoms. For all these reasons, aortic valve replacement without surgery, i.e., TAVI, could present a much-needed treatment for this disease.

CVB: In inoperable patients with severe aortic stenosis, what is the current role of BAV in the U.S.?

Tuzcu: While BAV is not an alternative for surgical valve replacement, it has a role to play. There are some patients who derive symptom improvement from BAV, such as easier breathing, even if it’s only temporarily. BAV can be used as a bridge-to-surgery strategy, as about 25 to 30 percent of patients are able to undergo surgery after improvement obtained by BAV.

The most recent ACC/AHA guidelines classified BAV as a class IIb recommendation for patients who are unsuitable for surgery, as indicated in our response [above]. The guideline distinction between class III and class IIb is dependent on whether a patient is a candidate for surgery. There is no doubt that BAV should not be used if the patient can be operated on. This was the strategy that we used in the recently published PARTNER trial.