As Renal Denervation Use Grows, New Benefits Emerge

MUNICH – Renal denervation remains investigational in the United States, where a large clinical trial testing its safety and efficacy is now in progress.

But in Europe, Australia, and elsewhere, renal denervation – an intravascular procedure that zaps the sympathetic innervation in a patient’s renal arteries with a few pulses of radiofrequency energy – is rapidly becoming the big new thing for treating patients with drug-resistant hypertension since marketing of a denervation catheter began in April 2010.

As of last spring, Medtronic, the company that sells the only renal denervation (RD) catheter currently commercially available, estimated that the 5,000th patient had been treated by RD, although Dr. Michael Böhm, who oversees what might be the most active RD program in the world, recently put his estimate upwards of 10,000 patients treated worldwide. Among the smaller number of closely followed patients included in this experience with reported outcomes data, perhaps 300-500 patients, the results have been striking: A drop in office blood pressure on the order of 28/10 mm Hg in patients who began treatment with pressures in the 180/100 mm Hg ballpark (despite treatment with as many as six antihypertensive drugs), that has been durable over follow-up as long as 36 months, with response rates among patients that rise over time and run over 90% once patients are followed longer than a year, and uniform reports of good safety during 6-36 months’ follow-up, with no evidence of impaired renal function or arterial sclerosis over time or other untoward effects.

And now emerging in new reports, both recently published and presented at the meeting in August, are hints of several effects beyond simple blood pressure reduction that hold promise for expanding the application of RD beyond just antihypertensive treatment and broadening the recognized benefits of this treatment.

RD "is a transformative area for treating hypertension, and now heart failure" and other disorders, commented Dr. Adrian Brady, a cardiologist and hypertension specialist in Glasgow, Scotland.

More Than Just Blood Pressure

Among the newest findings was a report on a small, controlled study with 43 normotensive patients with New York Heart Association class III or IV heart failure that showed RD could significantly raise left ventricular ejection fraction, reduce left ventricular end-systolic and end-diastolic volume index, and cut serum levels of brain natriuretic peptide during 12 months of follow-up. RD had these positive effects on surrogate markers of heart failure severity without causing hypotension or other adverse effects, and the treatment also cut the rate of heart failure hospitalizations over 12 months by more than half, although the study wasn’t powered to examine this end point, reported Dr. Milos Táborský, a cardiologist at Olomouc University Hospital in the Czech Republic.

For example, left ventricular ejection fraction rose from an average of 25% at baseline to an average of 31% 12 months after RD, compared with a 2% change in the control patients, a statistically significant difference, Dr. Táborský said.

In short, RD worked in normotensive patients with heart failure similar to a beta-blocker drug that cuts neurohormonal activation, commented Dr. José-Ramon Gonzalez-Juanatey, director of the cardiovascular department at the University Hospital of Santiago de Compostela in Spain. "This technique opens a new era in treating heart failure by decreasing sympathetic tone," he said.

In a similar vein, results reported at the meeting from another small, controlled study with 27 treatment-resistant hypertensive patients showed that by 6 months after RD, the treatment had significantly improved aortic augmentation index and aortic pulse-wave velocity, two markers of central vascular stiffness and central blood pressure. The average 1 m/sec improvement seen in aortic pulse-wave velocity 6 months after RD, reflecting a roughly 10% reduction in aortic stiffness, corresponds to about a10-year drop in the patients’ vascular age, said Klaas F. Franzen, a researcher at Schleswig-Holstein University Hospital in Lübeck, Germany.

"The idea is that by reducing whole-body sympathetic activity, you reduce vasoconstriction, and induce vasodilation in the renal arteries and central arteries," commented Dr. Felix Mahfoud, a cardiologist at Saarland University Hospital in Homburg, Germany.

The benefits from RD are not just cardiovascular. Another report at the meeting came from serial psychologic tests administered before and after 119 patients with drug-resistant hypertension underwent RD. In addition to producing an average drop in office blood pressure of 20/10 mm Hg, at both 3 and 6 months after treatment, RD also led to statistically and clinically significant drops in stress reaction, as measured on the Wiener Determination Task. In addition, among the roughly 20% of patients in the group of 119 who had clinically meaningful levels of anxiety or depression at baseline, RD also produced statistically and clinically significant falls in both anxiety and depression at both 3 and 6 months after treatment, reported Denise Fischer, Ph.D., a psychologist at Saarland University Hospital.

Another facet of her study looked at headache severity and found that at 3 and 6 months following RD all patients had statistically significant drops in headache intensity, and among the 20% of patients who entered the study with headaches self-rated as worse than 4 on a 0-10 visual analog scale, headache intensity fell from an average of about 8 before treatment to an average of less than 4 at 6 months after RD, Dr. Fischer said.

Follow-Ups to 18 Months, and Beyond

The most thorough assessment so far of RD as an antihypertensive treatment came in the Symplicity HTN-2 trial, a multicenter, multinational trial that randomized 106 patients with drug-resistant hypertension. In the 6-month results from the study, the primary end point showed that among 49 patients who underwent RD, office blood pressure fell by an average of 32/12 mm Hg, compared with virtually no change among 51 controls (Lancet 2010;376:1903-9).

During the August meeting, researchers from the study reported follow-up data, which included 18-month results from 43 patients in the original intervention arm of the study and from an additional 31 patients originally randomized to the control arm but who crossed over to RD treatment after the first 6 months.

The 18-month results showed stability of the initial blood pressure reduction in both subgroups of patients, with average reductions in office blood pressure remaining at 32/12 mm Hg compared with baseline in the 43 patients from the original intervention arm, and an average 28/11 mm Hg cut in office pressure in the 31 crossover patients, compared with their baseline levels, said Dr. Murray D. Esler, professor of medicine at Monash University in Melbourne, and lead investigator for the study. Patients in the initially treated arm also had an average 7 beats/min reduction in heart rate, compared with baseline that was statistically significant.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following renal denervation.   --Dr. Michael Böhm.

For safety, the 18 month results showed "no signal that renal function was harmed," he said. One patient had a renal-artery dissection early in the study, caused by the stiff catheter tip used at the study’s start but since replaced with a more flexible tip, Dr. Esler said. Other safety events during follow-up included one episode of hypotension that required hospitalization, one "mild" incidence of "transient" acute renal failure, and two deaths unrelated to RD.

Dr. Esler and his collaborators also cited the 36-month follow-up results on 24 patients from the initial, uncontrolled study of RD using the Symplicity catheter, the Symplicity HTN1 study (Lancet 2009;373:1275-81). These patients continue to show a durable blood pressure response and no signs of adverse effects, renal or otherwise, in this small number of patients followed for a prolonged period, said Dr. Böhm, director of internal medicine at Saarland University Hospital. (The 3-year follow-up of these 24 patients was first reported last March at the annual scientific session of the American College of Cardiology.) A very encouraging finding was that among the small number of patients followed this long, the percentage of patients with clinically important blood pressure drops continued to accumulate, so that at 36 months 99% of treated patients responded, Dr. Böhm said.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following RD, he said. "How long will [their response] last? No one knows, but if it lasts for at least 3 years, you can then justify a redo," a repeat treatment, although he also cautioned that so far, he knows of no patient who has undergone RD a second time.

In addition to the new evidence for pleiotropic effects from RD reported at the meeting, recently published reports from small studies provided preliminary documentation of other possible benefits. For example:

• RD led to a significantly reduced prevalence of albuminuria during 6-month follow-up in a study with 88 treated patients with drug-resistant hypertension (Hypertension 2012;60:419-24).

• RD led to significant improvements in glucose metabolism and insulin sensitivity during 3-month follow-up in a study with 37 treated patients with drug-resistant hypertension (Circulation 2011;123:1940-6).

• RD produced a reduction in blood pressure during exercise without affecting chronotropic competence during 3-month follow-up of 37 treated patients with drug-resistant hypertension (J. Amer. Coll. Cardiol. 2011;58:1176-83).

Novel Catheter May Speed Procedure Times

The Symplicity renal denervation catheter from Medtronic is not the only such device in clinical use. At the meeting, researchers reported 3-month follow-up results from a series of 46 patients with drug-resistant hypertension treated with a multielectrode catheter from St. Jude at four centers in Greece and Australia.

The main difference between the St. Jude EnligHTN device, which has four separate electrodes at its tip, and the Medtronic device, with a single electrode, is that the St. Jude device can denervate a renal artery with a single placement, as opposed to the four different placements, with rotation, used for the Medtronic device, meaning less arterial manipulation. Whether this will produce any discernable difference in safety, efficacy, or procedure time remains unclear.

The study enrolled patients with persistent hypertension, with an office systolic pressure above 160 mm Hg (150 mm Hg in patients with diabetes), despite treatment with at least three antihypertensive drugs, including at least one diuretic (similar enrollment criteria as the Symplicity studies). The patients’ averaged 60 years old, and their pressures averaged 176/98 mm Hg.

Average procedure time was 34 minutes, reported Dr. Costas Tsioufis, a professor of cardiology at the University of Athens, which may be modestly faster than the usual procedure time using the Symplicity catheter, which operators often estimate to require 40-50 minutes. Data from a series of 344 patients treated with the Symplicity catheter at Saarland University Hospital in Homburg showed an average procedure time of 44 minutes, said Dr. Felix Mahfoud, a cardiologist there.

Renal Denervation Shown Highly Cost Effective

Although renal denervation has an estimated up-front cost of about $12,500, the long-term benefits of the blood pressure reduction it usually produces are so potent that the treatment winds up costing about $3,000 for each additional quality-adjusted life-year it confers on patients, based on a cost-effectiveness analysis of data from the Symplicity HTN-2 trial.

This level of cost effectiveness is "more than an order of magnitude below the recognized threshold of $50,000/QALY [quality-adjusted life-year]," and provides fairly compelling evidence that "catheter-based renal denervation therapy is a cost-effective treatment strategy for resistant hypertension," Dr. Benjamin P. Geisler and his associates wrote in a report published online in September (J. Am. Coll. Cardiol. 2012 [doi:10.1016/j.jacc.2012.07.029]).

They based their cost-effectiveness model on data collected in the Symplicity HTN-2 trial (Lancet 2010;376:1903-9), described in the main story.

"When you look at societal decision making – how much a society is willing to pay for improved quality of life and increased duration of life – the recognized threshold in the United States is a cost of $50,000 or less/QALY. That means that $3,000/QALY is highly cost effective," said Jan B. Pietzsch, Ph.D., the lead investigator of the analysis. "It’s a very low incremental cost-effectiveness ratio compared with other innovative treatments," he said in an interview.

The model that Dr. Geisler, Dr. Pietzsch, and their associates produced estimated a sizeable impact that this blood-pressure reduction would have on improved survival, and on a reduced incidence of several cardiovascular disease end points presuming that the reduced blood pressure was sustained for 10 years, or for the rest of a patient’s life. For example, they estimated that over the 10 years following treatment, renal denervation would cut the incidence of stroke by 3.4 percentage points, the rate of coronary heart disease by 5.4 percentage points, the rate of cardiovascular mortality by 3.8 percentage points, and all-cause death by 3.5 percentage points. They also calculated an increase in median survival of 1.3 years.

They calculated a discounted, lifetime incremental cost-effectiveness ratio of $3,071/QALY. In addition, they found this incremental cost per quality-adjusted life-year was "quite robust" across a range of stating blood pressures, said Dr. Pietzsch, president of Wing Tech, a consulting company based in the United States and Germany.

At starting blood pressures of less than 172 mm Hg, renal denervation was actually cost saving. At a baseline pressure of 172 mm Hg or greater the cost per QALY increased steadily with baseline pressure, to a maximum or about $7,000/QALY in patients who had a systolic blood pressure of 200 mm Hg at the time they underwent renal denervation.

Dr. Pietzsch, Dr. Geisler, and another coauthors work for Wing Tech Inc., which provided consultant services to Medtronic Ardian to construct this health-economic model. (Medtronic Ardian is the company that markets the Symplicity catheter.) Another coauthor received salary support from Medtronic Ardian, a second coauthor received consultancy payments and travel expenses from Medtronic Ardian, and a third coauthor serves on the board of a group that received funding from Medtronic.

Official Recommendations Start Mainstreaming RD

The strikingly successful track record of RD so far led the European Society of Hypertension to last May issue recommendations on using the treatment in routine practice (J. Hypertens. 2012;30:837-41). The Society endorsed routinely treating patients who match the criteria for having dangerously high, treatment-resistant hypertension similar to the criteria that have been used in the Symplicity trials and other recent RD studies.

But investigator-driven research protocols at several European centers are now even moving beyond these criteria, as patients with milder levels of drug-resistant hypertension also clamor for RD.

"We are moving to treat less severe hypertension, but within a clinical study," said Dr. Roland E. Schmieder, professor of medicine and vice chairman of nephrology and hypertension at the University Hospital in Erlangen, Germany. He also stressed that these studies will still continue to exclude patients with impaired renal function at baseline. "Everyone in Germany agrees the focus must be on treatment-resistant hypertension, when physicians feel they have no other choice to offer patients. But as you move into patients with less severe hypertension you increase the need for hard–end-point trials" that are better able to prove an overall net benefit to patients from RD, he said in an interview.

"We have a lot of safety data" for RD, but long-term follow-up is still limited. "We don’t have experience with what happens when [RD-treated] patients become critically ill. They may still need some renal innervation to prevent traumatic shock," he said. "There are still unanswered safety questions, but so far the main concern, renal function, has improved" following RD.

Another caution about treating milder hypertension is that the treatment effect will generally be smaller than what’s seen in patients with more severe hypertension.

But Dr. Schmieder shares the enthusiasm of many of his colleagues who believe they now have an effective new tool for treating hypertension.

"Renal denervation is a very important step forward, because hypertension is killer No. 1 worldwide, and no new antihypertensive drugs are on the horizon," he said. We don’t expect any new antihypertensive drugs for at least the next 10 years. To have this new option is important, both for treating patients and to help increase awareness of the disease."

The Symplicity trials have been sponsored by Ardian, which first developed the Symplicity renal denervation catheter, and by Medtronic, which acquired Ardian and now produces and markets the catheter. Dr. Brady, Dr. Táborský, Mr. Franzen, Dr. Fischer, and Dr. Gonzalez-Juanatey did not have any relevant disclosures. Dr. Böhm, Dr. Esler, Dr. Mahfoud, and Dr. Schmieder said that they have received research, travel, and consultancy funding from Medtronic and Ardian. Dr. Mahfoud said that he has also received research funding from Vessix Vascular and ReCor Medical Technology, companies that are developing other devices for renal denervation.

MUNICH – Renal denervation remains investigational in the United States, where a large clinical trial testing its safety and efficacy is now in progress.

But in Europe, Australia, and elsewhere, renal denervation – an intravascular procedure that zaps the sympathetic innervation in a patient’s renal arteries with a few pulses of radiofrequency energy – is rapidly becoming the big new thing for treating patients with drug-resistant hypertension since marketing of a denervation catheter began in April 2010.

As of last spring, Medtronic, the company that sells the only renal denervation (RD) catheter currently commercially available, estimated that the 5,000th patient had been treated by RD, although Dr. Michael Böhm, who oversees what might be the most active RD program in the world, recently put his estimate upwards of 10,000 patients treated worldwide. Among the smaller number of closely followed patients included in this experience with reported outcomes data, perhaps 300-500 patients, the results have been striking: A drop in office blood pressure on the order of 28/10 mm Hg in patients who began treatment with pressures in the 180/100 mm Hg ballpark (despite treatment with as many as six antihypertensive drugs), that has been durable over follow-up as long as 36 months, with response rates among patients that rise over time and run over 90% once patients are followed longer than a year, and uniform reports of good safety during 6-36 months’ follow-up, with no evidence of impaired renal function or arterial sclerosis over time or other untoward effects.

And now emerging in new reports, both recently published and presented at the meeting in August, are hints of several effects beyond simple blood pressure reduction that hold promise for expanding the application of RD beyond just antihypertensive treatment and broadening the recognized benefits of this treatment.

RD "is a transformative area for treating hypertension, and now heart failure" and other disorders, commented Dr. Adrian Brady, a cardiologist and hypertension specialist in Glasgow, Scotland.

More Than Just Blood Pressure

Among the newest findings was a report on a small, controlled study with 43 normotensive patients with New York Heart Association class III or IV heart failure that showed RD could significantly raise left ventricular ejection fraction, reduce left ventricular end-systolic and end-diastolic volume index, and cut serum levels of brain natriuretic peptide during 12 months of follow-up. RD had these positive effects on surrogate markers of heart failure severity without causing hypotension or other adverse effects, and the treatment also cut the rate of heart failure hospitalizations over 12 months by more than half, although the study wasn’t powered to examine this end point, reported Dr. Milos Táborský, a cardiologist at Olomouc University Hospital in the Czech Republic.

For example, left ventricular ejection fraction rose from an average of 25% at baseline to an average of 31% 12 months after RD, compared with a 2% change in the control patients, a statistically significant difference, Dr. Táborský said.

In short, RD worked in normotensive patients with heart failure similar to a beta-blocker drug that cuts neurohormonal activation, commented Dr. José-Ramon Gonzalez-Juanatey, director of the cardiovascular department at the University Hospital of Santiago de Compostela in Spain. "This technique opens a new era in treating heart failure by decreasing sympathetic tone," he said.

In a similar vein, results reported at the meeting from another small, controlled study with 27 treatment-resistant hypertensive patients showed that by 6 months after RD, the treatment had significantly improved aortic augmentation index and aortic pulse-wave velocity, two markers of central vascular stiffness and central blood pressure. The average 1 m/sec improvement seen in aortic pulse-wave velocity 6 months after RD, reflecting a roughly 10% reduction in aortic stiffness, corresponds to about a10-year drop in the patients’ vascular age, said Klaas F. Franzen, a researcher at Schleswig-Holstein University Hospital in Lübeck, Germany.

"The idea is that by reducing whole-body sympathetic activity, you reduce vasoconstriction, and induce vasodilation in the renal arteries and central arteries," commented Dr. Felix Mahfoud, a cardiologist at Saarland University Hospital in Homburg, Germany.

The benefits from RD are not just cardiovascular. Another report at the meeting came from serial psychologic tests administered before and after 119 patients with drug-resistant hypertension underwent RD. In addition to producing an average drop in office blood pressure of 20/10 mm Hg, at both 3 and 6 months after treatment, RD also led to statistically and clinically significant drops in stress reaction, as measured on the Wiener Determination Task. In addition, among the roughly 20% of patients in the group of 119 who had clinically meaningful levels of anxiety or depression at baseline, RD also produced statistically and clinically significant falls in both anxiety and depression at both 3 and 6 months after treatment, reported Denise Fischer, Ph.D., a psychologist at Saarland University Hospital.

Another facet of her study looked at headache severity and found that at 3 and 6 months following RD all patients had statistically significant drops in headache intensity, and among the 20% of patients who entered the study with headaches self-rated as worse than 4 on a 0-10 visual analog scale, headache intensity fell from an average of about 8 before treatment to an average of less than 4 at 6 months after RD, Dr. Fischer said.

Follow-Ups to 18 Months, and Beyond

The most thorough assessment so far of RD as an antihypertensive treatment came in the Symplicity HTN-2 trial, a multicenter, multinational trial that randomized 106 patients with drug-resistant hypertension. In the 6-month results from the study, the primary end point showed that among 49 patients who underwent RD, office blood pressure fell by an average of 32/12 mm Hg, compared with virtually no change among 51 controls (Lancet 2010;376:1903-9).

During the August meeting, researchers from the study reported follow-up data, which included 18-month results from 43 patients in the original intervention arm of the study and from an additional 31 patients originally randomized to the control arm but who crossed over to RD treatment after the first 6 months.

The 18-month results showed stability of the initial blood pressure reduction in both subgroups of patients, with average reductions in office blood pressure remaining at 32/12 mm Hg compared with baseline in the 43 patients from the original intervention arm, and an average 28/11 mm Hg cut in office pressure in the 31 crossover patients, compared with their baseline levels, said Dr. Murray D. Esler, professor of medicine at Monash University in Melbourne, and lead investigator for the study. Patients in the initially treated arm also had an average 7 beats/min reduction in heart rate, compared with baseline that was statistically significant.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following renal denervation.   --Dr. Michael Böhm.

For safety, the 18 month results showed "no signal that renal function was harmed," he said. One patient had a renal-artery dissection early in the study, caused by the stiff catheter tip used at the study’s start but since replaced with a more flexible tip, Dr. Esler said. Other safety events during follow-up included one episode of hypotension that required hospitalization, one "mild" incidence of "transient" acute renal failure, and two deaths unrelated to RD.

Dr. Esler and his collaborators also cited the 36-month follow-up results on 24 patients from the initial, uncontrolled study of RD using the Symplicity catheter, the Symplicity HTN1 study (Lancet 2009;373:1275-81). These patients continue to show a durable blood pressure response and no signs of adverse effects, renal or otherwise, in this small number of patients followed for a prolonged period, said Dr. Böhm, director of internal medicine at Saarland University Hospital. (The 3-year follow-up of these 24 patients was first reported last March at the annual scientific session of the American College of Cardiology.) A very encouraging finding was that among the small number of patients followed this long, the percentage of patients with clinically important blood pressure drops continued to accumulate, so that at 36 months 99% of treated patients responded, Dr. Böhm said.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following RD, he said. "How long will [their response] last? No one knows, but if it lasts for at least 3 years, you can then justify a redo," a repeat treatment, although he also cautioned that so far, he knows of no patient who has undergone RD a second time.

In addition to the new evidence for pleiotropic effects from RD reported at the meeting, recently published reports from small studies provided preliminary documentation of other possible benefits. For example:

• RD led to a significantly reduced prevalence of albuminuria during 6-month follow-up in a study with 88 treated patients with drug-resistant hypertension (Hypertension 2012;60:419-24).

• RD led to significant improvements in glucose metabolism and insulin sensitivity during 3-month follow-up in a study with 37 treated patients with drug-resistant hypertension (Circulation 2011;123:1940-6).

• RD produced a reduction in blood pressure during exercise without affecting chronotropic competence during 3-month follow-up of 37 treated patients with drug-resistant hypertension (J. Amer. Coll. Cardiol. 2011;58:1176-83).

Novel Catheter May Speed Procedure Times

The Symplicity renal denervation catheter from Medtronic is not the only such device in clinical use. At the meeting, researchers reported 3-month follow-up results from a series of 46 patients with drug-resistant hypertension treated with a multielectrode catheter from St. Jude at four centers in Greece and Australia.

The main difference between the St. Jude EnligHTN device, which has four separate electrodes at its tip, and the Medtronic device, with a single electrode, is that the St. Jude device can denervate a renal artery with a single placement, as opposed to the four different placements, with rotation, used for the Medtronic device, meaning less arterial manipulation. Whether this will produce any discernable difference in safety, efficacy, or procedure time remains unclear.

The study enrolled patients with persistent hypertension, with an office systolic pressure above 160 mm Hg (150 mm Hg in patients with diabetes), despite treatment with at least three antihypertensive drugs, including at least one diuretic (similar enrollment criteria as the Symplicity studies). The patients’ averaged 60 years old, and their pressures averaged 176/98 mm Hg.

Average procedure time was 34 minutes, reported Dr. Costas Tsioufis, a professor of cardiology at the University of Athens, which may be modestly faster than the usual procedure time using the Symplicity catheter, which operators often estimate to require 40-50 minutes. Data from a series of 344 patients treated with the Symplicity catheter at Saarland University Hospital in Homburg showed an average procedure time of 44 minutes, said Dr. Felix Mahfoud, a cardiologist there.

Renal Denervation Shown Highly Cost Effective

Although renal denervation has an estimated up-front cost of about $12,500, the long-term benefits of the blood pressure reduction it usually produces are so potent that the treatment winds up costing about $3,000 for each additional quality-adjusted life-year it confers on patients, based on a cost-effectiveness analysis of data from the Symplicity HTN-2 trial.

This level of cost effectiveness is "more than an order of magnitude below the recognized threshold of $50,000/QALY [quality-adjusted life-year]," and provides fairly compelling evidence that "catheter-based renal denervation therapy is a cost-effective treatment strategy for resistant hypertension," Dr. Benjamin P. Geisler and his associates wrote in a report published online in September (J. Am. Coll. Cardiol. 2012 [doi:10.1016/j.jacc.2012.07.029]).

They based their cost-effectiveness model on data collected in the Symplicity HTN-2 trial (Lancet 2010;376:1903-9), described in the main story.

"When you look at societal decision making – how much a society is willing to pay for improved quality of life and increased duration of life – the recognized threshold in the United States is a cost of $50,000 or less/QALY. That means that $3,000/QALY is highly cost effective," said Jan B. Pietzsch, Ph.D., the lead investigator of the analysis. "It’s a very low incremental cost-effectiveness ratio compared with other innovative treatments," he said in an interview.

The model that Dr. Geisler, Dr. Pietzsch, and their associates produced estimated a sizeable impact that this blood-pressure reduction would have on improved survival, and on a reduced incidence of several cardiovascular disease end points presuming that the reduced blood pressure was sustained for 10 years, or for the rest of a patient’s life. For example, they estimated that over the 10 years following treatment, renal denervation would cut the incidence of stroke by 3.4 percentage points, the rate of coronary heart disease by 5.4 percentage points, the rate of cardiovascular mortality by 3.8 percentage points, and all-cause death by 3.5 percentage points. They also calculated an increase in median survival of 1.3 years.

They calculated a discounted, lifetime incremental cost-effectiveness ratio of $3,071/QALY. In addition, they found this incremental cost per quality-adjusted life-year was "quite robust" across a range of stating blood pressures, said Dr. Pietzsch, president of Wing Tech, a consulting company based in the United States and Germany.

At starting blood pressures of less than 172 mm Hg, renal denervation was actually cost saving. At a baseline pressure of 172 mm Hg or greater the cost per QALY increased steadily with baseline pressure, to a maximum or about $7,000/QALY in patients who had a systolic blood pressure of 200 mm Hg at the time they underwent renal denervation.

Dr. Pietzsch, Dr. Geisler, and another coauthors work for Wing Tech Inc., which provided consultant services to Medtronic Ardian to construct this health-economic model. (Medtronic Ardian is the company that markets the Symplicity catheter.) Another coauthor received salary support from Medtronic Ardian, a second coauthor received consultancy payments and travel expenses from Medtronic Ardian, and a third coauthor serves on the board of a group that received funding from Medtronic.

Official Recommendations Start Mainstreaming RD

The strikingly successful track record of RD so far led the European Society of Hypertension to last May issue recommendations on using the treatment in routine practice (J. Hypertens. 2012;30:837-41). The Society endorsed routinely treating patients who match the criteria for having dangerously high, treatment-resistant hypertension similar to the criteria that have been used in the Symplicity trials and other recent RD studies.

But investigator-driven research protocols at several European centers are now even moving beyond these criteria, as patients with milder levels of drug-resistant hypertension also clamor for RD.

"We are moving to treat less severe hypertension, but within a clinical study," said Dr. Roland E. Schmieder, professor of medicine and vice chairman of nephrology and hypertension at the University Hospital in Erlangen, Germany. He also stressed that these studies will still continue to exclude patients with impaired renal function at baseline. "Everyone in Germany agrees the focus must be on treatment-resistant hypertension, when physicians feel they have no other choice to offer patients. But as you move into patients with less severe hypertension you increase the need for hard–end-point trials" that are better able to prove an overall net benefit to patients from RD, he said in an interview.

"We have a lot of safety data" for RD, but long-term follow-up is still limited. "We don’t have experience with what happens when [RD-treated] patients become critically ill. They may still need some renal innervation to prevent traumatic shock," he said. "There are still unanswered safety questions, but so far the main concern, renal function, has improved" following RD.

Another caution about treating milder hypertension is that the treatment effect will generally be smaller than what’s seen in patients with more severe hypertension.

But Dr. Schmieder shares the enthusiasm of many of his colleagues who believe they now have an effective new tool for treating hypertension.

"Renal denervation is a very important step forward, because hypertension is killer No. 1 worldwide, and no new antihypertensive drugs are on the horizon," he said. We don’t expect any new antihypertensive drugs for at least the next 10 years. To have this new option is important, both for treating patients and to help increase awareness of the disease."

The Symplicity trials have been sponsored by Ardian, which first developed the Symplicity renal denervation catheter, and by Medtronic, which acquired Ardian and now produces and markets the catheter. Dr. Brady, Dr. Táborský, Mr. Franzen, Dr. Fischer, and Dr. Gonzalez-Juanatey did not have any relevant disclosures. Dr. Böhm, Dr. Esler, Dr. Mahfoud, and Dr. Schmieder said that they have received research, travel, and consultancy funding from Medtronic and Ardian. Dr. Mahfoud said that he has also received research funding from Vessix Vascular and ReCor Medical Technology, companies that are developing other devices for renal denervation.

MUNICH – Renal denervation remains investigational in the United States, where a large clinical trial testing its safety and efficacy is now in progress.

But in Europe, Australia, and elsewhere, renal denervation – an intravascular procedure that zaps the sympathetic innervation in a patient’s renal arteries with a few pulses of radiofrequency energy – is rapidly becoming the big new thing for treating patients with drug-resistant hypertension since marketing of a denervation catheter began in April 2010.

As of last spring, Medtronic, the company that sells the only renal denervation (RD) catheter currently commercially available, estimated that the 5,000th patient had been treated by RD, although Dr. Michael Böhm, who oversees what might be the most active RD program in the world, recently put his estimate upwards of 10,000 patients treated worldwide. Among the smaller number of closely followed patients included in this experience with reported outcomes data, perhaps 300-500 patients, the results have been striking: A drop in office blood pressure on the order of 28/10 mm Hg in patients who began treatment with pressures in the 180/100 mm Hg ballpark (despite treatment with as many as six antihypertensive drugs), that has been durable over follow-up as long as 36 months, with response rates among patients that rise over time and run over 90% once patients are followed longer than a year, and uniform reports of good safety during 6-36 months’ follow-up, with no evidence of impaired renal function or arterial sclerosis over time or other untoward effects.

And now emerging in new reports, both recently published and presented at the meeting in August, are hints of several effects beyond simple blood pressure reduction that hold promise for expanding the application of RD beyond just antihypertensive treatment and broadening the recognized benefits of this treatment.

RD "is a transformative area for treating hypertension, and now heart failure" and other disorders, commented Dr. Adrian Brady, a cardiologist and hypertension specialist in Glasgow, Scotland.

More Than Just Blood Pressure

Among the newest findings was a report on a small, controlled study with 43 normotensive patients with New York Heart Association class III or IV heart failure that showed RD could significantly raise left ventricular ejection fraction, reduce left ventricular end-systolic and end-diastolic volume index, and cut serum levels of brain natriuretic peptide during 12 months of follow-up. RD had these positive effects on surrogate markers of heart failure severity without causing hypotension or other adverse effects, and the treatment also cut the rate of heart failure hospitalizations over 12 months by more than half, although the study wasn’t powered to examine this end point, reported Dr. Milos Táborský, a cardiologist at Olomouc University Hospital in the Czech Republic.

For example, left ventricular ejection fraction rose from an average of 25% at baseline to an average of 31% 12 months after RD, compared with a 2% change in the control patients, a statistically significant difference, Dr. Táborský said.

In short, RD worked in normotensive patients with heart failure similar to a beta-blocker drug that cuts neurohormonal activation, commented Dr. José-Ramon Gonzalez-Juanatey, director of the cardiovascular department at the University Hospital of Santiago de Compostela in Spain. "This technique opens a new era in treating heart failure by decreasing sympathetic tone," he said.

In a similar vein, results reported at the meeting from another small, controlled study with 27 treatment-resistant hypertensive patients showed that by 6 months after RD, the treatment had significantly improved aortic augmentation index and aortic pulse-wave velocity, two markers of central vascular stiffness and central blood pressure. The average 1 m/sec improvement seen in aortic pulse-wave velocity 6 months after RD, reflecting a roughly 10% reduction in aortic stiffness, corresponds to about a10-year drop in the patients’ vascular age, said Klaas F. Franzen, a researcher at Schleswig-Holstein University Hospital in Lübeck, Germany.

"The idea is that by reducing whole-body sympathetic activity, you reduce vasoconstriction, and induce vasodilation in the renal arteries and central arteries," commented Dr. Felix Mahfoud, a cardiologist at Saarland University Hospital in Homburg, Germany.

The benefits from RD are not just cardiovascular. Another report at the meeting came from serial psychologic tests administered before and after 119 patients with drug-resistant hypertension underwent RD. In addition to producing an average drop in office blood pressure of 20/10 mm Hg, at both 3 and 6 months after treatment, RD also led to statistically and clinically significant drops in stress reaction, as measured on the Wiener Determination Task. In addition, among the roughly 20% of patients in the group of 119 who had clinically meaningful levels of anxiety or depression at baseline, RD also produced statistically and clinically significant falls in both anxiety and depression at both 3 and 6 months after treatment, reported Denise Fischer, Ph.D., a psychologist at Saarland University Hospital.

Another facet of her study looked at headache severity and found that at 3 and 6 months following RD all patients had statistically significant drops in headache intensity, and among the 20% of patients who entered the study with headaches self-rated as worse than 4 on a 0-10 visual analog scale, headache intensity fell from an average of about 8 before treatment to an average of less than 4 at 6 months after RD, Dr. Fischer said.

Follow-Ups to 18 Months, and Beyond

The most thorough assessment so far of RD as an antihypertensive treatment came in the Symplicity HTN-2 trial, a multicenter, multinational trial that randomized 106 patients with drug-resistant hypertension. In the 6-month results from the study, the primary end point showed that among 49 patients who underwent RD, office blood pressure fell by an average of 32/12 mm Hg, compared with virtually no change among 51 controls (Lancet 2010;376:1903-9).

During the August meeting, researchers from the study reported follow-up data, which included 18-month results from 43 patients in the original intervention arm of the study and from an additional 31 patients originally randomized to the control arm but who crossed over to RD treatment after the first 6 months.

The 18-month results showed stability of the initial blood pressure reduction in both subgroups of patients, with average reductions in office blood pressure remaining at 32/12 mm Hg compared with baseline in the 43 patients from the original intervention arm, and an average 28/11 mm Hg cut in office pressure in the 31 crossover patients, compared with their baseline levels, said Dr. Murray D. Esler, professor of medicine at Monash University in Melbourne, and lead investigator for the study. Patients in the initially treated arm also had an average 7 beats/min reduction in heart rate, compared with baseline that was statistically significant.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following renal denervation.   --Dr. Michael Böhm.

For safety, the 18 month results showed "no signal that renal function was harmed," he said. One patient had a renal-artery dissection early in the study, caused by the stiff catheter tip used at the study’s start but since replaced with a more flexible tip, Dr. Esler said. Other safety events during follow-up included one episode of hypotension that required hospitalization, one "mild" incidence of "transient" acute renal failure, and two deaths unrelated to RD.

Dr. Esler and his collaborators also cited the 36-month follow-up results on 24 patients from the initial, uncontrolled study of RD using the Symplicity catheter, the Symplicity HTN1 study (Lancet 2009;373:1275-81). These patients continue to show a durable blood pressure response and no signs of adverse effects, renal or otherwise, in this small number of patients followed for a prolonged period, said Dr. Böhm, director of internal medicine at Saarland University Hospital. (The 3-year follow-up of these 24 patients was first reported last March at the annual scientific session of the American College of Cardiology.) A very encouraging finding was that among the small number of patients followed this long, the percentage of patients with clinically important blood pressure drops continued to accumulate, so that at 36 months 99% of treated patients responded, Dr. Böhm said.

"In our experience at Saarland University Hospital with more than 400 patients, they all achieved a blood pressure response" following RD, he said. "How long will [their response] last? No one knows, but if it lasts for at least 3 years, you can then justify a redo," a repeat treatment, although he also cautioned that so far, he knows of no patient who has undergone RD a second time.

In addition to the new evidence for pleiotropic effects from RD reported at the meeting, recently published reports from small studies provided preliminary documentation of other possible benefits. For example:

• RD led to a significantly reduced prevalence of albuminuria during 6-month follow-up in a study with 88 treated patients with drug-resistant hypertension (Hypertension 2012;60:419-24).

• RD led to significant improvements in glucose metabolism and insulin sensitivity during 3-month follow-up in a study with 37 treated patients with drug-resistant hypertension (Circulation 2011;123:1940-6).

• RD produced a reduction in blood pressure during exercise without affecting chronotropic competence during 3-month follow-up of 37 treated patients with drug-resistant hypertension (J. Amer. Coll. Cardiol. 2011;58:1176-83).

Novel Catheter May Speed Procedure Times

The Symplicity renal denervation catheter from Medtronic is not the only such device in clinical use. At the meeting, researchers reported 3-month follow-up results from a series of 46 patients with drug-resistant hypertension treated with a multielectrode catheter from St. Jude at four centers in Greece and Australia.

The main difference between the St. Jude EnligHTN device, which has four separate electrodes at its tip, and the Medtronic device, with a single electrode, is that the St. Jude device can denervate a renal artery with a single placement, as opposed to the four different placements, with rotation, used for the Medtronic device, meaning less arterial manipulation. Whether this will produce any discernable difference in safety, efficacy, or procedure time remains unclear.

The study enrolled patients with persistent hypertension, with an office systolic pressure above 160 mm Hg (150 mm Hg in patients with diabetes), despite treatment with at least three antihypertensive drugs, including at least one diuretic (similar enrollment criteria as the Symplicity studies). The patients’ averaged 60 years old, and their pressures averaged 176/98 mm Hg.

Average procedure time was 34 minutes, reported Dr. Costas Tsioufis, a professor of cardiology at the University of Athens, which may be modestly faster than the usual procedure time using the Symplicity catheter, which operators often estimate to require 40-50 minutes. Data from a series of 344 patients treated with the Symplicity catheter at Saarland University Hospital in Homburg showed an average procedure time of 44 minutes, said Dr. Felix Mahfoud, a cardiologist there.

Renal Denervation Shown Highly Cost Effective

Although renal denervation has an estimated up-front cost of about $12,500, the long-term benefits of the blood pressure reduction it usually produces are so potent that the treatment winds up costing about $3,000 for each additional quality-adjusted life-year it confers on patients, based on a cost-effectiveness analysis of data from the Symplicity HTN-2 trial.

This level of cost effectiveness is "more than an order of magnitude below the recognized threshold of $50,000/QALY [quality-adjusted life-year]," and provides fairly compelling evidence that "catheter-based renal denervation therapy is a cost-effective treatment strategy for resistant hypertension," Dr. Benjamin P. Geisler and his associates wrote in a report published online in September (J. Am. Coll. Cardiol. 2012 [doi:10.1016/j.jacc.2012.07.029]).

They based their cost-effectiveness model on data collected in the Symplicity HTN-2 trial (Lancet 2010;376:1903-9), described in the main story.

"When you look at societal decision making – how much a society is willing to pay for improved quality of life and increased duration of life – the recognized threshold in the United States is a cost of $50,000 or less/QALY. That means that $3,000/QALY is highly cost effective," said Jan B. Pietzsch, Ph.D., the lead investigator of the analysis. "It’s a very low incremental cost-effectiveness ratio compared with other innovative treatments," he said in an interview.

The model that Dr. Geisler, Dr. Pietzsch, and their associates produced estimated a sizeable impact that this blood-pressure reduction would have on improved survival, and on a reduced incidence of several cardiovascular disease end points presuming that the reduced blood pressure was sustained for 10 years, or for the rest of a patient’s life. For example, they estimated that over the 10 years following treatment, renal denervation would cut the incidence of stroke by 3.4 percentage points, the rate of coronary heart disease by 5.4 percentage points, the rate of cardiovascular mortality by 3.8 percentage points, and all-cause death by 3.5 percentage points. They also calculated an increase in median survival of 1.3 years.

They calculated a discounted, lifetime incremental cost-effectiveness ratio of $3,071/QALY. In addition, they found this incremental cost per quality-adjusted life-year was "quite robust" across a range of stating blood pressures, said Dr. Pietzsch, president of Wing Tech, a consulting company based in the United States and Germany.

At starting blood pressures of less than 172 mm Hg, renal denervation was actually cost saving. At a baseline pressure of 172 mm Hg or greater the cost per QALY increased steadily with baseline pressure, to a maximum or about $7,000/QALY in patients who had a systolic blood pressure of 200 mm Hg at the time they underwent renal denervation.

Dr. Pietzsch, Dr. Geisler, and another coauthors work for Wing Tech Inc., which provided consultant services to Medtronic Ardian to construct this health-economic model. (Medtronic Ardian is the company that markets the Symplicity catheter.) Another coauthor received salary support from Medtronic Ardian, a second coauthor received consultancy payments and travel expenses from Medtronic Ardian, and a third coauthor serves on the board of a group that received funding from Medtronic.

Official Recommendations Start Mainstreaming RD

The strikingly successful track record of RD so far led the European Society of Hypertension to last May issue recommendations on using the treatment in routine practice (J. Hypertens. 2012;30:837-41). The Society endorsed routinely treating patients who match the criteria for having dangerously high, treatment-resistant hypertension similar to the criteria that have been used in the Symplicity trials and other recent RD studies.

But investigator-driven research protocols at several European centers are now even moving beyond these criteria, as patients with milder levels of drug-resistant hypertension also clamor for RD.

"We are moving to treat less severe hypertension, but within a clinical study," said Dr. Roland E. Schmieder, professor of medicine and vice chairman of nephrology and hypertension at the University Hospital in Erlangen, Germany. He also stressed that these studies will still continue to exclude patients with impaired renal function at baseline. "Everyone in Germany agrees the focus must be on treatment-resistant hypertension, when physicians feel they have no other choice to offer patients. But as you move into patients with less severe hypertension you increase the need for hard–end-point trials" that are better able to prove an overall net benefit to patients from RD, he said in an interview.

"We have a lot of safety data" for RD, but long-term follow-up is still limited. "We don’t have experience with what happens when [RD-treated] patients become critically ill. They may still need some renal innervation to prevent traumatic shock," he said. "There are still unanswered safety questions, but so far the main concern, renal function, has improved" following RD.

Another caution about treating milder hypertension is that the treatment effect will generally be smaller than what’s seen in patients with more severe hypertension.

But Dr. Schmieder shares the enthusiasm of many of his colleagues who believe they now have an effective new tool for treating hypertension.

"Renal denervation is a very important step forward, because hypertension is killer No. 1 worldwide, and no new antihypertensive drugs are on the horizon," he said. We don’t expect any new antihypertensive drugs for at least the next 10 years. To have this new option is important, both for treating patients and to help increase awareness of the disease."

The Symplicity trials have been sponsored by Ardian, which first developed the Symplicity renal denervation catheter, and by Medtronic, which acquired Ardian and now produces and markets the catheter. Dr. Brady, Dr. Táborský, Mr. Franzen, Dr. Fischer, and Dr. Gonzalez-Juanatey did not have any relevant disclosures. Dr. Böhm, Dr. Esler, Dr. Mahfoud, and Dr. Schmieder said that they have received research, travel, and consultancy funding from Medtronic and Ardian. Dr. Mahfoud said that he has also received research funding from Vessix Vascular and ReCor Medical Technology, companies that are developing other devices for renal denervation.