In the Journals

FDA panel discusses study design, indications for renal denervation as hypertension treatment

Laura Mauri
Laura Mauri

An FDA advisory committee panel discussed several topics regarding the clinical evaluation of device-based therapies, including renal denervation for patients with hypertension.

Industry and FDA members presented information during the meeting on the premarket clinical trial design, postapproval study design, indications and labeling for device-based treatments for patients with hypertension.

“We’re putting a lot of stock on post-marketing surveillance here,” Patrick H. Nachman, MD, director of the division of renal diseases and hypertension and professor of medicine at University of Minnesota in Minneapolis and temporary nonvoting member of the panel, said during the meeting. “The devil is going to be in the detail of how that is done and if there is a control group and what the metrics are going to be. That’s something that still gives me a little bit of anxiety. … It can’t be just observational.”

Richard A. Lange, MD, president of Texas Tech University Health Sciences Center El Paso, dean of the Texas Paul L. Foster School of Medicine and panel chairperson, added, “Until we see those studies, it’s going to be hard to recommend, but what we can certainly do is tell the sponsors right now that it’s not of interest, it’s imperative, and we need to start thinking about that now.”

The field of renal denervation has been reenergized now that there is a stronger focus on studying it further.

“This is a remarkable day,” John Somberg, MD, director of the master of science in clinical research program and professor in the division of cardiology at Rush University and temporary nonvoting member of the panel, said during the meeting. “This is a field that almost died a few years ago. This is in some ways the resurrection of it. It’s going to benefit a lot of patients. One of the reasons it almost died was operator difficulties, and I wish some of the device companies would try to address that. I’ve been urging that for a while. Secondly, I hope once we see these devices in practice, they’re introduced in a stepwise fashion and not everybody who has hypertension gets a renal ablation or a carotid device as first-line therapy.”

Besides indications and labeling, questions for the FDA included clinical study design, safety endpoints, effectiveness endpoints and the benefit-risk profile.

The FDA said it recognizes the importance of adequate evidence regarding the treatment of patients with hypertension, especially since medication adherence is a common issue in this patient population.

“As newer technologies evolve, it is important to provide sufficient evidence to establish a reasonable benefit-risk profile for the investigational device,” Hiren Mistry, MS, lead reviewer at the FDA, said during the agency presentation. “The FDA is open to a variety of study designs, but the future of clinical studies should aim to substantiate the benefit-risk profile of the therapy. To conclude, I would like to emphasize that this is the start for additional discussions as the technology and therapy continue to develop.”

David E. Kandzari
David E. Kandzari

Several manufacturers of renal denervation devices presented information during the meeting. Medtronic had performed the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials assessing the safety and efficacy of its renal denervation catheter (Symplicity Spyral). Through this, the company has determined that key elements of successful feasibility studies and ongoing pivotal trials include randomization, a sham control, meticulous attention to medical adherence and careful ambulatory BP ascertainment, according to the presentation.

“Pivotal trials may address an unmet need in patients who seek alternatives to medications,” Laura Mauri, MD, MSc, vice president of global clinical research and analytics for Medtronic, said during the presentation. “When measuring efficacy in these studies, it’s important to recognize that there’s a growing body of evidence showing that 24-hour ambulatory systolic blood pressure reductions are associated with a prevention of both cerebrovascular cardiovascular events as well as mortality.”

During Medtronic’s presentation, Raymond Townsend, MD, professor of medicine and director of the hypertension program at the Perelman School of Medicine, University of Pennsylvania, also discussed the importance of duplex ultrasound to assess renal artery stenosis, as it has a low rate of major adverse events, and its appropriateness for renal denervation studies. In addition, medical adherence is a complicated factor to study, although Medtronic’s SPYRAL HTN global clinical trial program is designed to factor that in along with the efficacy of renal denervation.

Michael A. Weber
Michael A. Weber

“In a study program altogether representing varied clinical trial design and varied clinical patient populations, the intent is to support an indication in the presence and the absence of medication,” David E. Kandzari, MD, director of interventional cardiology at Piedmont Heart Institute and chief scientific officer of Piedmont Healthcare in Atlanta, said during the presentation.

Renal denervation has been shown to be effective in lowering BP in patients with hypertension, although it is not immediate, as it can take up to 12 months for the treatment to take effect, Michael A. Weber, MD, professor of medicine at SUNY Downstate College of Medicine in New York, editor-in-chief of The Journal of Clinical Hypertension and Cardiology Today Editorial Board Member, said during a presentation from ReCor Medical.

The company’s renal denervation system (Paradise) is used to perform circumferential ablation of the renal nerves as it protects the renal arterial wall. The proposed target population from a clinical perspective for renal denervation includes patients with hypertension who have been prescribed antihypertensive medications, prefer device therapy and have an uncontrolled BP, Michael Bloch, MD, FASH, FAHA, FACP, FNLA, FSVM, associate professor at the University of Nevada School of Medicine and medical director of vascular care at Renown Institute for Heart and Vascular Health in Reno, Nevada, said during the presentation.

“The always-on aspect of renal denervation reduced dependence on medication adherence and potentially improved the side-effect profile of the overall treatment modality for hypertension,” Bloch said.

More aggressive BP control has become the global consensus, especially after the American Heart Association, American College of Cardiology and other societies published updated BP guidelines in 2017, which defined hypertension as a BP reading of 130 mm Hg/80 mm Hg.

Even with the shown effectiveness of renal denervation, future studies should consider certain factors related to uncontrolled BP.

“I don’t think every device is similar in its ability to lower blood pressure promptly,” Kenneth A. Jamerson, MD, professor of internal medicine and Frederick G.L. Huetwell professor of cardiovascular medicine at University of Michigan, said during a presentation by Rox Medical. “In considering equipoise in allowing these higher, untreated blood pressures, I challenge that every device company ought to look at the signal they get, look at the profile of how the blood pressure comes down and see if there’s a way to try to minimize how long people stay uncontrolled and how high we allow those blood pressures.”

Chandan Devireddy
Chandan Devireddy

Regardless, the mechanism behind renal denervation has been shown in studies to be an effective way to reduce BP in patients with hypertension.

“The intervention of [the carotid] reflex mechanism has been clearly and very elegantly defined as a way to lower blood pressure and try to reset the carotid baroreceptor to a point in patients who are elderly and hypertensive or patients with resistant hypertension to try to use the body’s own natural mechanism of feedback to result in effective blood pressure lowering that can hopefully reduce the overall cardiovascular morbidity and potential mortality in the long term,” Chandan Devireddy, MD, FACC, FSCAI, associate professor of medicine and associate fellowship director at Emory University and Cardiology Today Next Gen Innovator, said during a presentation by Vascular Dynamic. – by Darlene Dobkowski

Reference:

FDA Executive Summary.

Disclosures: Aside from an industry representative employed by Alpha Medical, the members of the Circulatory System Devices Panel report no relevant financial disclosures. Bloch reports he received research support from AstraZeneca, ReCor Medical and Vascular Dynamics, and consultant/honoraria from Amgen, Esperion, Janssen, Medtronic, Pfizer, ReCor Medical Relypsa and Takeda International. Devireddy reports he serves on a scientific advisory board for Medtronic. Kandzari reports he has received institutional grant or research support from Biotronik, Boston Scientific, Medtronic CardioVascular, Medinol and OrbusNeich, and he has received consultant fees from Biotronik, Boston Scientific, Medtronic CardioVascular and Cardinal Health. Mauri is an employee of Medtronic. Mistry is an employee of the FDA. Townsend reports he receives institutional support for the conduct of clinical trials and consultant fees from Medtronic. Weber reports he has relationships with AbbVie, Ablative Solutions, Astellas, Boston Scientific, Johnson & Johnson, Medtronic and ReCor Medical. Cardiology Today could not confirm relevant financial disclosures for Jamerson at the time of publication.

Laura Mauri
Laura Mauri

An FDA advisory committee panel discussed several topics regarding the clinical evaluation of device-based therapies, including renal denervation for patients with hypertension.

Industry and FDA members presented information during the meeting on the premarket clinical trial design, postapproval study design, indications and labeling for device-based treatments for patients with hypertension.

“We’re putting a lot of stock on post-marketing surveillance here,” Patrick H. Nachman, MD, director of the division of renal diseases and hypertension and professor of medicine at University of Minnesota in Minneapolis and temporary nonvoting member of the panel, said during the meeting. “The devil is going to be in the detail of how that is done and if there is a control group and what the metrics are going to be. That’s something that still gives me a little bit of anxiety. … It can’t be just observational.”

Richard A. Lange, MD, president of Texas Tech University Health Sciences Center El Paso, dean of the Texas Paul L. Foster School of Medicine and panel chairperson, added, “Until we see those studies, it’s going to be hard to recommend, but what we can certainly do is tell the sponsors right now that it’s not of interest, it’s imperative, and we need to start thinking about that now.”

The field of renal denervation has been reenergized now that there is a stronger focus on studying it further.

“This is a remarkable day,” John Somberg, MD, director of the master of science in clinical research program and professor in the division of cardiology at Rush University and temporary nonvoting member of the panel, said during the meeting. “This is a field that almost died a few years ago. This is in some ways the resurrection of it. It’s going to benefit a lot of patients. One of the reasons it almost died was operator difficulties, and I wish some of the device companies would try to address that. I’ve been urging that for a while. Secondly, I hope once we see these devices in practice, they’re introduced in a stepwise fashion and not everybody who has hypertension gets a renal ablation or a carotid device as first-line therapy.”

Besides indications and labeling, questions for the FDA included clinical study design, safety endpoints, effectiveness endpoints and the benefit-risk profile.

The FDA said it recognizes the importance of adequate evidence regarding the treatment of patients with hypertension, especially since medication adherence is a common issue in this patient population.

“As newer technologies evolve, it is important to provide sufficient evidence to establish a reasonable benefit-risk profile for the investigational device,” Hiren Mistry, MS, lead reviewer at the FDA, said during the agency presentation. “The FDA is open to a variety of study designs, but the future of clinical studies should aim to substantiate the benefit-risk profile of the therapy. To conclude, I would like to emphasize that this is the start for additional discussions as the technology and therapy continue to develop.”

David E. Kandzari
David E. Kandzari

Several manufacturers of renal denervation devices presented information during the meeting. Medtronic had performed the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials assessing the safety and efficacy of its renal denervation catheter (Symplicity Spyral). Through this, the company has determined that key elements of successful feasibility studies and ongoing pivotal trials include randomization, a sham control, meticulous attention to medical adherence and careful ambulatory BP ascertainment, according to the presentation.

“Pivotal trials may address an unmet need in patients who seek alternatives to medications,” Laura Mauri, MD, MSc, vice president of global clinical research and analytics for Medtronic, said during the presentation. “When measuring efficacy in these studies, it’s important to recognize that there’s a growing body of evidence showing that 24-hour ambulatory systolic blood pressure reductions are associated with a prevention of both cerebrovascular cardiovascular events as well as mortality.”

During Medtronic’s presentation, Raymond Townsend, MD, professor of medicine and director of the hypertension program at the Perelman School of Medicine, University of Pennsylvania, also discussed the importance of duplex ultrasound to assess renal artery stenosis, as it has a low rate of major adverse events, and its appropriateness for renal denervation studies. In addition, medical adherence is a complicated factor to study, although Medtronic’s SPYRAL HTN global clinical trial program is designed to factor that in along with the efficacy of renal denervation.

PAGE BREAK
Michael A. Weber
Michael A. Weber

“In a study program altogether representing varied clinical trial design and varied clinical patient populations, the intent is to support an indication in the presence and the absence of medication,” David E. Kandzari, MD, director of interventional cardiology at Piedmont Heart Institute and chief scientific officer of Piedmont Healthcare in Atlanta, said during the presentation.

Renal denervation has been shown to be effective in lowering BP in patients with hypertension, although it is not immediate, as it can take up to 12 months for the treatment to take effect, Michael A. Weber, MD, professor of medicine at SUNY Downstate College of Medicine in New York, editor-in-chief of The Journal of Clinical Hypertension and Cardiology Today Editorial Board Member, said during a presentation from ReCor Medical.

The company’s renal denervation system (Paradise) is used to perform circumferential ablation of the renal nerves as it protects the renal arterial wall. The proposed target population from a clinical perspective for renal denervation includes patients with hypertension who have been prescribed antihypertensive medications, prefer device therapy and have an uncontrolled BP, Michael Bloch, MD, FASH, FAHA, FACP, FNLA, FSVM, associate professor at the University of Nevada School of Medicine and medical director of vascular care at Renown Institute for Heart and Vascular Health in Reno, Nevada, said during the presentation.

“The always-on aspect of renal denervation reduced dependence on medication adherence and potentially improved the side-effect profile of the overall treatment modality for hypertension,” Bloch said.

More aggressive BP control has become the global consensus, especially after the American Heart Association, American College of Cardiology and other societies published updated BP guidelines in 2017, which defined hypertension as a BP reading of 130 mm Hg/80 mm Hg.

Even with the shown effectiveness of renal denervation, future studies should consider certain factors related to uncontrolled BP.

“I don’t think every device is similar in its ability to lower blood pressure promptly,” Kenneth A. Jamerson, MD, professor of internal medicine and Frederick G.L. Huetwell professor of cardiovascular medicine at University of Michigan, said during a presentation by Rox Medical. “In considering equipoise in allowing these higher, untreated blood pressures, I challenge that every device company ought to look at the signal they get, look at the profile of how the blood pressure comes down and see if there’s a way to try to minimize how long people stay uncontrolled and how high we allow those blood pressures.”

PAGE BREAK
Chandan Devireddy
Chandan Devireddy

Regardless, the mechanism behind renal denervation has been shown in studies to be an effective way to reduce BP in patients with hypertension.

“The intervention of [the carotid] reflex mechanism has been clearly and very elegantly defined as a way to lower blood pressure and try to reset the carotid baroreceptor to a point in patients who are elderly and hypertensive or patients with resistant hypertension to try to use the body’s own natural mechanism of feedback to result in effective blood pressure lowering that can hopefully reduce the overall cardiovascular morbidity and potential mortality in the long term,” Chandan Devireddy, MD, FACC, FSCAI, associate professor of medicine and associate fellowship director at Emory University and Cardiology Today Next Gen Innovator, said during a presentation by Vascular Dynamic. – by Darlene Dobkowski

Reference:

FDA Executive Summary.

Disclosures: Aside from an industry representative employed by Alpha Medical, the members of the Circulatory System Devices Panel report no relevant financial disclosures. Bloch reports he received research support from AstraZeneca, ReCor Medical and Vascular Dynamics, and consultant/honoraria from Amgen, Esperion, Janssen, Medtronic, Pfizer, ReCor Medical Relypsa and Takeda International. Devireddy reports he serves on a scientific advisory board for Medtronic. Kandzari reports he has received institutional grant or research support from Biotronik, Boston Scientific, Medtronic CardioVascular, Medinol and OrbusNeich, and he has received consultant fees from Biotronik, Boston Scientific, Medtronic CardioVascular and Cardinal Health. Mauri is an employee of Medtronic. Mistry is an employee of the FDA. Townsend reports he receives institutional support for the conduct of clinical trials and consultant fees from Medtronic. Weber reports he has relationships with AbbVie, Ablative Solutions, Astellas, Boston Scientific, Johnson & Johnson, Medtronic and ReCor Medical. Cardiology Today could not confirm relevant financial disclosures for Jamerson at the time of publication.

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