American Journal of Therapeutics 22, 167–170 (2015)
Lesson to Be Learned From the Renal Denervation Trials John Somberg, MD1* and Janos Molnar, MD2,3
BACKGROUND A long history exists regarding neural mediation of hypertension that has led investigators to evaluate the possible role of renal denervation in the treatment of resistant hypertension. Early work on thoracolumbar surgical sympathectomy showed that it could effectively lower blood pressure.1 Case reports and case series dating back to the 1930s showed that surgical sympathectomy could be effective in treating malignant hypertension. However, the adverse effects of impotence, incontinence, and orthostatic hypotension were severe, greatly limiting the procedure. Renal selective denervation in animal models of hypertension2 reintroduced the concept of neural modulation in the treatment of hypertension. Early “proof of concept” studies by Krum et al3 and Ormsen et al4 provided support for the possible benefit of renal sympathetic nerve denervation techniques for the treatment of hypertension. Appropriately, early studies were performed on patients with resistant hypertension, systolic BP greater than 160 mm Hg on 3 or more antihypertensive agents (one being a diuretic). Some reports were negative with unilateral renal nerve ablation5 and the presence of accessory renal arteries (uninterrupted neural innervation) emphasizing the importance of bilateral and compete neural denervation for effective BP reduction.
THE SIMPLICITY HTN TRIALS Esler6 first began employing the Symplicity Arch Catheter with radio frequency ablation of nerves running along the renal artery to treat hypertension. The first series reported using this catheter was the Symplicity I Trial reported by Krum et al.7 They studied 50 patients in an open registry and reported a significant
1
Rush University Medical Center; 2American Institute Therapeutics; and 3The Chicago Medical School. The authors have no conflicts of interest to declare. *Address for correspondence: 21 N Skokie Highway, Lake Bluff, IL 60044. E-mail: [email protected]
reduction in blood pressure (214 mm Hg systolic and 210 diastole). In a follow-up report, the BP reduction persisted for 24 months.3 A second study was a randomized trial, unblinded evaluating 52 patients with RND and 54 controls.6 At 6 months, a 10-mm Hg fall in BP was found that was significant in 84% of patients. At 6 months, the group that did not receive RND was crossed over to receive RND and was reported to have a 24 mm (significant) reduction in BP. The promising results reported in early trials then lead to the initiation of Symplicity HTN-3 Trial first reported by Bhatt et al8 in 2014 with a subsequent report on ambulatory BP in 2014.9 The Simplicity HTN-3 Trial screened 1441 patients at 88 sites. This was a randomized, blinded, Sham control group study with 364 patients receiving RND and 171 sham controls. In the RND group, BP was reduced by 14 6 23 mm Hg mean systolic BP, whereas in the sham procedure group, BP was reduced by 12 6 26 mm Hg mean systolic, a nonsignificant 2.4 mm Hg difference. With this finding, the study failed its primary end point. The renal denervation field was shocked and many advocated abandoning RND as a therapeutic approach for blood pressure control. There were some interesting findings in the Symplicity HTN-3 Trial, one being that the percentage “of nondippers” who converted to “dippers” was 21% in the RND group and 15% in the sham group. Still the negative study lead to widespread disillusionment with the RND approach, the questioning of studying resistant hypertension and proposals for new approaches to studying renal nerve denervation techniques.10,11 Perhaps, the simplest and most appropriate decision was to conclude that renal denervation is an ineffective technique. That the results of Simplicity 1 and 2, as well as other small studies was the result of a “placebo” effect and that the sham control group in Simplicity HTN-3 revealed a placebo effect, and thus the study was negative. However, reviewing the results of Symplicity 3 reveals a number of problems that may have led to a negative study. The first question was about the patient population. That the population may not have had resistant hypertension is brought out by the observation that only 1 in 5 patients received a trial of spironolactone or
1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
168
eperolone.12 An aldosterone inhibiting diuretic is requisite to establish resistant hypertension. Perhaps far more important is the persistence of elevated blood pressure on stable medical therapy. It is reported that 22% of patients had a medication change 2–6 weeks before study start. Antihypertensive medications can take months to have a full effect, and thus, changes in mediation can have delayed effects, lowering BP in the control group and thus diluting the procedure effect. In addition, 39% of patients had medication changes in the baseline to 6-month study period. Changes in medication could easily obscure the RND procedure effect. The changes could have had a larger effect in the sham group, diminishing the comparative reduction in BP in the intervention group caused by RND. One of the most striking reports from the Symplicity HTM-3 Trial is the difference in subgroup response based on ethnicity. Most studies in RND were done in whites. Simplicity 3 had a recruitment goal to recruit African Americans. Surprisingly, there was a very significant difference in response between white and African American patients with resistant hypertension.13,14 In whites, systolic BP fell 15 mm Hg in RND group and 9 mm Hg in the sham Group, a significant drop. In the African American group, comprising 26% of the study population, systolic BP fell 16 mm Hg in the RND group and 18 mm Hg in the control group.15 An 18-mm Hg fall in the sham control group was unexpected and suggests a medication compliance issue. One could hypothesize that African American patients were less medication compliant, did not have resistant hypertension, and when undergoing either the procedure or the sham became more compliant (Horthorn Effect). This will cause a reduction in BP in both study groups, alibi more BP lowering would be seen in the sham group, since BP reduction by RND in the intervention group reduced BP to a level that medication compliance could not reduce further, “celling effect.” In addition to the above issue, Symplicity HTN-3 had a number of technical issues that could impact the results. The first consideration relates to a “training effect” that can be problematic in procedural studies. The administration of renal denervation lesions is technically challenging. The anatomy of the renal arteries varies and is complex. The angular takeoff creates difficulties in having the catheter tip against the vascular endothelial wall. The presence of accessory renal arteries needs to be evaluated, and these accessory arteries need to be ablated if renal ablation is to be complete. This issue requires experienced proceduralists, experience gained with frequency of undertaking the procedure. In Simplicity HTN-3, there were 364 patients and 111 proceduralists for about 3 procedures per operator. Furthermore, it is known that the greater American Journal of Therapeutics (2015) 22(3)
Somberg and Molnar
the number of ablations in a patient correlates with greater BP reduction.6,15 With 15 ablations or less, a 14-mm Hg BP reduction is reported versus with 16 ablations or more, a 21-mm drop in BP is reported. There were a low number of ablation sites in individual patients reported in Symplicity HTN-3. In addition, proper ablation requires spatial ablation completeness. Renal nerves run along the renal arteries in the anterior, posterior, inferior, and superior quadrants. The nerves are more numerous and closer to the vessel in the adventica in the distal artery segments, facilitating the heat-induced injury leading to ablation.16 To cover all aspects of the ramifying nerves, one needs to ablate the 4 quadrants that the nerve can be divided into.6 In Simplicity 3, only 6% of patients received two 4 quadrant ablations, only 20% received one 4 quadrant ablation, and 74% received no 4 quadrant ablations.14 In the 19 patients receiving two 4 quadrant ablations in both renal arteries, systolic BP fell 24 mm Hg and 10 mm Hg on ABPM, a clinically substantial and significant amount.14,15 Another way to assess ablation effectiveness is the presence of a notch on renal angiography, a sign of vascular injury and thus possible ablation success. In Symplicity 3, 6% of patients had 1 or more notiches,14 a sign of limited ablation energy delivery. These technical issues raise serious questions as to the effective delivery of ablation radiofrequency energy to the renal nerves. Without effective ablation, one would not expect a significant lowering in blood pressure. The technical questions, combined with the medication changes, the unexpected and confounding results with the African American patient’s all combine to raise serious questions regarding the Symplicity HTN-3 trial. These issues are not meant as a criticism of those conducting the trial, but as a poststudy analysis that leads to questioning the negative results of the study. The Symplicity Trial has made a major contribution to the field, but should not be the final determination of whether renal nerve ablation is effective.
LESSONS TO BE LEARNED AND FUTURE DIRECTIONS The introduction of a Sham control group in a procedural study to exclude a placebo effect has merit, but a Sham group does not alone avoid other study limitations and pitfalls. In any procedural study, the effect of a learning curve on results needs to be taken into account. Vigorous expert proctoring with “training” cases, excluded from the study results are needed. Some may argue that the procedural effect needs to be evaluated as part of the efficacy evaluation. This www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
169
Renal Denervation Trials
is true, but the procedural learning needs to be separated from the cases used for efficacy determination. Demonstrating efficacy of a procedure is different than showing that a learning curve exists and how operators can be appropriately trained to provide consistent procedural excellence. In all therapeutic studies, medication changes should not be made during the study, and in blood pressure studies, medication changes must not occur just before patient entry, since changes can take a long time to have full effect. In trials where medication compliance is critical, such as in resistant hypertension studies, it is essential to evaluate for medication compliance, especially in a sham procedure group. It is not so much an issue of lack of compliance, but the positive motivating effect of a sham procedure, motivating subsequent medication compliance, and thus potentially equalizing the BP effect in the sham group to that of the active procedure effect on blood pressure.
THE PATH FORWARD Although the Symplicity catheter is not the only approach to ablation, the Simplicity program, hopefully, will not stop with the Symplicity HTN-3 trial, and other RND programs will initiate clinical trials. It is appropriate that trials continue in the area of resistant hypertension. Patients need to be truly resistant hypertensives with a trial of spironolactone or eperolone before entry, if they can tolerate these therapies. Patients must be on stable blood pressure treatment, no changes during the study and medication compliance checked in the control group, as well as the procedural intervention group. Medication compliance must be verified in both groups with urine measurement of drug metabolites. The effect of a “learning curve” for the procedure needs to be minimized with rigorous expert proctoring with the first 1–3 patients per operator analyzed separately and excluded from the primary end point results if a training effect is found. In addition, addressing the technical issues of ablation, the number of ablations, spatial aspects of ablation, distal versus proximal ablation, and ablation of accessory renal arteries if needed need to be taken into account. Those patients with accessory renal arteries that cannot be ablated must be excluded from the study. Perhaps, the most important consideration is the development of a feedback system during the procedure to evaluate the effectiveness of the ablation. Currently, ablation is undertaken and blood pressure results are evaluated several months later. What is needed is a way to assess whether the procedure effectively disrupts the renal efferent and afferent nerves www.americantherapeutics.com
that are involved. A number of approaches are being investigated, and this needs to be a priority to enhance the effectiveness of renal nerve ablation. In addition, the evaluation postprocedure of the extent of neural ablation in each patient using techniques evaluating cardiac norepinephrine “spillover,” muscle sympathetic nerve activity, tyrosine hydroxylase fragments, or other ways to assess the extent of renal afferent or efferent nerve ablation will be most helpful in determining whether effective ablation was accomplished. With these types of data, it may be necessary to analyze separately patients who show effective ablation from patients not showing effective ablation. It would be better to have a way of ensuring effective ablation during the procedure than to have to retrospectively separate the intervention going into prespecified subgroups of those with and without markers of effective ablation.
REFERENCES 1. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. JAMA. 1953;152:1501–1504. 2. DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2013;298:R245–R254. 3. Krum H, Schlaich MP, Bohm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study. Lancet. 2014;838:622–629. 4. Ormiston JA, Anderson T, Brinton TJ, et al. Non-invasive renal denervation using externally delivered focused ultrasound: early experience using Doppler-based image targeting for treatment. J Am Coll Cardiol. 2014;64(11 Suppl):TCT-412. 5. Grassi G, Seravalle G, Brambilla G, et al. Failure of monolateral renal nerve ablation to exert sympathoinhibitory and blood pressure lowering effects in a patient with resistant hypertension: a case report. Int J Cardiol. 2013;169:e120–e121. 6. Esler M. Renal denervation for treatment of drugresistant hypertension. Trends Cardiovasc Med. 2014;25: 1050–1738. 7. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicenter safety and proof-of-principle cohort study. Lancet. 2009;373:1275–1281. 8. Bhatt DL, Kandazri DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370;15. 9. Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure. J Am Coll Cardiol. 2014;64:1071–1078. 10. Lobo MD, de Belder MA, Cleveland T, et al. Joint UK societies’ 2014 consensus statement on renal denervation for resistant hypertension. Heart. 2015;101:10–16. American Journal of Therapeutics (2015) 22(3)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
170 11. Zannad F, Stough WG, Mahfoud F, et al. Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure. Hypertension. 2015;65:5–15. 12. Sever P. Resistant hypertension and renal denervation: who’s kidding whom? J Renin Angiotensin Aldostermone Syst. 2014;15:205–208. 13. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 TRIAL. Eur Heart J. 2015;36:219–227.
American Journal of Therapeutics (2015) 22(3)
Somberg and Molnar 14. Mahfoud F, Luscher TF. Renal denervation: simply trapped by complexity? Eur Heart J. 2015;36:100–202. 15. Epstein M, de Marchena E. Is the failure of SYMPLICITY HTN-3 trial to meet its efficacy endpoint the “end of the road” for renal denervation? J Am Soc Hypertens. 2015;9: 140–149. 16. Aatherton DS, Deep NL, Mendelsohn FO. Microanatomy of the renal sympathetic nervous system: a human post-mortem histologic study. Clin Anat. 2012;25: 628–633.
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Lesson to Be Learned From the Renal Denervation Trials John Somberg, MD1* and Janos Molnar, MD2,3
BACKGROUND A long history exists regarding neural mediation of hypertension that has led investigators to evaluate the possible role of renal denervation in the treatment of resistant hypertension. Early work on thoracolumbar surgical sympathectomy showed that it could effectively lower blood pressure.1 Case reports and case series dating back to the 1930s showed that surgical sympathectomy could be effective in treating malignant hypertension. However, the adverse effects of impotence, incontinence, and orthostatic hypotension were severe, greatly limiting the procedure. Renal selective denervation in animal models of hypertension2 reintroduced the concept of neural modulation in the treatment of hypertension. Early “proof of concept” studies by Krum et al3 and Ormsen et al4 provided support for the possible benefit of renal sympathetic nerve denervation techniques for the treatment of hypertension. Appropriately, early studies were performed on patients with resistant hypertension, systolic BP greater than 160 mm Hg on 3 or more antihypertensive agents (one being a diuretic). Some reports were negative with unilateral renal nerve ablation5 and the presence of accessory renal arteries (uninterrupted neural innervation) emphasizing the importance of bilateral and compete neural denervation for effective BP reduction.
THE SIMPLICITY HTN TRIALS Esler6 first began employing the Symplicity Arch Catheter with radio frequency ablation of nerves running along the renal artery to treat hypertension. The first series reported using this catheter was the Symplicity I Trial reported by Krum et al.7 They studied 50 patients in an open registry and reported a significant
1
Rush University Medical Center; 2American Institute Therapeutics; and 3The Chicago Medical School. The authors have no conflicts of interest to declare. *Address for correspondence: 21 N Skokie Highway, Lake Bluff, IL 60044. E-mail: [email protected]
reduction in blood pressure (214 mm Hg systolic and 210 diastole). In a follow-up report, the BP reduction persisted for 24 months.3 A second study was a randomized trial, unblinded evaluating 52 patients with RND and 54 controls.6 At 6 months, a 10-mm Hg fall in BP was found that was significant in 84% of patients. At 6 months, the group that did not receive RND was crossed over to receive RND and was reported to have a 24 mm (significant) reduction in BP. The promising results reported in early trials then lead to the initiation of Symplicity HTN-3 Trial first reported by Bhatt et al8 in 2014 with a subsequent report on ambulatory BP in 2014.9 The Simplicity HTN-3 Trial screened 1441 patients at 88 sites. This was a randomized, blinded, Sham control group study with 364 patients receiving RND and 171 sham controls. In the RND group, BP was reduced by 14 6 23 mm Hg mean systolic BP, whereas in the sham procedure group, BP was reduced by 12 6 26 mm Hg mean systolic, a nonsignificant 2.4 mm Hg difference. With this finding, the study failed its primary end point. The renal denervation field was shocked and many advocated abandoning RND as a therapeutic approach for blood pressure control. There were some interesting findings in the Symplicity HTN-3 Trial, one being that the percentage “of nondippers” who converted to “dippers” was 21% in the RND group and 15% in the sham group. Still the negative study lead to widespread disillusionment with the RND approach, the questioning of studying resistant hypertension and proposals for new approaches to studying renal nerve denervation techniques.10,11 Perhaps, the simplest and most appropriate decision was to conclude that renal denervation is an ineffective technique. That the results of Simplicity 1 and 2, as well as other small studies was the result of a “placebo” effect and that the sham control group in Simplicity HTN-3 revealed a placebo effect, and thus the study was negative. However, reviewing the results of Symplicity 3 reveals a number of problems that may have led to a negative study. The first question was about the patient population. That the population may not have had resistant hypertension is brought out by the observation that only 1 in 5 patients received a trial of spironolactone or
1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
168
eperolone.12 An aldosterone inhibiting diuretic is requisite to establish resistant hypertension. Perhaps far more important is the persistence of elevated blood pressure on stable medical therapy. It is reported that 22% of patients had a medication change 2–6 weeks before study start. Antihypertensive medications can take months to have a full effect, and thus, changes in mediation can have delayed effects, lowering BP in the control group and thus diluting the procedure effect. In addition, 39% of patients had medication changes in the baseline to 6-month study period. Changes in medication could easily obscure the RND procedure effect. The changes could have had a larger effect in the sham group, diminishing the comparative reduction in BP in the intervention group caused by RND. One of the most striking reports from the Symplicity HTM-3 Trial is the difference in subgroup response based on ethnicity. Most studies in RND were done in whites. Simplicity 3 had a recruitment goal to recruit African Americans. Surprisingly, there was a very significant difference in response between white and African American patients with resistant hypertension.13,14 In whites, systolic BP fell 15 mm Hg in RND group and 9 mm Hg in the sham Group, a significant drop. In the African American group, comprising 26% of the study population, systolic BP fell 16 mm Hg in the RND group and 18 mm Hg in the control group.15 An 18-mm Hg fall in the sham control group was unexpected and suggests a medication compliance issue. One could hypothesize that African American patients were less medication compliant, did not have resistant hypertension, and when undergoing either the procedure or the sham became more compliant (Horthorn Effect). This will cause a reduction in BP in both study groups, alibi more BP lowering would be seen in the sham group, since BP reduction by RND in the intervention group reduced BP to a level that medication compliance could not reduce further, “celling effect.” In addition to the above issue, Symplicity HTN-3 had a number of technical issues that could impact the results. The first consideration relates to a “training effect” that can be problematic in procedural studies. The administration of renal denervation lesions is technically challenging. The anatomy of the renal arteries varies and is complex. The angular takeoff creates difficulties in having the catheter tip against the vascular endothelial wall. The presence of accessory renal arteries needs to be evaluated, and these accessory arteries need to be ablated if renal ablation is to be complete. This issue requires experienced proceduralists, experience gained with frequency of undertaking the procedure. In Simplicity HTN-3, there were 364 patients and 111 proceduralists for about 3 procedures per operator. Furthermore, it is known that the greater American Journal of Therapeutics (2015) 22(3)
Somberg and Molnar
the number of ablations in a patient correlates with greater BP reduction.6,15 With 15 ablations or less, a 14-mm Hg BP reduction is reported versus with 16 ablations or more, a 21-mm drop in BP is reported. There were a low number of ablation sites in individual patients reported in Symplicity HTN-3. In addition, proper ablation requires spatial ablation completeness. Renal nerves run along the renal arteries in the anterior, posterior, inferior, and superior quadrants. The nerves are more numerous and closer to the vessel in the adventica in the distal artery segments, facilitating the heat-induced injury leading to ablation.16 To cover all aspects of the ramifying nerves, one needs to ablate the 4 quadrants that the nerve can be divided into.6 In Simplicity 3, only 6% of patients received two 4 quadrant ablations, only 20% received one 4 quadrant ablation, and 74% received no 4 quadrant ablations.14 In the 19 patients receiving two 4 quadrant ablations in both renal arteries, systolic BP fell 24 mm Hg and 10 mm Hg on ABPM, a clinically substantial and significant amount.14,15 Another way to assess ablation effectiveness is the presence of a notch on renal angiography, a sign of vascular injury and thus possible ablation success. In Symplicity 3, 6% of patients had 1 or more notiches,14 a sign of limited ablation energy delivery. These technical issues raise serious questions as to the effective delivery of ablation radiofrequency energy to the renal nerves. Without effective ablation, one would not expect a significant lowering in blood pressure. The technical questions, combined with the medication changes, the unexpected and confounding results with the African American patient’s all combine to raise serious questions regarding the Symplicity HTN-3 trial. These issues are not meant as a criticism of those conducting the trial, but as a poststudy analysis that leads to questioning the negative results of the study. The Symplicity Trial has made a major contribution to the field, but should not be the final determination of whether renal nerve ablation is effective.
LESSONS TO BE LEARNED AND FUTURE DIRECTIONS The introduction of a Sham control group in a procedural study to exclude a placebo effect has merit, but a Sham group does not alone avoid other study limitations and pitfalls. In any procedural study, the effect of a learning curve on results needs to be taken into account. Vigorous expert proctoring with “training” cases, excluded from the study results are needed. Some may argue that the procedural effect needs to be evaluated as part of the efficacy evaluation. This www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
169
Renal Denervation Trials
is true, but the procedural learning needs to be separated from the cases used for efficacy determination. Demonstrating efficacy of a procedure is different than showing that a learning curve exists and how operators can be appropriately trained to provide consistent procedural excellence. In all therapeutic studies, medication changes should not be made during the study, and in blood pressure studies, medication changes must not occur just before patient entry, since changes can take a long time to have full effect. In trials where medication compliance is critical, such as in resistant hypertension studies, it is essential to evaluate for medication compliance, especially in a sham procedure group. It is not so much an issue of lack of compliance, but the positive motivating effect of a sham procedure, motivating subsequent medication compliance, and thus potentially equalizing the BP effect in the sham group to that of the active procedure effect on blood pressure.
THE PATH FORWARD Although the Symplicity catheter is not the only approach to ablation, the Simplicity program, hopefully, will not stop with the Symplicity HTN-3 trial, and other RND programs will initiate clinical trials. It is appropriate that trials continue in the area of resistant hypertension. Patients need to be truly resistant hypertensives with a trial of spironolactone or eperolone before entry, if they can tolerate these therapies. Patients must be on stable blood pressure treatment, no changes during the study and medication compliance checked in the control group, as well as the procedural intervention group. Medication compliance must be verified in both groups with urine measurement of drug metabolites. The effect of a “learning curve” for the procedure needs to be minimized with rigorous expert proctoring with the first 1–3 patients per operator analyzed separately and excluded from the primary end point results if a training effect is found. In addition, addressing the technical issues of ablation, the number of ablations, spatial aspects of ablation, distal versus proximal ablation, and ablation of accessory renal arteries if needed need to be taken into account. Those patients with accessory renal arteries that cannot be ablated must be excluded from the study. Perhaps, the most important consideration is the development of a feedback system during the procedure to evaluate the effectiveness of the ablation. Currently, ablation is undertaken and blood pressure results are evaluated several months later. What is needed is a way to assess whether the procedure effectively disrupts the renal efferent and afferent nerves www.americantherapeutics.com
that are involved. A number of approaches are being investigated, and this needs to be a priority to enhance the effectiveness of renal nerve ablation. In addition, the evaluation postprocedure of the extent of neural ablation in each patient using techniques evaluating cardiac norepinephrine “spillover,” muscle sympathetic nerve activity, tyrosine hydroxylase fragments, or other ways to assess the extent of renal afferent or efferent nerve ablation will be most helpful in determining whether effective ablation was accomplished. With these types of data, it may be necessary to analyze separately patients who show effective ablation from patients not showing effective ablation. It would be better to have a way of ensuring effective ablation during the procedure than to have to retrospectively separate the intervention going into prespecified subgroups of those with and without markers of effective ablation.
REFERENCES 1. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. JAMA. 1953;152:1501–1504. 2. DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2013;298:R245–R254. 3. Krum H, Schlaich MP, Bohm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study. Lancet. 2014;838:622–629. 4. Ormiston JA, Anderson T, Brinton TJ, et al. Non-invasive renal denervation using externally delivered focused ultrasound: early experience using Doppler-based image targeting for treatment. J Am Coll Cardiol. 2014;64(11 Suppl):TCT-412. 5. Grassi G, Seravalle G, Brambilla G, et al. Failure of monolateral renal nerve ablation to exert sympathoinhibitory and blood pressure lowering effects in a patient with resistant hypertension: a case report. Int J Cardiol. 2013;169:e120–e121. 6. Esler M. Renal denervation for treatment of drugresistant hypertension. Trends Cardiovasc Med. 2014;25: 1050–1738. 7. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicenter safety and proof-of-principle cohort study. Lancet. 2009;373:1275–1281. 8. Bhatt DL, Kandazri DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370;15. 9. Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure. J Am Coll Cardiol. 2014;64:1071–1078. 10. Lobo MD, de Belder MA, Cleveland T, et al. Joint UK societies’ 2014 consensus statement on renal denervation for resistant hypertension. Heart. 2015;101:10–16. American Journal of Therapeutics (2015) 22(3)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
170 11. Zannad F, Stough WG, Mahfoud F, et al. Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure. Hypertension. 2015;65:5–15. 12. Sever P. Resistant hypertension and renal denervation: who’s kidding whom? J Renin Angiotensin Aldostermone Syst. 2014;15:205–208. 13. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 TRIAL. Eur Heart J. 2015;36:219–227.
American Journal of Therapeutics (2015) 22(3)
Somberg and Molnar 14. Mahfoud F, Luscher TF. Renal denervation: simply trapped by complexity? Eur Heart J. 2015;36:100–202. 15. Epstein M, de Marchena E. Is the failure of SYMPLICITY HTN-3 trial to meet its efficacy endpoint the “end of the road” for renal denervation? J Am Soc Hypertens. 2015;9: 140–149. 16. Aatherton DS, Deep NL, Mendelsohn FO. Microanatomy of the renal sympathetic nervous system: a human post-mortem histologic study. Clin Anat. 2012;25: 628–633.
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
