What is the Role of Denervation Following the Publication of the SYMPLICITY HTN-3 Trial Results

In this edition of Clinical Forum, we asked 3 Cardiology Review editorial board members to comment on the role of renal denervation following the publication of the SYMPLICITY HTN-3 trial results.

Please send your comments or suggestions for future Cardiology Review Clinical Forum questions to Dr Mukherjee at debabrata.mukherjee@ttuhsc.edu. Space permitting, we will post them online and in the iPad edition of the next issue.

Q: What is the role for renal denervation since the publication of the SYMPLICITY HTN-3 trial results?

Hitinder S. Gurm, MD

Associate Professor of Internal Medicine

Director, Inpatient Cardiology Services

Director, Carotid Interventions in Cardiovascular Medicine

University of Michigan Ann Arbor, MI

Hitinder S. Gurm, MD

A: Renal denervation was at one time considered to be among the most significant breakthroughs in the field of hypertension in the last 2 decades. The results of the SYMPLICITY HTN-3 trial, however, failed to demonstrate any benefit of this therapy over best medical therapy, and the future of this procedure is now being questioned.^1,2

The elegantly designed SYMPLICITY HTN-3 trial once again confirmed the need to evaluate invasive therapies in a randomized, blinded, and, if possible, sham-controlled fashion. Prior uncontrolled studies demonstrated remarkable reduction in blood pressure with renal denervation, but in SYMPLICITY HTN-3, there was no difference in either the office blood pressure or the 24-hour ambulatory blood pressure in those undergoing denervation or a sham procedure.

The trial has been criticized (mostly by denervation experts outside the United States) for purported operator inexperience and inability to confirm successful renal denervation. Although it is possible that ensuring complete denervation might have resulted in a different finding, the dramatic benefits that have been previously demonstrated with renal denervation (albeit in

poorly designed studies) with respect to blood pressure reduction and improvement in cardiometabolic parameters were generally obtained using the same catheter. Another factor that has not received enough attention is the rarity of true resistant hypertension. While a significant number of patients with hypertension have less than ideal control, this is often the result of noncompliance, untreated obstructive sleep apnea, or secondary causes of hypertension, and true resistant hypertension is exceedingly uncommon. Most patients referred to specialist hypertension centers are successfully treated with medical therapy, and in a small study, medication adjustment was more effective than renal denervation.³ This would suggest that the target population for renal denervation is much smaller than previously assumed.⁴ On a positive note, SYMPLICITY-3 has resulted in wider awareness of treatment options for uncontrolled hypertension, which will result in better control of blood pressure in the community.

Some would argue that the results of SYMPLICITY HTN-3 spell the end of renal denervation. Catheter-based renal denervation is a novel concept and may yet prove to be a major breakthrough for the treatment of select patient populations. The procedure appears to hold promise for treatment of arrhythmias and for patients with heart failure, but well-designed studies are needed to assess if this promise will be fruitful. The most important target for this therapy may still be hypertension. Non-compliance is probably the single biggest contributor to poorly controlled hypertension. A therapy that successfully reduces blood pressure and is independent of patient compliance could be highly effective in reducing morbidity (and possibly mortality), as well as health care costs associated with poorly controlled hypertension. Because noncompliant patients are typically not enrolled in clinical trials, and it will require innovative clinical trial design and regulatory policy to test this hypothesis.

References

1. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401.

2. Messerli FH, Bangalore S. Renal denervation for resistant hypertension? N Engl J Med. 2014;370:1454-1457.

3. Fadl Elmula FE, Hoffmann P, Larstorp AC, et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension. 2014;63:991-999.

4. Savard S, Frank M, Bobrie G, Plouin PF, Sapoval M, Azizi M. Eligibility for renal denervation in patients with resistant hypertension: when enthusiasm meets reality in real-life patients. JACC.2012;60:2422-2424.

Q: Renal Denervation: What Went Wrong? or Did It?

Mehdi H. Shishehbor, DO, MPH, PhD

Director, Endovascular Services

Associate Program Director, Interventional Cardiology

Heart and Vascular Institute

Cleveland Clinic

Cleveland, OH

Mehdi Shishehbor, DO, MPH, PhD

A: Treatment of hypertension has evolved significantly from the early 1940s to the current era, with multiple drug classes now available for use in treating patients.¹ Despite these advances, a significant portion of patients have uncontrolled, undertreated, or resistant hypertension.^2,3 While the exact prevalence of resistant hypertension is unknown, there is little doubt that hypertension treatment requires the use of multiple drug classes, and hence there is low patient compliance. Given these issues and the clinical risk associated with hypertension, inventors and entrepreneurs Howard Levin and Mark Gelfand embarked on building an endovascular device to treat hypertension.⁴ The concept was renal sympathetic denervation utilizing radiofrequency ablation, a treatment that was the mainstay of therapy for hypertension in the 1940s and 1950s using surgical splanchnicectomy.⁵ Indeed, in 1953 Smithwick and Thompson had detailed their clinical experience with more than 1200 patients in the Journal of the American Medical Association.⁵ The results were intriguing and compelling: at 5 years, 54% of patients in medical therapy had died versus 19% in the surgical group. It is interesting that despite the reduction in mortality, over 50% of patients had no reduction in blood pressure. Despite its early success, this procedure fell out of favor due to significant morbidity and advances in medical therapy.

Mechanistically, the sympathetic nervous system contains both efferent and afferent nerves that communicate between the kidneys and central nervous system.^6,7 The efferent limb promotes renin release, reduces renal blood flow via arterial constriction, and increases tubular sodium reabsorption (Figure 1).⁶ The afferent limb modulates central nervous system outflow, and sends feedback to the hypothalamus and contralateral kidney. Anatomically, the majority of the sympathetic nerves arborize around the renal arteries and primarily lie within 0.5 mm to 1.0 mm of the lumen within the adventitia.⁸ In addition to the clinical data presented above, a number of animal studies have also shown the hormonal and neuronal benefit associated with an interruption of the afferent and efferent sympathetic nervous system via renal radiofrequency ablation.^9-13

Collectively, these compelling data led to the first multicenter phase 1 study (SYMPLICITY HTN-1) of 45 patients with resistant hypertension using the Ardian renal denervation technology.¹⁴ This single-arm study was published in 2009 and showed a reduction of 27 mm Hg in systolic and 17 mm Hg in diastolic blood pressure. The results were impressive but nonrandomized. Subsequently, December 2010 saw the completion of SYMPLICITY HTN-2, a randomized trial of 49 patients who underwent renal denervation and 51 who were treated with medical therapy alone.¹⁵ All patients were considered resistant (on 3 blood pressure medications at maximum tolerated dose, with a systolic blood pressure ≥160 mm Hg), with a glomerular filtration rate of >45.¹⁵ The results once again were impressive: a reduction of 32 mm Hg in systolic blood pressure and 12 mm Hg in diastolic blood pressure. Immediately after the publication of this trial, Ardian obtained a CE mark in Europe, and companies ranging from small start-ups to major players began pursuing a similar or alternative approach to renal denervation for the treatment of resistant hypertension. However, a few, including our group, raised concerns about the disproportionate enthusiasm based on a single, small, non-placebo-controlled trial.¹⁶ Indeed, we had major concerns about the discrepancy between office-based (the primary end point of all renal denervation trials) versus ambulatory blood pressure measurements in SYMPLICITY HTN- 2.^16,17

Eventually, Medtronic bought Ardian in November 2010 for more than $800 million, and shortly thereafter Boston Scientific’s Vessix, St. Jude’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—had received CE marks in Europe and Australia and were put into use in those countries as part of routine care. Other alternative therapies were on the horizon, such as intravascular and external ultrasound-based renal denervation, and tissue-directed pharmacologic ablation.⁶ Multiple small, nonrandomized, single-center studies were soon published in major medical journals, touting renal denervation as a potential therapy for diabetes mellitus, metabolic syndrome, obstructive sleep apnea, and even atrial fibrillation and other arrhythmias.⁶ Frustration was growing in the United States among investigators, clinicians, and patients because none of the devices were approved in the United States.

Finally, in 2011 Medtronic announced that a large phase 3 study with a placebo control arm would be conducted in the United States to examine the safety and efficacy of Ardian renal denervation, and also to seek FDA approval.¹⁸ The SYMPLICITY HTN-3 enrolled 1441 patients but eventually randomized 364 to denervation and 171 to sham. The results were published and presented at the American College of Cardiology meeting in early 2014.¹⁷ Unfortunately, despite all the enthusiasm about renal denervation, the study failed to reach its primary or secondary efficacy end points; however, it was found to be safe. So what went wrong?

Many have attempted to explain the failed results of SYMPLICITY HTN-3. Were they related to patient demographics, operator experience, catheter design, trial design, the Hawthorne effect, regression to the mean, adherence, or just placebo effect? While no one has the right answer, one thing is very clear: it was one of the most well designed, conducted, and executed clinical trials in modern device history. The mean baseline systolic blood pressure was 188 mm Hg, with an average of 5 medications in each group. Both the operators and patients were blinded to the procedure.

Medications were closely monitored and patients were followed frequently and carefully. The catheter was the exact design that had been used in SYMPLICITY HTN-1 and HTN-2 as well as for many patients in clinical practice. It is very unlikely that operator experience played much of a role—an analysis of operator volume did not find any association between this variable and the outcomes. Importantly, each case was supervised by at least 1 (and in most cases 2) certified Medtronic representatives, who made sure meticulous attention was paid to details and no “short cuts” were taken during the procedure. The majority of patients were white; however, African Americans were also well represented. There was a trend favoring renal denervation in non—African Americans, but this may be related to multiple comparisons, and at best is hypothesis generating. A Hawthorne effect is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications at 6 months beyond the reduction seen in the sham group. Additionally, while the blood pressure reduction in both arms was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation had been effective, one would have expected a higher reduction in blood pressure or at least a decrease in 1 to 2 medications in the denervation group compared with sham. Whether the results represent a statistical error such as regression to the mean is unknown but, again, unlikely.

Where do we stand now? Unfortunately, all clinical programs in renal denervation have been placed on hold or completely eliminated. Covidien has completely stopped its program and Boston Scientific, St Jude, and Medtronic have stopped all clinical trials in the United States and abroad on renal denervation.

Is renal denervation dead? We have seen similar situations with other devices and technologies; renal artery stenosis is a perfect example. After 7 trials, many feel that for some select patients renal artery stenting is still an important option. We hope that Medtronic and others continue to pursue this therapy; obviously, we need better ways to identify the exact location of these sympathetic nerves within the renal artery, and to have a clearer sense of procedural success. Until then, our colleagues in Europe and Australia will continue to treat patients with this technology, while we wait for level 1 clinical evidence that shows efficacy!

References

1. Chobanian AV. Shattuck lecture: the hypertension paradox: more uncontrolled disease despite improved therapy. N Engl J Med. 2009;361:878-887.

2. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension.2003;42:1206-1252.

3. Thomas G, Shishehbor M, Brill D, Nally JV, Jr. New hypertension guidelines: one size fits most? Cleve Clin J Med. 2014;81:178-188.

4. Gertner J. Meet the tech duo that’s revitalizing the medical device industry. April 2013. Fast Company website. http://www.fastcompany.com/3007845/meet-tech-duo-thats-revitalizing-medical-device-industry.

5. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. JAMA. 1953;152:1501-1504.

6. Bunte MC, Infante de Oliveira E, Shishehbor MH. Endovascular treatment of resistant and uncontrolled hypertension: therapies on the horizon. JACC Cardiovasc Interv. 2013;6:1-9.

7. Thomas G, Shishehbor MH, Bravo EL, Nally JV. Renal denervation to treat resistant hypertension: guarded optimism. Cleve Clin J Med. 2012;79:501-510.

8. Atherton DS, Deep NL, Mendelsohn FO. Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study. Clin Anat. 2012;25:628-633.

9. Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963;27:282-293.

10. Winternitz SR, Katholi RE, Oparil S. Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat. J Clin Invest. 1980;66:971-978.

11. Katholi RE, Whitlow PL, Hageman GR, Woods WT. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J Hypertens.1984;2:349-359.

12. Vallbo AB, Hagbarth KE, Wallin BG. Microneurography: how the technique developed and its role in the investigation of the sympathetic nervous system. J Appl Physiol(1985). 2004;96:1262-1269.

13. Esler M, Jennings G, Korner P, et al. Total, and organ-specific, noradrenaline plasma kinetics in essential hypertension. Clin Exp Hypertens A. 1984;6:507-521.

14. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275-1281.

15. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

16. Bunte MC. Renal sympathetic denervation for refractory hypertension. Lancet. 2011;377:1074; author reply, 1075-1075.

17. Shishehbor MH, Bunte MC. Anatomical exclusion for renal denervation: are we putting the cart before the horse? JACC Cardiovasc Interv. 2014;7:193-194.

18. Bhatt DL, Bakris GL. Renal denervation for resistant hypertension. N Engl J Med.2014;371:184.

Q: What is the role of renal denervation?

Khaled M. Ziada, MD, FACC, FSCAI

Professor of Medicine

Gill Foundation Professor of Interventional Cardiology

Director, Cardiac Catheterization Laboratories and Interventional Fellowship Program

Gill Heart Institute

University of Kentucky

Lexington, KY

Khaled M. Ziada, MD, FACC, FSCAI

A: This is a timely question. Renal denervation is a procedure that is used in an attempt to interrupt renal sympathetic nerve signals, which normally enhance central sympathetic nerve activity. Hypertension is associated with high levels of sympathetic activity, particularly in severe or uncontrolled hypertension.¹ Several other medical conditions (such as central sleep apnea, insulin resistance, arrhythmia, and heart failure) are associated with higher levels of sympathetic activity, but most clinical research and utilization of renal denervation so far has been on its role in controlling resistant hypertension. Small trials have demonstrated effective and sustained reduction of systolic and diastolic blood pressure (BP) in the range of 22 to 32 mm Hg and 10 to 19 mm Hg, respectively.^2,3This, as well as the absence of any safety concerns, led to approval of the procedure and several of its devices in many parts of the world. A global registry aims to collect information and follow 5000 patients who undergo renal denervation for resistant hypertension and other indications. A preliminary report on the 6-month outcome of the first 1000 patients demonstrated that in those with baseline systolic BP ≥160 mm Hg, denervation resulted in effective office systolic BP reduction (—19.8 mm Hg) and 24-hour ambulatory systolic BP (–9.2 mm Hg).⁴

The only large randomized trial utilizing an active control group was conducted in the United States to gain FDA approval of the procedure. The results were reported in spring 2014.⁵ SYMPLICITY HTN-3 was a prospective, randomized, single-blind, sham-controlled multicenter trial that included 535 patients with resistant hypertension. After 2 weeks of maximally tolerated and stable medical therapy, patients were included if their systolic BP was ≥160 mm Hg. They were randomized to renal denervation versus sham procedure in a 2:1 fashion. At 6 months, the mean change in systolic BP was —14mm Hg in the denervation group and –11.7 mm Hg in the sham-procedure group. The change in 24-hour ambulatory systolic BP was −6.8 mm Hg and –4.8 mm Hg, respectively. In both groups, all changes were statistically significantly lower than respective measurements at baseline. There was no significant difference between the BP reduction in the denervation arm versus the sham procedure arm, thus failing to establish the superiority of renal denervation over optimal medial therapy in resistant hypertension.

Several explanations have been put forward to explain the failure of denervation to impact BP more than medical therapy in SYMPLICITY HTN-3. This was the first randomized controlled trial with a sham control group, thus raising the possibility that the effect of denervation was exaggerated in the smaller uncontrolled trials.⁶ Additionally, protocol-mandated medical therapy guidelines may not have achieved the most optimal and stable medical therapy intended. This is supported by the fact that systolic BP continued to drop in the control group, even as these patients were deemed “resistant” at the time of randomization. Moreover, it was difficult to maintain the randomized patients on stable medications over the 6 months of the trial, thus introducing significant confounding variability. In subgroup analysis, medical therapy was extremely effective in African Americans, almost nullifying the effect of denervation in this patient population. Questions were raised about the technique of denervation used, reliability of the ablating catheter, and the relative inexperience of many operators.

Given the results of the randomized controlled trial, the role of denervation in treatment of resistant hypertension is not established and should not be considered in daily clinical practice. Future randomized trials will address the concerns raised by SYMPLICITY HTN-3 and attempt to prove that the failure to demonstrate superiority of denervation was due to methodologic concerns. These trials will utilize different devices, consider racial differences, and be powered to detect smaller differences between groups. It will be essential to enroll patients in these trials, as the results will be critical in determining the future of renal denervation as a therapeutic modality for resistant hypertension. Additionally, denervation is being tested in a number of other trials for its role in management of heart failure, sleep apnea, insulin resistance, and atrial fibrillation. These potential uses have not been established either, though trials are ongoing outside the United States to determine whether denervation has a role to play in this wide range of medical conditions.

References

1. Schlaich MP, Lambert E, Kaye DM, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension. 2004;43:169-175.

2. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study. Lancet. 2014;383:622-629.

3. Esler MD, Bohm M, Sievert H, et al. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial. Eur Heart J. 2014;35:1752-1759.

4. Bohm M. The global SYMPLICITY registry: Safety and effectiveness of renal artery denervation in real world patients with uncontrolled hypertension. Oral Presentation at the American College of Cardiology Meeting, April 2014, Washington, DC.

5. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401.

6. Messerli FH, Bangalore S. Renal denervation for resistant hypertension? N Engl J Med. 2014;370:1454-1457.

Division of Cardiovascular Medicine