Mitchel L. Zoler, PhD

PARIS  – At least three different factors undermined the SYMPLICITY HTN-3 trial that earlier this year did not show a significant difference in blood pressure lowering between renal denervation and a sham-control procedure, most notably the failure of the vast majority of operators in the study to follow ablation instructions and produce thorough and reliable interruptions of sympathetic innervation of the kidneys, according to new data released by the trial’s investigators.

As the full range of problems with the U.S.-based SYMPLICITY HTN-3 trial, which had its main results reported in April (N. Engl. J. Med. 2014;370:1393-1401), became apparent in a report at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, many top European practitioners and supporters of renal denervation voiced their belief that the treatment is an effective and safe option for many patients with true drug-resistant, severe hypertension.

The only qualifications they now add are that renal denervation is not easily performed and must be done carefully and in a more targeted way, with an ongoing need to find the patients best suited for treatment and the best methods for delivering treatment.

During the meeting, Dr. Felix Mahfoud, an interventional cardiologist at the University Hospital of Saarland in Homburg/Saar, Germany, joined with hypertension specialist Dr. Konstantinos Tsioufis of the University of Athens and Dr. William Wijns, codirector of EuroPCR, in an official statement from the meeting that despite the SYMPLICITY HTN-3 results they continued to support renal denervation as a treatment option for selected patients with drug-resistant, severe hypertension.

Their sentiment echoed another endorsement made a few weeks earlier for continued use and study of renal denervation from the European Society of Hypertension (ESH) in reaction to the SYMPLICITY HTN-3 results.

Mitchel L. Zoler/Frontline Medical News

The ESH "sticks to its statement" from 2013 on using renal denervation in appropriate patients with treatment-resistant, severe hypertension (Eurointervention 2013;9:R58-R66), said Dr. Roland E. Schmieder, first author for the 2013 ESH position paper and a leader in European use of renal denervation.

"We need more studies to prove that renal denervation works, and in particular to get more precise information on which patients get the greatest benefit," Dr. Schmieder said in a separate talk at the meeting. For the time being, he said he was comfortable with routine use of renal denervation in patients with an office systolic BP of at least 160 mm Hg that remains at this level despite maximally tolerated treatment with at least three antihypertensive drugs, including a diuretic, the use endorsed by current European guidelines. It remains appropriate to investigate the impact of renal denervation on other disorders, such as heart failure, arrhythmia, metabolic syndrome, and depressed renal function, said Dr. Schmieder, professor and head of hypertension and vascular medicine research at University Hospital in Erlangen, Germany.

The problems with SYMPLICITY HTN-3

While much speculation swirled around what had gone wrong in the SYMPLICITY HTN-3 trial after researchers on the study gave their first report on the results early in the spring, the full extent of the study’s problems didn’t flesh out until a follow-up report during EuroPCR by coinvestigator Dr. David E. Kandzari. In his analysis, Dr. Kandzari highlighted three distinct problems with the trial that he and his associates identified in a series of post hoc analyses:

• The failure of a large minority of enrolled patients in both arms of the study to remain on a stable medical regimen during the 6 months of follow-up before the primary efficacy outcomes were measured.

• The inexplicably large reduction in BP among the sham-control patients, especially among African American patients, who made up a quarter of the trial’s population.

• The vastly incomplete nerve-ablation treatment that most patients received, treatments that usually failed to meet the standards specified in the trial’s protocol.

The background medical regimens that patients received proved unstable during SYMPLICITY HTN-3 even though the study design mandated that patients be on a stable regimen for at least 2 weeks before entering the study. Roughly 80% of enrolled patients in both the denervation and sham-control arms of the study had been on a stable regimen for at least 6 weeks before they entered. Despite that, during the 6 months of follow-up, 211 (39%) of patients in the study underwent a change in their medication regimen. The changes occurred at virtually identical rates in both study arms, and in more than two-thirds of cases were driven by medical necessity.

Mitchel L. Zoler/Frontline Medical News

"The pattern of drug changes challenges the notion of maximally tolerated therapy," Dr. Kandzari said during his report. "Can this [maximally tolerated therapy] be sustained in a randomized, controlled trial?" It also raised the issues of how trial design can better limit drug changes.

 

Even though it remains unclear why blood pressure reduction was so pronounced among the African Americans in the sham-control group, the impact of this unexpected effect substantially upended the trial’s endpoints. Among the 49 African Americans randomized to sham treatment, office-measured systolic pressure dropped by an average of 17.8 mm Hg, far exceeding the 8.6–mm Hg decline seen among the non–African Americans in the control arm and even exceeding the average 15.5–mm Hg drop in office systolic BP among African Americans treated with renal denervation.

"The absolute reduction in blood pressure by renal denervation in African Americans was identical to non–African Americans." The problem that arose "related more to what happened in the sham-control group of African Americans, who had a nearly 18–mm Hg reduction in blood pressure," said Dr. Kandzari, chief scientific officer and director of interventional cardiology at Piedmont Heart Institute in Atlanta.

The low rate at which patients assigned to receive renal denervation actually received the type of treatment spelled out in the study’s protocol may have been the biggest problem of all, although Dr. Kandzari stressed that, in his opinion "no single factor led to the neutral efficacy seen in the study."

The supplementary methods section of the SYMPLICITY HTN-3 report published in April explicitly called for patients to receive "4-6 ablations" per side, delivering them in a spiral, circumferential pattern starting distally in each renal artery. That meant each patient was to receive a minimum of eight total ablations.

But analysis of data recorded independently by the research nurse and by the proctor during each procedure, as well as cineangiography films made and submitted by the operator for each ablation, clearly showed that many patients did not receive the treatment that the protocol spelled out. Synthesis of the data collected by the three methods showed that about half of the 364 patients randomized to renal denervation received at least eight ablations, while the other half did not receive this minimum number.

The three separate sets of ablation records also contained information on whether ablations occurred in the anterior, posterior, superior, or inferior quadrants of each renal artery. Full circumferential ablation, what the protocol prescribed, required an ablation in at least one of each of these quadrants per side. What actually happened was that 253 patients (70%) received no circumferential ablations, 68 patients (19%) received circumferential ablation on just one side, and 19 patients (5%) received the bilateral circumferential ablations that the protocol called for. Data for the remaining 24 patients treated with renal denervation were not amenable to analysis for this parameter.

As might be expected, greater ablation number and completeness strongly linked with a robust blood pressure effect.

Among patients who received at least eight ablations, office systolic pressure fell by an average 13.1 mm Hg. But among the nine patients who received 16 or more ablations, the average systolic BP reduction at 6 months was 30.9 mm Hg. Among the 18 patients who received at least 15 ablations, the average systolic pressure reduction was 25.4 mm Hg. A very similar relationship occurred for BPs measured by ambulatory monitoring (see graphic), and the data also suggested a positive link between an increasing number of ablations and an increased effect on heart rate. The consistency of the association across all three measures lent further support to this as a real relationship, Dr. Kandzari noted.

Circumferentiality of the ablations showed a similar pattern. The average office systolic pressure fall in patients with no circumferential ablations was 14.2 mm Hg, and it was 16.1 mm Hg in patients who received just one circumferential ablation. But in the 19 patients who received circumferential ablations bilaterally, the average office systolic pressure reduction was 24.3 mm Hg, with a similar pattern seen for ambulatory measures as well as for home-based BP measurements.

"All patients randomized to renal denervation received renal denervation, but they may not have received it in a fashion that seemed to translate into a greater blood pressure reduction," Dr. Kandzari concluded.

Who to treat, where to treat, how to treat

"One result of the neutral HTN-3 result was a call to revisit the basic science behind renal denervation. The clinical enthusiasm had exceeded the science behind renal denervation," Dr. Kandzari observed.

Renal denervation’s many European advocates seem to agree, and have begun the process of determining characteristics of the best patients to receive renal denervation and where and how ablations are best delivered within the renal artery to achieve interruption of sympathetic innervation, although the targeting information they have right now is rudimentary.

 

"Probably most important is patient selection. You must be sure to get the right patient, one with high sympathetic activity, because the treatment lowers sympathetic activity," said Dr. Atul Pathak, an interventional cardiologist at Paul Sabatier University in Toulouse, France.

Some clues for patient selection have come from the Global SYMPLICITY Registry, which is enrolling patients treated with renal denervation at more than 200 experienced centers worldwide, many of them in Germany but also elsewhere in Europe, Australia, Canada, Korea, and other locations. Initial findings from the first 1,000 patients entered into the registry and followed for 6 months came out in March at the annual meeting of the American College of Cardiology, and Dr. Mahfoud presented new analyses of the data at EuroPCR.

"The major concern we had when we started renal denervation was its safety. I believe the safety issue is now answered," especially with the data collected in the global registry as well as in the SYMPLICITY HTN-3 trial, by far the largest trial completed for the procedure, said Dr. Thomas Zeller, professor and head of clinical and interventional angiology at the Heart Center in Bad Krozingen, Germany. "I was concerned that we might harm the renal arteries with long-lasting stenosis or embolic showers, but this does not happen, at least with the Symplicity catheter," he said during a talk at the meeting.

"The number of patients suitable for renal denervation is potentially much smaller than we initially expected. Real drug resistance is rare, poor adherence is common, and the Symplicity catheter is technically challenging and not effective in every patient. It is hard to rotate the catheter in the tortuous iliac arteries that some patients with hypertension have; the anatomic conditions of hypertension may not be suited to the Symplicity flex catheter," said Dr. Zeller, who added that he has performed renal denervations with the Symplicity catheter since 2009.

"We should focus on the patients that the HTN-3 trial identified as responders, including patients younger than 65, and patients on an aldosterone antagonist," he suggested in a talk at the meeting.

Finding the right patients and the right ablation targets

In the SYMPLICITY HTN-3 trial, 123 (23%) of the 535 patients remained severely hypertensive despite treatment with an aldosterone antagonist such as spironolactone at the time of entry into the study. In this subgroup, renal denervation produced an average 8.1–mm Hg additional reduction in office systolic BP compared with the average reduction seen among the sham-control patients, a much larger effect than the average 3.2–mm Hg incremental reduction by renal denervation over control seen in the patients who were not on an aldosterone antagonist at baseline, Dr. Manesh Patel reported in a talk at the meeting.

One possible explanation for this effect is that "these patients were resistant to an aldosterone antagonist and hence have a good chance of having high sympathetic activity," explained Dr. Patel, director of interventional cardiology at Duke University in Durham, N.C., and a coinvestigator on the SYMPLICITY HTN-3 trial. Another possibility is that "aldosterone antagonist use is a marker for patients who have been treated in a hypertension clinic to receive this fourth-line agent," and hence are more likely to have true drug-resistant hypertension, he added. More recent analyses of the HTN-3 results also showed that the 38% of patients who entered the study while on treatment with a vasodilator had absolutely no added benefit from renal denervation compared with the sham controls, while in the patients not on a vasodilator renal denervation produced an average 6.7–mm Hg reduction in office systolic BP compared with control patients, a statistically significant difference.

"We must accept that currently denervation is a ‘black box’ procedure. You deliver energy and you hope blood pressure goes down, but the main confounder is we are not sure if we have damaged the nerve fibers," Dr. Mahfoud said.

According to data he compiled, the depth of ablation penetration varies by device, with several devices including the Symplicity producing an ablation depth of 3 mm, while a few other systems produce ablation depths of 4 mm or even 6 mm.

Results from autopsy studies he analyzed suggested that afferent nerve density closer to the renal-artery lumen is highest in the distal section of the renal artery compared with the more proximal side, and that the posterior and anterior quadrants of the distal renal artery harbor a higher concentration of nerve fibers closer to the lumen than the superior and inferior quadrants.

This information begins to define the "sweet spot" for applying denervation energy, Dr. Mahfoud said. When he performs renal denervation today "we go even more distally, into the branches [off the distal renal arteries] if they are large enough" to accommodate the catheter. "Nerves are not equally distributed over the entire renal artery," and ideally this information should help guide ablation placements, he said.

 

The global divide in renal denervation use

The inability of the SYMPLICITY HTN-3 trial to prove the treatment’s efficacy has further divided use of renal denervation by geography. The technology remains unapproved for U.S. use, and will remain that way until another large, sham-controlled trial finishes and shows a clear benefit for BP reduction. In contrast, the procedure’s use in Europe seems on track to continue and grow further, although European thought leaders urge caution and further research to identify the best denervation techniques and optimal patients.

European leaders such as Dr. Mahfoud and Dr. Schmieder also see great promise in using renal denervation for other types of patients, such as those with heart failure or arrhythmias. Just one example of the wide-ranging effects examined for renal denervation was a report Dr. Mahfoud cited published earlier this year that focused on changes in left ventricular mass in 55 patients with resistant hypertension who underwent renal denervation. The results collected by Dr. Mahfoud and his associates showed that even when patients experienced little or no change in their systolic BP they often had substantial reductions in left ventricular mass (Eur. Heart J. 2014 March 6 [doi:10.1093/eurheartj/ehu093]).

"Reducing systolic blood pressure by 10 mm Hg [in patients with severe, drug-resistant hypertension] would have a massive impact, so renal denervation remains an important tool for potentially benefiting patients with uncontrolled hypertension," Dr. Wijns, codirector of the Cardiovascular Center in Aalst, Belgium, said in an interview.

But the renal denervation tool that is increasingly seen as important by the cardiovascular disease leadership in Europe will remain beyond the reach of U.S. physicians for some time to come.

The SYMPLICITY HTN-3 trial and the Global SYMPLICITY Registry were sponsored by Medtronic, which markets the Symplicity catheter. All of the sources for this article have received speaker fees, consulting fees, and/or research grants from Medtronic and numerous other medical device, drug, or biotechnology companies.

mzoler@frontinemedcom.com

On Twitter @mitchelzoler

PARIS  – At least three different factors undermined the SYMPLICITY HTN-3 trial that earlier this year did not show a significant difference in blood pressure lowering between renal denervation and a sham-control procedure, most notably the failure of the vast majority of operators in the study to follow ablation instructions and produce thorough and reliable interruptions of sympathetic innervation of the kidneys, according to new data released by the trial’s investigators.

As the full range of problems with the U.S.-based SYMPLICITY HTN-3 trial, which had its main results reported in April (N. Engl. J. Med. 2014;370:1393-1401), became apparent in a report at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, many top European practitioners and supporters of renal denervation voiced their belief that the treatment is an effective and safe option for many patients with true drug-resistant, severe hypertension.

The only qualifications they now add are that renal denervation is not easily performed and must be done carefully and in a more targeted way, with an ongoing need to find the patients best suited for treatment and the best methods for delivering treatment.

During the meeting, Dr. Felix Mahfoud, an interventional cardiologist at the University Hospital of Saarland in Homburg/Saar, Germany, joined with hypertension specialist Dr. Konstantinos Tsioufis of the University of Athens and Dr. William Wijns, codirector of EuroPCR, in an official statement from the meeting that despite the SYMPLICITY HTN-3 results they continued to support renal denervation as a treatment option for selected patients with drug-resistant, severe hypertension.

Their sentiment echoed another endorsement made a few weeks earlier for continued use and study of renal denervation from the European Society of Hypertension (ESH) in reaction to the SYMPLICITY HTN-3 results.

Mitchel L. Zoler/Frontline Medical News

The ESH "sticks to its statement" from 2013 on using renal denervation in appropriate patients with treatment-resistant, severe hypertension (Eurointervention 2013;9:R58-R66), said Dr. Roland E. Schmieder, first author for the 2013 ESH position paper and a leader in European use of renal denervation.

"We need more studies to prove that renal denervation works, and in particular to get more precise information on which patients get the greatest benefit," Dr. Schmieder said in a separate talk at the meeting. For the time being, he said he was comfortable with routine use of renal denervation in patients with an office systolic BP of at least 160 mm Hg that remains at this level despite maximally tolerated treatment with at least three antihypertensive drugs, including a diuretic, the use endorsed by current European guidelines. It remains appropriate to investigate the impact of renal denervation on other disorders, such as heart failure, arrhythmia, metabolic syndrome, and depressed renal function, said Dr. Schmieder, professor and head of hypertension and vascular medicine research at University Hospital in Erlangen, Germany.

The problems with SYMPLICITY HTN-3

While much speculation swirled around what had gone wrong in the SYMPLICITY HTN-3 trial after researchers on the study gave their first report on the results early in the spring, the full extent of the study’s problems didn’t flesh out until a follow-up report during EuroPCR by coinvestigator Dr. David E. Kandzari. In his analysis, Dr. Kandzari highlighted three distinct problems with the trial that he and his associates identified in a series of post hoc analyses:

• The failure of a large minority of enrolled patients in both arms of the study to remain on a stable medical regimen during the 6 months of follow-up before the primary efficacy outcomes were measured.

• The inexplicably large reduction in BP among the sham-control patients, especially among African American patients, who made up a quarter of the trial’s population.

• The vastly incomplete nerve-ablation treatment that most patients received, treatments that usually failed to meet the standards specified in the trial’s protocol.

The background medical regimens that patients received proved unstable during SYMPLICITY HTN-3 even though the study design mandated that patients be on a stable regimen for at least 2 weeks before entering the study. Roughly 80% of enrolled patients in both the denervation and sham-control arms of the study had been on a stable regimen for at least 6 weeks before they entered. Despite that, during the 6 months of follow-up, 211 (39%) of patients in the study underwent a change in their medication regimen. The changes occurred at virtually identical rates in both study arms, and in more than two-thirds of cases were driven by medical necessity.

Mitchel L. Zoler/Frontline Medical News

"The pattern of drug changes challenges the notion of maximally tolerated therapy," Dr. Kandzari said during his report. "Can this [maximally tolerated therapy] be sustained in a randomized, controlled trial?" It also raised the issues of how trial design can better limit drug changes.

 

Even though it remains unclear why blood pressure reduction was so pronounced among the African Americans in the sham-control group, the impact of this unexpected effect substantially upended the trial’s endpoints. Among the 49 African Americans randomized to sham treatment, office-measured systolic pressure dropped by an average of 17.8 mm Hg, far exceeding the 8.6–mm Hg decline seen among the non–African Americans in the control arm and even exceeding the average 15.5–mm Hg drop in office systolic BP among African Americans treated with renal denervation.

"The absolute reduction in blood pressure by renal denervation in African Americans was identical to non–African Americans." The problem that arose "related more to what happened in the sham-control group of African Americans, who had a nearly 18–mm Hg reduction in blood pressure," said Dr. Kandzari, chief scientific officer and director of interventional cardiology at Piedmont Heart Institute in Atlanta.

The low rate at which patients assigned to receive renal denervation actually received the type of treatment spelled out in the study’s protocol may have been the biggest problem of all, although Dr. Kandzari stressed that, in his opinion "no single factor led to the neutral efficacy seen in the study."

The supplementary methods section of the SYMPLICITY HTN-3 report published in April explicitly called for patients to receive "4-6 ablations" per side, delivering them in a spiral, circumferential pattern starting distally in each renal artery. That meant each patient was to receive a minimum of eight total ablations.

But analysis of data recorded independently by the research nurse and by the proctor during each procedure, as well as cineangiography films made and submitted by the operator for each ablation, clearly showed that many patients did not receive the treatment that the protocol spelled out. Synthesis of the data collected by the three methods showed that about half of the 364 patients randomized to renal denervation received at least eight ablations, while the other half did not receive this minimum number.

The three separate sets of ablation records also contained information on whether ablations occurred in the anterior, posterior, superior, or inferior quadrants of each renal artery. Full circumferential ablation, what the protocol prescribed, required an ablation in at least one of each of these quadrants per side. What actually happened was that 253 patients (70%) received no circumferential ablations, 68 patients (19%) received circumferential ablation on just one side, and 19 patients (5%) received the bilateral circumferential ablations that the protocol called for. Data for the remaining 24 patients treated with renal denervation were not amenable to analysis for this parameter.

As might be expected, greater ablation number and completeness strongly linked with a robust blood pressure effect.

Among patients who received at least eight ablations, office systolic pressure fell by an average 13.1 mm Hg. But among the nine patients who received 16 or more ablations, the average systolic BP reduction at 6 months was 30.9 mm Hg. Among the 18 patients who received at least 15 ablations, the average systolic pressure reduction was 25.4 mm Hg. A very similar relationship occurred for BPs measured by ambulatory monitoring (see graphic), and the data also suggested a positive link between an increasing number of ablations and an increased effect on heart rate. The consistency of the association across all three measures lent further support to this as a real relationship, Dr. Kandzari noted.

Circumferentiality of the ablations showed a similar pattern. The average office systolic pressure fall in patients with no circumferential ablations was 14.2 mm Hg, and it was 16.1 mm Hg in patients who received just one circumferential ablation. But in the 19 patients who received circumferential ablations bilaterally, the average office systolic pressure reduction was 24.3 mm Hg, with a similar pattern seen for ambulatory measures as well as for home-based BP measurements.

"All patients randomized to renal denervation received renal denervation, but they may not have received it in a fashion that seemed to translate into a greater blood pressure reduction," Dr. Kandzari concluded.

Who to treat, where to treat, how to treat

"One result of the neutral HTN-3 result was a call to revisit the basic science behind renal denervation. The clinical enthusiasm had exceeded the science behind renal denervation," Dr. Kandzari observed.

Renal denervation’s many European advocates seem to agree, and have begun the process of determining characteristics of the best patients to receive renal denervation and where and how ablations are best delivered within the renal artery to achieve interruption of sympathetic innervation, although the targeting information they have right now is rudimentary.

 

"Probably most important is patient selection. You must be sure to get the right patient, one with high sympathetic activity, because the treatment lowers sympathetic activity," said Dr. Atul Pathak, an interventional cardiologist at Paul Sabatier University in Toulouse, France.

Some clues for patient selection have come from the Global SYMPLICITY Registry, which is enrolling patients treated with renal denervation at more than 200 experienced centers worldwide, many of them in Germany but also elsewhere in Europe, Australia, Canada, Korea, and other locations. Initial findings from the first 1,000 patients entered into the registry and followed for 6 months came out in March at the annual meeting of the American College of Cardiology, and Dr. Mahfoud presented new analyses of the data at EuroPCR.

"The major concern we had when we started renal denervation was its safety. I believe the safety issue is now answered," especially with the data collected in the global registry as well as in the SYMPLICITY HTN-3 trial, by far the largest trial completed for the procedure, said Dr. Thomas Zeller, professor and head of clinical and interventional angiology at the Heart Center in Bad Krozingen, Germany. "I was concerned that we might harm the renal arteries with long-lasting stenosis or embolic showers, but this does not happen, at least with the Symplicity catheter," he said during a talk at the meeting.

"The number of patients suitable for renal denervation is potentially much smaller than we initially expected. Real drug resistance is rare, poor adherence is common, and the Symplicity catheter is technically challenging and not effective in every patient. It is hard to rotate the catheter in the tortuous iliac arteries that some patients with hypertension have; the anatomic conditions of hypertension may not be suited to the Symplicity flex catheter," said Dr. Zeller, who added that he has performed renal denervations with the Symplicity catheter since 2009.

"We should focus on the patients that the HTN-3 trial identified as responders, including patients younger than 65, and patients on an aldosterone antagonist," he suggested in a talk at the meeting.

Finding the right patients and the right ablation targets

In the SYMPLICITY HTN-3 trial, 123 (23%) of the 535 patients remained severely hypertensive despite treatment with an aldosterone antagonist such as spironolactone at the time of entry into the study. In this subgroup, renal denervation produced an average 8.1–mm Hg additional reduction in office systolic BP compared with the average reduction seen among the sham-control patients, a much larger effect than the average 3.2–mm Hg incremental reduction by renal denervation over control seen in the patients who were not on an aldosterone antagonist at baseline, Dr. Manesh Patel reported in a talk at the meeting.

One possible explanation for this effect is that "these patients were resistant to an aldosterone antagonist and hence have a good chance of having high sympathetic activity," explained Dr. Patel, director of interventional cardiology at Duke University in Durham, N.C., and a coinvestigator on the SYMPLICITY HTN-3 trial. Another possibility is that "aldosterone antagonist use is a marker for patients who have been treated in a hypertension clinic to receive this fourth-line agent," and hence are more likely to have true drug-resistant hypertension, he added. More recent analyses of the HTN-3 results also showed that the 38% of patients who entered the study while on treatment with a vasodilator had absolutely no added benefit from renal denervation compared with the sham controls, while in the patients not on a vasodilator renal denervation produced an average 6.7–mm Hg reduction in office systolic BP compared with control patients, a statistically significant difference.

"We must accept that currently denervation is a ‘black box’ procedure. You deliver energy and you hope blood pressure goes down, but the main confounder is we are not sure if we have damaged the nerve fibers," Dr. Mahfoud said.

According to data he compiled, the depth of ablation penetration varies by device, with several devices including the Symplicity producing an ablation depth of 3 mm, while a few other systems produce ablation depths of 4 mm or even 6 mm.

Results from autopsy studies he analyzed suggested that afferent nerve density closer to the renal-artery lumen is highest in the distal section of the renal artery compared with the more proximal side, and that the posterior and anterior quadrants of the distal renal artery harbor a higher concentration of nerve fibers closer to the lumen than the superior and inferior quadrants.

This information begins to define the "sweet spot" for applying denervation energy, Dr. Mahfoud said. When he performs renal denervation today "we go even more distally, into the branches [off the distal renal arteries] if they are large enough" to accommodate the catheter. "Nerves are not equally distributed over the entire renal artery," and ideally this information should help guide ablation placements, he said.

 

The global divide in renal denervation use

The inability of the SYMPLICITY HTN-3 trial to prove the treatment’s efficacy has further divided use of renal denervation by geography. The technology remains unapproved for U.S. use, and will remain that way until another large, sham-controlled trial finishes and shows a clear benefit for BP reduction. In contrast, the procedure’s use in Europe seems on track to continue and grow further, although European thought leaders urge caution and further research to identify the best denervation techniques and optimal patients.

European leaders such as Dr. Mahfoud and Dr. Schmieder also see great promise in using renal denervation for other types of patients, such as those with heart failure or arrhythmias. Just one example of the wide-ranging effects examined for renal denervation was a report Dr. Mahfoud cited published earlier this year that focused on changes in left ventricular mass in 55 patients with resistant hypertension who underwent renal denervation. The results collected by Dr. Mahfoud and his associates showed that even when patients experienced little or no change in their systolic BP they often had substantial reductions in left ventricular mass (Eur. Heart J. 2014 March 6 [doi:10.1093/eurheartj/ehu093]).

"Reducing systolic blood pressure by 10 mm Hg [in patients with severe, drug-resistant hypertension] would have a massive impact, so renal denervation remains an important tool for potentially benefiting patients with uncontrolled hypertension," Dr. Wijns, codirector of the Cardiovascular Center in Aalst, Belgium, said in an interview.

But the renal denervation tool that is increasingly seen as important by the cardiovascular disease leadership in Europe will remain beyond the reach of U.S. physicians for some time to come.

The SYMPLICITY HTN-3 trial and the Global SYMPLICITY Registry were sponsored by Medtronic, which markets the Symplicity catheter. All of the sources for this article have received speaker fees, consulting fees, and/or research grants from Medtronic and numerous other medical device, drug, or biotechnology companies.

mzoler@frontinemedcom.com

On Twitter @mitchelzoler

PARIS  – At least three different factors undermined the SYMPLICITY HTN-3 trial that earlier this year did not show a significant difference in blood pressure lowering between renal denervation and a sham-control procedure, most notably the failure of the vast majority of operators in the study to follow ablation instructions and produce thorough and reliable interruptions of sympathetic innervation of the kidneys, according to new data released by the trial’s investigators.

As the full range of problems with the U.S.-based SYMPLICITY HTN-3 trial, which had its main results reported in April (N. Engl. J. Med. 2014;370:1393-1401), became apparent in a report at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, many top European practitioners and supporters of renal denervation voiced their belief that the treatment is an effective and safe option for many patients with true drug-resistant, severe hypertension.

The only qualifications they now add are that renal denervation is not easily performed and must be done carefully and in a more targeted way, with an ongoing need to find the patients best suited for treatment and the best methods for delivering treatment.

During the meeting, Dr. Felix Mahfoud, an interventional cardiologist at the University Hospital of Saarland in Homburg/Saar, Germany, joined with hypertension specialist Dr. Konstantinos Tsioufis of the University of Athens and Dr. William Wijns, codirector of EuroPCR, in an official statement from the meeting that despite the SYMPLICITY HTN-3 results they continued to support renal denervation as a treatment option for selected patients with drug-resistant, severe hypertension.

Their sentiment echoed another endorsement made a few weeks earlier for continued use and study of renal denervation from the European Society of Hypertension (ESH) in reaction to the SYMPLICITY HTN-3 results.

Mitchel L. Zoler/Frontline Medical News

The ESH "sticks to its statement" from 2013 on using renal denervation in appropriate patients with treatment-resistant, severe hypertension (Eurointervention 2013;9:R58-R66), said Dr. Roland E. Schmieder, first author for the 2013 ESH position paper and a leader in European use of renal denervation.

"We need more studies to prove that renal denervation works, and in particular to get more precise information on which patients get the greatest benefit," Dr. Schmieder said in a separate talk at the meeting. For the time being, he said he was comfortable with routine use of renal denervation in patients with an office systolic BP of at least 160 mm Hg that remains at this level despite maximally tolerated treatment with at least three antihypertensive drugs, including a diuretic, the use endorsed by current European guidelines. It remains appropriate to investigate the impact of renal denervation on other disorders, such as heart failure, arrhythmia, metabolic syndrome, and depressed renal function, said Dr. Schmieder, professor and head of hypertension and vascular medicine research at University Hospital in Erlangen, Germany.

The problems with SYMPLICITY HTN-3

While much speculation swirled around what had gone wrong in the SYMPLICITY HTN-3 trial after researchers on the study gave their first report on the results early in the spring, the full extent of the study’s problems didn’t flesh out until a follow-up report during EuroPCR by coinvestigator Dr. David E. Kandzari. In his analysis, Dr. Kandzari highlighted three distinct problems with the trial that he and his associates identified in a series of post hoc analyses:

• The failure of a large minority of enrolled patients in both arms of the study to remain on a stable medical regimen during the 6 months of follow-up before the primary efficacy outcomes were measured.

• The inexplicably large reduction in BP among the sham-control patients, especially among African American patients, who made up a quarter of the trial’s population.

• The vastly incomplete nerve-ablation treatment that most patients received, treatments that usually failed to meet the standards specified in the trial’s protocol.

The background medical regimens that patients received proved unstable during SYMPLICITY HTN-3 even though the study design mandated that patients be on a stable regimen for at least 2 weeks before entering the study. Roughly 80% of enrolled patients in both the denervation and sham-control arms of the study had been on a stable regimen for at least 6 weeks before they entered. Despite that, during the 6 months of follow-up, 211 (39%) of patients in the study underwent a change in their medication regimen. The changes occurred at virtually identical rates in both study arms, and in more than two-thirds of cases were driven by medical necessity.

Mitchel L. Zoler/Frontline Medical News

"The pattern of drug changes challenges the notion of maximally tolerated therapy," Dr. Kandzari said during his report. "Can this [maximally tolerated therapy] be sustained in a randomized, controlled trial?" It also raised the issues of how trial design can better limit drug changes.

 

Even though it remains unclear why blood pressure reduction was so pronounced among the African Americans in the sham-control group, the impact of this unexpected effect substantially upended the trial’s endpoints. Among the 49 African Americans randomized to sham treatment, office-measured systolic pressure dropped by an average of 17.8 mm Hg, far exceeding the 8.6–mm Hg decline seen among the non–African Americans in the control arm and even exceeding the average 15.5–mm Hg drop in office systolic BP among African Americans treated with renal denervation.

"The absolute reduction in blood pressure by renal denervation in African Americans was identical to non–African Americans." The problem that arose "related more to what happened in the sham-control group of African Americans, who had a nearly 18–mm Hg reduction in blood pressure," said Dr. Kandzari, chief scientific officer and director of interventional cardiology at Piedmont Heart Institute in Atlanta.

The low rate at which patients assigned to receive renal denervation actually received the type of treatment spelled out in the study’s protocol may have been the biggest problem of all, although Dr. Kandzari stressed that, in his opinion "no single factor led to the neutral efficacy seen in the study."

The supplementary methods section of the SYMPLICITY HTN-3 report published in April explicitly called for patients to receive "4-6 ablations" per side, delivering them in a spiral, circumferential pattern starting distally in each renal artery. That meant each patient was to receive a minimum of eight total ablations.

But analysis of data recorded independently by the research nurse and by the proctor during each procedure, as well as cineangiography films made and submitted by the operator for each ablation, clearly showed that many patients did not receive the treatment that the protocol spelled out. Synthesis of the data collected by the three methods showed that about half of the 364 patients randomized to renal denervation received at least eight ablations, while the other half did not receive this minimum number.

The three separate sets of ablation records also contained information on whether ablations occurred in the anterior, posterior, superior, or inferior quadrants of each renal artery. Full circumferential ablation, what the protocol prescribed, required an ablation in at least one of each of these quadrants per side. What actually happened was that 253 patients (70%) received no circumferential ablations, 68 patients (19%) received circumferential ablation on just one side, and 19 patients (5%) received the bilateral circumferential ablations that the protocol called for. Data for the remaining 24 patients treated with renal denervation were not amenable to analysis for this parameter.

As might be expected, greater ablation number and completeness strongly linked with a robust blood pressure effect.

Among patients who received at least eight ablations, office systolic pressure fell by an average 13.1 mm Hg. But among the nine patients who received 16 or more ablations, the average systolic BP reduction at 6 months was 30.9 mm Hg. Among the 18 patients who received at least 15 ablations, the average systolic pressure reduction was 25.4 mm Hg. A very similar relationship occurred for BPs measured by ambulatory monitoring (see graphic), and the data also suggested a positive link between an increasing number of ablations and an increased effect on heart rate. The consistency of the association across all three measures lent further support to this as a real relationship, Dr. Kandzari noted.

Circumferentiality of the ablations showed a similar pattern. The average office systolic pressure fall in patients with no circumferential ablations was 14.2 mm Hg, and it was 16.1 mm Hg in patients who received just one circumferential ablation. But in the 19 patients who received circumferential ablations bilaterally, the average office systolic pressure reduction was 24.3 mm Hg, with a similar pattern seen for ambulatory measures as well as for home-based BP measurements.

"All patients randomized to renal denervation received renal denervation, but they may not have received it in a fashion that seemed to translate into a greater blood pressure reduction," Dr. Kandzari concluded.

Who to treat, where to treat, how to treat

"One result of the neutral HTN-3 result was a call to revisit the basic science behind renal denervation. The clinical enthusiasm had exceeded the science behind renal denervation," Dr. Kandzari observed.

Renal denervation’s many European advocates seem to agree, and have begun the process of determining characteristics of the best patients to receive renal denervation and where and how ablations are best delivered within the renal artery to achieve interruption of sympathetic innervation, although the targeting information they have right now is rudimentary.

 

"Probably most important is patient selection. You must be sure to get the right patient, one with high sympathetic activity, because the treatment lowers sympathetic activity," said Dr. Atul Pathak, an interventional cardiologist at Paul Sabatier University in Toulouse, France.

Some clues for patient selection have come from the Global SYMPLICITY Registry, which is enrolling patients treated with renal denervation at more than 200 experienced centers worldwide, many of them in Germany but also elsewhere in Europe, Australia, Canada, Korea, and other locations. Initial findings from the first 1,000 patients entered into the registry and followed for 6 months came out in March at the annual meeting of the American College of Cardiology, and Dr. Mahfoud presented new analyses of the data at EuroPCR.

"The major concern we had when we started renal denervation was its safety. I believe the safety issue is now answered," especially with the data collected in the global registry as well as in the SYMPLICITY HTN-3 trial, by far the largest trial completed for the procedure, said Dr. Thomas Zeller, professor and head of clinical and interventional angiology at the Heart Center in Bad Krozingen, Germany. "I was concerned that we might harm the renal arteries with long-lasting stenosis or embolic showers, but this does not happen, at least with the Symplicity catheter," he said during a talk at the meeting.

"The number of patients suitable for renal denervation is potentially much smaller than we initially expected. Real drug resistance is rare, poor adherence is common, and the Symplicity catheter is technically challenging and not effective in every patient. It is hard to rotate the catheter in the tortuous iliac arteries that some patients with hypertension have; the anatomic conditions of hypertension may not be suited to the Symplicity flex catheter," said Dr. Zeller, who added that he has performed renal denervations with the Symplicity catheter since 2009.

"We should focus on the patients that the HTN-3 trial identified as responders, including patients younger than 65, and patients on an aldosterone antagonist," he suggested in a talk at the meeting.

Finding the right patients and the right ablation targets

In the SYMPLICITY HTN-3 trial, 123 (23%) of the 535 patients remained severely hypertensive despite treatment with an aldosterone antagonist such as spironolactone at the time of entry into the study. In this subgroup, renal denervation produced an average 8.1–mm Hg additional reduction in office systolic BP compared with the average reduction seen among the sham-control patients, a much larger effect than the average 3.2–mm Hg incremental reduction by renal denervation over control seen in the patients who were not on an aldosterone antagonist at baseline, Dr. Manesh Patel reported in a talk at the meeting.

One possible explanation for this effect is that "these patients were resistant to an aldosterone antagonist and hence have a good chance of having high sympathetic activity," explained Dr. Patel, director of interventional cardiology at Duke University in Durham, N.C., and a coinvestigator on the SYMPLICITY HTN-3 trial. Another possibility is that "aldosterone antagonist use is a marker for patients who have been treated in a hypertension clinic to receive this fourth-line agent," and hence are more likely to have true drug-resistant hypertension, he added. More recent analyses of the HTN-3 results also showed that the 38% of patients who entered the study while on treatment with a vasodilator had absolutely no added benefit from renal denervation compared with the sham controls, while in the patients not on a vasodilator renal denervation produced an average 6.7–mm Hg reduction in office systolic BP compared with control patients, a statistically significant difference.

"We must accept that currently denervation is a ‘black box’ procedure. You deliver energy and you hope blood pressure goes down, but the main confounder is we are not sure if we have damaged the nerve fibers," Dr. Mahfoud said.

According to data he compiled, the depth of ablation penetration varies by device, with several devices including the Symplicity producing an ablation depth of 3 mm, while a few other systems produce ablation depths of 4 mm or even 6 mm.

Results from autopsy studies he analyzed suggested that afferent nerve density closer to the renal-artery lumen is highest in the distal section of the renal artery compared with the more proximal side, and that the posterior and anterior quadrants of the distal renal artery harbor a higher concentration of nerve fibers closer to the lumen than the superior and inferior quadrants.

This information begins to define the "sweet spot" for applying denervation energy, Dr. Mahfoud said. When he performs renal denervation today "we go even more distally, into the branches [off the distal renal arteries] if they are large enough" to accommodate the catheter. "Nerves are not equally distributed over the entire renal artery," and ideally this information should help guide ablation placements, he said.

 

The global divide in renal denervation use

The inability of the SYMPLICITY HTN-3 trial to prove the treatment’s efficacy has further divided use of renal denervation by geography. The technology remains unapproved for U.S. use, and will remain that way until another large, sham-controlled trial finishes and shows a clear benefit for BP reduction. In contrast, the procedure’s use in Europe seems on track to continue and grow further, although European thought leaders urge caution and further research to identify the best denervation techniques and optimal patients.

European leaders such as Dr. Mahfoud and Dr. Schmieder also see great promise in using renal denervation for other types of patients, such as those with heart failure or arrhythmias. Just one example of the wide-ranging effects examined for renal denervation was a report Dr. Mahfoud cited published earlier this year that focused on changes in left ventricular mass in 55 patients with resistant hypertension who underwent renal denervation. The results collected by Dr. Mahfoud and his associates showed that even when patients experienced little or no change in their systolic BP they often had substantial reductions in left ventricular mass (Eur. Heart J. 2014 March 6 [doi:10.1093/eurheartj/ehu093]).

"Reducing systolic blood pressure by 10 mm Hg [in patients with severe, drug-resistant hypertension] would have a massive impact, so renal denervation remains an important tool for potentially benefiting patients with uncontrolled hypertension," Dr. Wijns, codirector of the Cardiovascular Center in Aalst, Belgium, said in an interview.

But the renal denervation tool that is increasingly seen as important by the cardiovascular disease leadership in Europe will remain beyond the reach of U.S. physicians for some time to come.

The SYMPLICITY HTN-3 trial and the Global SYMPLICITY Registry were sponsored by Medtronic, which markets the Symplicity catheter. All of the sources for this article have received speaker fees, consulting fees, and/or research grants from Medtronic and numerous other medical device, drug, or biotechnology companies.

mzoler@frontinemedcom.com

On Twitter @mitchelzoler

PARIS  – A joint European Society of Cardiology and European Association for Cardio-Thoracic Surgery task force that will publish revised revascularization guidelines in late August gave a sneak peak of some important elements of the revision, including renewed endorsement of and a refinement to the heart team concept that was first introduced in the prior, 2010 version of the guidelines.

"One of the most important aspects of the 2010 guidelines was the introduction of the heart team (Eur. Heart J. 2010;31:2501-55) said Dr. Philippe H. Kolh. "In 2010, the heart team concept was still controversial, but I think now it is well accepted. We are further supporting and emphasizing the importance of the heart team," he said of the revised guidelines that will be released in August, during a session that previewed selected parts of the new guidelines at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, an organization that also collaborated on the guidelines.

Mitchel L. Zoler/Frontline Medical News

The revision also calls on each institution where operators perform revascularization to establish local protocols to guide the choice in routine cases between percutaneous coronary interventions (PCIs) or coronary artery bypass grafting (CABG), said Dr. Kolh, a cardiac surgeon at University Hospital in Liège, Belgium, and cochairman of the guideline-writing panel.

"The 2010 guidelines produced a misconception that every patient needs to be discussed by a heart team; the 2014 revision makes it clear that the heart team should develop institutional protocols for appropriate revascularization strategies for different types of patients. So if a patient has single-vessel disease, you can go ahead and do PCI and not wait for a heart-team decision," said Dr. Ulf Landmesser, professor and head of the acute cardiology clinic at University Hospital, Zurich, and a member of the 2014 panel. "Hopefully, it will now be clear that the heart team only needs to discuss complex patients that involve difficult decisions, and that institutional protocols can handle routine cases," Dr. Landmesser said.

The revision comes at a time when "the competition today is not so much between CABG and PCI; the more burning question is who should have revascularization, and how do patients get to the cath lab," noted Dr. Spencer B. King III, an interventional cardiologist at St. Joseph’s Medical Group in Atlanta who was invited to the session to comment on the new revision.

Mitchel L. Zoler/Frontline Medical News

Results from a new meta-analysis highlight the critical role of revascularization relative to medical therapy alone in improving outcomes of patients with coronary artery disease. This finding is especially relevant in 2014, because it marks the 50th anniversary of the launch of revascularization with the first successful CABG performed, observed Dr. Stephan Windecker, professor and chief of cardiology at University Hospital in Bern, Switzerland, and cochairman of the guidelines-writing panel.

He presented an analysis of results from 100 randomized, controlled trials that compared some form of revascularization against medical therapy in 93,553 randomized patients followed for more than 260,000 patient-years. The results showed that CABG cut the rate of all-cause mortality by 20%, compared with medical therapy, a statistically significant difference, and that treatment with new-generation drug-eluting stents produced a significant reduction of more than 25%, according to an as-yet unpublished report by members of the European Myocardial Revascularization Collaborative. Dr. Windecker also noted that all the recommendations in the new revision were approved with 100% consensus by the panel, which included cardiac surgeons, interventional cardiologists, and noninterventional cardiologists in equal numbers.

The session highlighted several other notable new elements in the revised guidelines, although Dr. Windecker stressed several times during the session that everything presented remained pending until the final version is released later this summer. The changes include:

• An "upgrade" of the recommendation for PCI use in patients with left main disease and a SYNTAX score of 23-32 to a IIa, "should be considered" class recommendation, boosted from class III "not recommended" status in 2010. Five-year outcomes from the SYNTAX trial showed "no difference in outcomes between PCI and CABG, a major reason to upgrade the recommendation for PCI," said Dr. Landmesser (Lancet 2013;381:629-38). "The guidelines put a lot of weight on SYNTAX score."

• When performing PCI in patients with non–ST-elevation myocardial infarction (NSTEMI), bivalirudin (Angiomax) is recommended exclusively as the anticoagulant to use during and immediately following PCI – with unfractionated heparin recommended only for patients who cannot receive bivalirudin – based on bivalirudin’s proven reduced risk for causing major bleeds, said Dr. Franz-Josef Neumann, professor and director of the University Heart Center in Bad Krozingen, Germany.

 

• But for patients with ST-elevation MI (STEMI) undergoing primary PCI, unfractionated heparin received the only unqualified, level I recommendation for anticoagulation, with bivalirudin receiving a level IIa, "should be considered" recommendation. This repositioning of the two options occurred, based to some extent on yet unpublished results from a very large, single-center study in Liverpool, HEAT-PPCI, reported at the annual meeting of the American College of Cardiology meeting in March that showed unfractionated heparin outperformed bivalirudin for 28-day outcomes, Dr. Neumann said. "I was very pleased and sort of amazed that results from HEAT-PPCI jumped into the guidelines, and it’s not even published yet. That [recommendation] will have an impact, I suspect," commented Dr. King.

• For patients with either STEMI or NSTEMI, the preferred antiplatelet P2Y₁₂ inhibitors are prasugrel (Effient) and ticagrelor (Brilinta), with clopidogrel reduced to a back-up role "only when prasugrel or ticagrelor are not available," said Dr. Neumann. "I was a little surprised that clopidogrel has fallen off the charts. With the new stents having a low stent thrombosis rate, U.S. physicians tend to stick with clopidogrel; there has been more of a shift in Europe," commented Dr. King. "For elective cases, we still have a clear statement in favor of clopidogrel," countered Dr. Neumann. "It is only for higher risk, acute coronary syndrome and STEMI patients where the guidelines recommend the new agents."

Dr. Kolh said that he has received honoraria from Astra Zeneca and Braun, and research support from Edwards. Dr. Landmesser said that he had no disclosures. Dr. King said that he had no disclosures. Dr. Windecker said that he had received honoraria from, had been a consultant to, or had been a speaker for nine companies and had received research grants from seven companies. Dr. Neumann said that his institution had received research grants from 15 companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

PARIS  – A joint European Society of Cardiology and European Association for Cardio-Thoracic Surgery task force that will publish revised revascularization guidelines in late August gave a sneak peak of some important elements of the revision, including renewed endorsement of and a refinement to the heart team concept that was first introduced in the prior, 2010 version of the guidelines.

"One of the most important aspects of the 2010 guidelines was the introduction of the heart team (Eur. Heart J. 2010;31:2501-55) said Dr. Philippe H. Kolh. "In 2010, the heart team concept was still controversial, but I think now it is well accepted. We are further supporting and emphasizing the importance of the heart team," he said of the revised guidelines that will be released in August, during a session that previewed selected parts of the new guidelines at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, an organization that also collaborated on the guidelines.

Mitchel L. Zoler/Frontline Medical News

The revision also calls on each institution where operators perform revascularization to establish local protocols to guide the choice in routine cases between percutaneous coronary interventions (PCIs) or coronary artery bypass grafting (CABG), said Dr. Kolh, a cardiac surgeon at University Hospital in Liège, Belgium, and cochairman of the guideline-writing panel.

"The 2010 guidelines produced a misconception that every patient needs to be discussed by a heart team; the 2014 revision makes it clear that the heart team should develop institutional protocols for appropriate revascularization strategies for different types of patients. So if a patient has single-vessel disease, you can go ahead and do PCI and not wait for a heart-team decision," said Dr. Ulf Landmesser, professor and head of the acute cardiology clinic at University Hospital, Zurich, and a member of the 2014 panel. "Hopefully, it will now be clear that the heart team only needs to discuss complex patients that involve difficult decisions, and that institutional protocols can handle routine cases," Dr. Landmesser said.

The revision comes at a time when "the competition today is not so much between CABG and PCI; the more burning question is who should have revascularization, and how do patients get to the cath lab," noted Dr. Spencer B. King III, an interventional cardiologist at St. Joseph’s Medical Group in Atlanta who was invited to the session to comment on the new revision.

Mitchel L. Zoler/Frontline Medical News

Results from a new meta-analysis highlight the critical role of revascularization relative to medical therapy alone in improving outcomes of patients with coronary artery disease. This finding is especially relevant in 2014, because it marks the 50th anniversary of the launch of revascularization with the first successful CABG performed, observed Dr. Stephan Windecker, professor and chief of cardiology at University Hospital in Bern, Switzerland, and cochairman of the guidelines-writing panel.

He presented an analysis of results from 100 randomized, controlled trials that compared some form of revascularization against medical therapy in 93,553 randomized patients followed for more than 260,000 patient-years. The results showed that CABG cut the rate of all-cause mortality by 20%, compared with medical therapy, a statistically significant difference, and that treatment with new-generation drug-eluting stents produced a significant reduction of more than 25%, according to an as-yet unpublished report by members of the European Myocardial Revascularization Collaborative. Dr. Windecker also noted that all the recommendations in the new revision were approved with 100% consensus by the panel, which included cardiac surgeons, interventional cardiologists, and noninterventional cardiologists in equal numbers.

The session highlighted several other notable new elements in the revised guidelines, although Dr. Windecker stressed several times during the session that everything presented remained pending until the final version is released later this summer. The changes include:

• An "upgrade" of the recommendation for PCI use in patients with left main disease and a SYNTAX score of 23-32 to a IIa, "should be considered" class recommendation, boosted from class III "not recommended" status in 2010. Five-year outcomes from the SYNTAX trial showed "no difference in outcomes between PCI and CABG, a major reason to upgrade the recommendation for PCI," said Dr. Landmesser (Lancet 2013;381:629-38). "The guidelines put a lot of weight on SYNTAX score."

• When performing PCI in patients with non–ST-elevation myocardial infarction (NSTEMI), bivalirudin (Angiomax) is recommended exclusively as the anticoagulant to use during and immediately following PCI – with unfractionated heparin recommended only for patients who cannot receive bivalirudin – based on bivalirudin’s proven reduced risk for causing major bleeds, said Dr. Franz-Josef Neumann, professor and director of the University Heart Center in Bad Krozingen, Germany.

 

• But for patients with ST-elevation MI (STEMI) undergoing primary PCI, unfractionated heparin received the only unqualified, level I recommendation for anticoagulation, with bivalirudin receiving a level IIa, "should be considered" recommendation. This repositioning of the two options occurred, based to some extent on yet unpublished results from a very large, single-center study in Liverpool, HEAT-PPCI, reported at the annual meeting of the American College of Cardiology meeting in March that showed unfractionated heparin outperformed bivalirudin for 28-day outcomes, Dr. Neumann said. "I was very pleased and sort of amazed that results from HEAT-PPCI jumped into the guidelines, and it’s not even published yet. That [recommendation] will have an impact, I suspect," commented Dr. King.

• For patients with either STEMI or NSTEMI, the preferred antiplatelet P2Y₁₂ inhibitors are prasugrel (Effient) and ticagrelor (Brilinta), with clopidogrel reduced to a back-up role "only when prasugrel or ticagrelor are not available," said Dr. Neumann. "I was a little surprised that clopidogrel has fallen off the charts. With the new stents having a low stent thrombosis rate, U.S. physicians tend to stick with clopidogrel; there has been more of a shift in Europe," commented Dr. King. "For elective cases, we still have a clear statement in favor of clopidogrel," countered Dr. Neumann. "It is only for higher risk, acute coronary syndrome and STEMI patients where the guidelines recommend the new agents."

Dr. Kolh said that he has received honoraria from Astra Zeneca and Braun, and research support from Edwards. Dr. Landmesser said that he had no disclosures. Dr. King said that he had no disclosures. Dr. Windecker said that he had received honoraria from, had been a consultant to, or had been a speaker for nine companies and had received research grants from seven companies. Dr. Neumann said that his institution had received research grants from 15 companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

PARIS  – A joint European Society of Cardiology and European Association for Cardio-Thoracic Surgery task force that will publish revised revascularization guidelines in late August gave a sneak peak of some important elements of the revision, including renewed endorsement of and a refinement to the heart team concept that was first introduced in the prior, 2010 version of the guidelines.

"One of the most important aspects of the 2010 guidelines was the introduction of the heart team (Eur. Heart J. 2010;31:2501-55) said Dr. Philippe H. Kolh. "In 2010, the heart team concept was still controversial, but I think now it is well accepted. We are further supporting and emphasizing the importance of the heart team," he said of the revised guidelines that will be released in August, during a session that previewed selected parts of the new guidelines at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, an organization that also collaborated on the guidelines.

Mitchel L. Zoler/Frontline Medical News

The revision also calls on each institution where operators perform revascularization to establish local protocols to guide the choice in routine cases between percutaneous coronary interventions (PCIs) or coronary artery bypass grafting (CABG), said Dr. Kolh, a cardiac surgeon at University Hospital in Liège, Belgium, and cochairman of the guideline-writing panel.

"The 2010 guidelines produced a misconception that every patient needs to be discussed by a heart team; the 2014 revision makes it clear that the heart team should develop institutional protocols for appropriate revascularization strategies for different types of patients. So if a patient has single-vessel disease, you can go ahead and do PCI and not wait for a heart-team decision," said Dr. Ulf Landmesser, professor and head of the acute cardiology clinic at University Hospital, Zurich, and a member of the 2014 panel. "Hopefully, it will now be clear that the heart team only needs to discuss complex patients that involve difficult decisions, and that institutional protocols can handle routine cases," Dr. Landmesser said.

The revision comes at a time when "the competition today is not so much between CABG and PCI; the more burning question is who should have revascularization, and how do patients get to the cath lab," noted Dr. Spencer B. King III, an interventional cardiologist at St. Joseph’s Medical Group in Atlanta who was invited to the session to comment on the new revision.

Mitchel L. Zoler/Frontline Medical News

Results from a new meta-analysis highlight the critical role of revascularization relative to medical therapy alone in improving outcomes of patients with coronary artery disease. This finding is especially relevant in 2014, because it marks the 50th anniversary of the launch of revascularization with the first successful CABG performed, observed Dr. Stephan Windecker, professor and chief of cardiology at University Hospital in Bern, Switzerland, and cochairman of the guidelines-writing panel.

He presented an analysis of results from 100 randomized, controlled trials that compared some form of revascularization against medical therapy in 93,553 randomized patients followed for more than 260,000 patient-years. The results showed that CABG cut the rate of all-cause mortality by 20%, compared with medical therapy, a statistically significant difference, and that treatment with new-generation drug-eluting stents produced a significant reduction of more than 25%, according to an as-yet unpublished report by members of the European Myocardial Revascularization Collaborative. Dr. Windecker also noted that all the recommendations in the new revision were approved with 100% consensus by the panel, which included cardiac surgeons, interventional cardiologists, and noninterventional cardiologists in equal numbers.

The session highlighted several other notable new elements in the revised guidelines, although Dr. Windecker stressed several times during the session that everything presented remained pending until the final version is released later this summer. The changes include:

• An "upgrade" of the recommendation for PCI use in patients with left main disease and a SYNTAX score of 23-32 to a IIa, "should be considered" class recommendation, boosted from class III "not recommended" status in 2010. Five-year outcomes from the SYNTAX trial showed "no difference in outcomes between PCI and CABG, a major reason to upgrade the recommendation for PCI," said Dr. Landmesser (Lancet 2013;381:629-38). "The guidelines put a lot of weight on SYNTAX score."

• When performing PCI in patients with non–ST-elevation myocardial infarction (NSTEMI), bivalirudin (Angiomax) is recommended exclusively as the anticoagulant to use during and immediately following PCI – with unfractionated heparin recommended only for patients who cannot receive bivalirudin – based on bivalirudin’s proven reduced risk for causing major bleeds, said Dr. Franz-Josef Neumann, professor and director of the University Heart Center in Bad Krozingen, Germany.

 

• But for patients with ST-elevation MI (STEMI) undergoing primary PCI, unfractionated heparin received the only unqualified, level I recommendation for anticoagulation, with bivalirudin receiving a level IIa, "should be considered" recommendation. This repositioning of the two options occurred, based to some extent on yet unpublished results from a very large, single-center study in Liverpool, HEAT-PPCI, reported at the annual meeting of the American College of Cardiology meeting in March that showed unfractionated heparin outperformed bivalirudin for 28-day outcomes, Dr. Neumann said. "I was very pleased and sort of amazed that results from HEAT-PPCI jumped into the guidelines, and it’s not even published yet. That [recommendation] will have an impact, I suspect," commented Dr. King.

• For patients with either STEMI or NSTEMI, the preferred antiplatelet P2Y₁₂ inhibitors are prasugrel (Effient) and ticagrelor (Brilinta), with clopidogrel reduced to a back-up role "only when prasugrel or ticagrelor are not available," said Dr. Neumann. "I was a little surprised that clopidogrel has fallen off the charts. With the new stents having a low stent thrombosis rate, U.S. physicians tend to stick with clopidogrel; there has been more of a shift in Europe," commented Dr. King. "For elective cases, we still have a clear statement in favor of clopidogrel," countered Dr. Neumann. "It is only for higher risk, acute coronary syndrome and STEMI patients where the guidelines recommend the new agents."

Dr. Kolh said that he has received honoraria from Astra Zeneca and Braun, and research support from Edwards. Dr. Landmesser said that he had no disclosures. Dr. King said that he had no disclosures. Dr. Windecker said that he had received honoraria from, had been a consultant to, or had been a speaker for nine companies and had received research grants from seven companies. Dr. Neumann said that his institution had received research grants from 15 companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

PARIS – A drug-eluting balloon produced a stentlike rate of primary patency and need for target vessel revascularization in a multinational, controlled trial with 331 patients with claudication.

The results showed that the paclitaxel-eluting angioplasty balloon used in the study, the IN.PACT model made by Medtronic, has the "potential to become the standard of care" for treating stenoses in the superficial femoral and popliteal arteries, Dr. Marianne Brodmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions. After 1 year, the rate of clinically driven target-vessel revascularizations was 2% in the 220 patients treated with the drug-eluting balloon and 21% in 111 control patients treated with plain balloon angioplasty, a statistically significant difference, reported Dr. Brodmann, professor of angiology at the Medical University of Graz (Austria).*

Mitchel L. Zoler/Frontline Medical News

The results seen in this trial contrast with results from studies of other types of drug-eluting balloons in these arteries, said Dr. Marc Bosiers, head of the department of vascular surgery at St. Blasius Hospital in Dendermonde, Belgium, and a coinvestigator in the study. "What we’ve learned from this trial, if you look at the results from other trials [of drug-eluting balloons], is that not all drug-eluting balloons are equal, just as not all stents are equal," Dr. Bosiers said.

The IN.PACT SFA Trial enrolled 150 patients at 13 centers in Europe and 181 patients at 44 U.S. centers. All patients were adults with Rutherford stage 2, 3, or 4 disease; claudication and rest pain; and a single or closely tandem lesion in the superficial femoral or popliteal arteries with a total length of no more than 18 cm. Their average age was 68, and about 40% had diabetes. The trial protocol allowed provisional stenting, which occurred in 7% of the patients treated with a paclitaxel-eluting balloon and in 13% of those treated with a plain balloon. The average lesion length treated was about 9 cm in both arms of the study.

The study’s primary endpoint was the rate of primary patency at 12 months, defined as freedom from clinically driven target-vessel revascularization and freedom from restenosis assessed by Doppler ultrasound at 12 months, which was 82% in patients treated with the drug-eluting balloon and 52% among patients in the control arm, a statistically significant difference.

The study’s primary safety endpoint was the combined rate of procedure- and device-related death at 30 days, freedom from target-limb major amputation at 1 year, and freedom from clinically driven target-vessel revascularization at 1 year, which occurred in 96% of patients treated with the paclitaxel-eluting balloon and in 77% of the control patients, a statistically significant difference.

These outcomes included "the lowest target-vessel revascularization rates and the highest patency rates ever reported" in this setting, and provide "robust, level 1 evidence" for the safety and efficacy of the paclitaxel-eluting balloon for this indication, Dr. Brodmann concluded.

If restenosis were to occur in the target vessel following treatment with the paclitaxel-eluting balloon, it would be possible to retreat the same vessel with a second paclitaxel-eluting balloon, although that scenario was not tested in the trial, Dr. Brodmann said in an interview. The paclitaxel essentially disappears within a few months of treatment, which should allow safe retreatment.

A written statement from Medtronic said that the company has an application pending with the Food and Drug Administration for U.S. marketing approval of the IN.PACT balloon for this indication. The balloon has been available in Europe since 2009.

The IN.PACT SFA Trial was sponsored by Medtronic, which markets the IN.PACT drug-eluting balloon. Dr. Brodmann said she is a consultant to Medtronic. Dr. Bosiers said that he had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 6/24/2014: A previous version of this article misstated the number of patients in the control arm, the number of study centers, the name of the study, and two references to the device.

PARIS – A drug-eluting balloon produced a stentlike rate of primary patency and need for target vessel revascularization in a multinational, controlled trial with 331 patients with claudication.

The results showed that the paclitaxel-eluting angioplasty balloon used in the study, the IN.PACT model made by Medtronic, has the "potential to become the standard of care" for treating stenoses in the superficial femoral and popliteal arteries, Dr. Marianne Brodmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions. After 1 year, the rate of clinically driven target-vessel revascularizations was 2% in the 220 patients treated with the drug-eluting balloon and 21% in 111 control patients treated with plain balloon angioplasty, a statistically significant difference, reported Dr. Brodmann, professor of angiology at the Medical University of Graz (Austria).*

Mitchel L. Zoler/Frontline Medical News

The results seen in this trial contrast with results from studies of other types of drug-eluting balloons in these arteries, said Dr. Marc Bosiers, head of the department of vascular surgery at St. Blasius Hospital in Dendermonde, Belgium, and a coinvestigator in the study. "What we’ve learned from this trial, if you look at the results from other trials [of drug-eluting balloons], is that not all drug-eluting balloons are equal, just as not all stents are equal," Dr. Bosiers said.

The IN.PACT SFA Trial enrolled 150 patients at 13 centers in Europe and 181 patients at 44 U.S. centers. All patients were adults with Rutherford stage 2, 3, or 4 disease; claudication and rest pain; and a single or closely tandem lesion in the superficial femoral or popliteal arteries with a total length of no more than 18 cm. Their average age was 68, and about 40% had diabetes. The trial protocol allowed provisional stenting, which occurred in 7% of the patients treated with a paclitaxel-eluting balloon and in 13% of those treated with a plain balloon. The average lesion length treated was about 9 cm in both arms of the study.

The study’s primary endpoint was the rate of primary patency at 12 months, defined as freedom from clinically driven target-vessel revascularization and freedom from restenosis assessed by Doppler ultrasound at 12 months, which was 82% in patients treated with the drug-eluting balloon and 52% among patients in the control arm, a statistically significant difference.

The study’s primary safety endpoint was the combined rate of procedure- and device-related death at 30 days, freedom from target-limb major amputation at 1 year, and freedom from clinically driven target-vessel revascularization at 1 year, which occurred in 96% of patients treated with the paclitaxel-eluting balloon and in 77% of the control patients, a statistically significant difference.

These outcomes included "the lowest target-vessel revascularization rates and the highest patency rates ever reported" in this setting, and provide "robust, level 1 evidence" for the safety and efficacy of the paclitaxel-eluting balloon for this indication, Dr. Brodmann concluded.

If restenosis were to occur in the target vessel following treatment with the paclitaxel-eluting balloon, it would be possible to retreat the same vessel with a second paclitaxel-eluting balloon, although that scenario was not tested in the trial, Dr. Brodmann said in an interview. The paclitaxel essentially disappears within a few months of treatment, which should allow safe retreatment.

A written statement from Medtronic said that the company has an application pending with the Food and Drug Administration for U.S. marketing approval of the IN.PACT balloon for this indication. The balloon has been available in Europe since 2009.

The IN.PACT SFA Trial was sponsored by Medtronic, which markets the IN.PACT drug-eluting balloon. Dr. Brodmann said she is a consultant to Medtronic. Dr. Bosiers said that he had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 6/24/2014: A previous version of this article misstated the number of patients in the control arm, the number of study centers, the name of the study, and two references to the device.

PARIS – A drug-eluting balloon produced a stentlike rate of primary patency and need for target vessel revascularization in a multinational, controlled trial with 331 patients with claudication.

The results showed that the paclitaxel-eluting angioplasty balloon used in the study, the IN.PACT model made by Medtronic, has the "potential to become the standard of care" for treating stenoses in the superficial femoral and popliteal arteries, Dr. Marianne Brodmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions. After 1 year, the rate of clinically driven target-vessel revascularizations was 2% in the 220 patients treated with the drug-eluting balloon and 21% in 111 control patients treated with plain balloon angioplasty, a statistically significant difference, reported Dr. Brodmann, professor of angiology at the Medical University of Graz (Austria).*

Mitchel L. Zoler/Frontline Medical News

The results seen in this trial contrast with results from studies of other types of drug-eluting balloons in these arteries, said Dr. Marc Bosiers, head of the department of vascular surgery at St. Blasius Hospital in Dendermonde, Belgium, and a coinvestigator in the study. "What we’ve learned from this trial, if you look at the results from other trials [of drug-eluting balloons], is that not all drug-eluting balloons are equal, just as not all stents are equal," Dr. Bosiers said.

The IN.PACT SFA Trial enrolled 150 patients at 13 centers in Europe and 181 patients at 44 U.S. centers. All patients were adults with Rutherford stage 2, 3, or 4 disease; claudication and rest pain; and a single or closely tandem lesion in the superficial femoral or popliteal arteries with a total length of no more than 18 cm. Their average age was 68, and about 40% had diabetes. The trial protocol allowed provisional stenting, which occurred in 7% of the patients treated with a paclitaxel-eluting balloon and in 13% of those treated with a plain balloon. The average lesion length treated was about 9 cm in both arms of the study.

The study’s primary endpoint was the rate of primary patency at 12 months, defined as freedom from clinically driven target-vessel revascularization and freedom from restenosis assessed by Doppler ultrasound at 12 months, which was 82% in patients treated with the drug-eluting balloon and 52% among patients in the control arm, a statistically significant difference.

The study’s primary safety endpoint was the combined rate of procedure- and device-related death at 30 days, freedom from target-limb major amputation at 1 year, and freedom from clinically driven target-vessel revascularization at 1 year, which occurred in 96% of patients treated with the paclitaxel-eluting balloon and in 77% of the control patients, a statistically significant difference.

These outcomes included "the lowest target-vessel revascularization rates and the highest patency rates ever reported" in this setting, and provide "robust, level 1 evidence" for the safety and efficacy of the paclitaxel-eluting balloon for this indication, Dr. Brodmann concluded.

If restenosis were to occur in the target vessel following treatment with the paclitaxel-eluting balloon, it would be possible to retreat the same vessel with a second paclitaxel-eluting balloon, although that scenario was not tested in the trial, Dr. Brodmann said in an interview. The paclitaxel essentially disappears within a few months of treatment, which should allow safe retreatment.

A written statement from Medtronic said that the company has an application pending with the Food and Drug Administration for U.S. marketing approval of the IN.PACT balloon for this indication. The balloon has been available in Europe since 2009.

The IN.PACT SFA Trial was sponsored by Medtronic, which markets the IN.PACT drug-eluting balloon. Dr. Brodmann said she is a consultant to Medtronic. Dr. Bosiers said that he had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

*Correction, 6/24/2014: A previous version of this article misstated the number of patients in the control arm, the number of study centers, the name of the study, and two references to the device.