Gender, missing data take center stage at FDA's PARTNER panel
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The cardiovascular community has been buzzing about transcatheter aortic valve replacement (TAVR) procedures ever since the results of the PARTNER trial showed procedural benefits for inoperable aortic stenosis patients. Now, luminaries at the FDA Circulatory Systems Devices Panel are attempting to take the use of the technology a step further and tack on an additional indication for Edwards Lifesciences' Sapien heart valve system: treating patients with severe, symptomatic aortic stenosis who are high risk for surgery.

Martin B. Leon, MD, and Craig R. Smith, MD, kicked off the June 13 meeting by presenting PARTNER data and touching on the sensitive topics of the trial, including stroke risk and mortality differences between gender with both aortic valve replacement (AVR) and TAVR.

“The PARTNER trial targeted patients who straddle the [untreatable population] between those patients who do and those who do not receive AVR,” said Smith, chairman of the department of surgery at Columbia University College of Physicians and Surgeons and chief of the division of cardiothoracic surgery at New York-Presbyterian Hospital/Columbia University Medical Center in New York City.

Smith suggested that TAVR is a good alternative to AVR and said that the procedure will be very attractive for patients who are eligible for surgery but may have declined it. “Patients and the surgeons who treat them might appreciate an equivalent alternative to open heart surgery,” he added.

While AVR has been known to correct aortic stenosis and extend survival, he said that one should not forget its limitations, especially within the high-risk, elderly population. While the principal investigators of the PARTNER trial outlined the benefits in mortality seen with TAVR, they also addressed the potential risks. Many panelists were quick to point out the heightened rate of stroke and transient ischemic attack (TIA) seen in the TAVR group, as well as the heightened risk of vascular complications.

The primary endpoint data seen within the PARTNER trial received particular attention by the panel. Leon, director of the Center for Interventional Vascular Therapy at Columbia University Medical Center in New York City, reported all-cause mortality data to be 26.8 percent for AVR and 24.3 percent for TAVR. He noted that the mortality outcomes were “well within the non-inferiority margins.”

Another hot topic surrounded the gender differences seen in the PARTNER trial. Women were found to have a higher mortality with AVR when compared with TAVR at both 12 and 24 months. Leon said that the gender differences between baseline characteristics were “striking,” adding that the women were older and frailer and the men had a higher frequency of comorbities.

“Gender-specific differences start to develop at six months and become very apparent at one year,” Leon said. Men treated with TAVR had a 10 percent higher mortality than women at 12 months. The differences between male and female morality may be due to increased comorbidities in men.

To piggyback off Leon’s presentation on gender differences, panelist Xiting Yang, PhD, of the FDA’s Cardiovascular and Ophthalmic Devices Branch, in the division of biostatistics, office of surveillance and biometrics, said men seemed to perform better with AVR when compared with TAVR, while women performed better with TAVR.

Many asked for additional gender data, especially  longer-term results. However, panelist Veronica Sansing, PhD, cardiovascular epidemiologist at the FDA, said that the PARTNER trial was not powered to test differences in outcomes between gender.

Yang, on behalf of the FDA, also questioned PARTNER data. “The missing data and worst case scenario analyses carried out in the PARTNER trial did not address Sapien patients receiving AVR or AVR patients undergoing concomitant operations.” She said due to missing data, it is difficult to draw firm conclusions on certain endpoints.

Sansing added that there is a need for post-approval studies that look at long-term performance, including device performance, training programs and outcomes. She noted that these issues, including long-term patient quality of life and learning curve assessments, should be evaluated in future studies.

Lastly, panelist Sonna Patel-Raman, PhD, branch chief at FDA, said that there was limited data within the PARTNER trial regarding long-term performance. “How much information is enough to convey the benefit versus the risk for patients?” she asked.

“How long is long enough to obtain longer term performance and outcomes data to assess if we are really prolonging life or postponing death?” she added.

Smith called TAVR "a radical but completely logical evolutionary simplification of aortic valve replacement.”

As the panel discussion continues, FDA panelists will be asked to review the safety and efficacy as it pertains to stroke and vascular complications, among others, of the first transcatheter aortic heart valve for patients at a high risk of surgery.

Will Edwards' Sapien hit its mark and get a nod for the new indication? Stay tuned for the finale at