Resistant hypertension is, by definition, a challenge to most physicians treating hypertension. Renal sympathetic denervation has shown promising early results in treating this condition. The SYMPLICITY HTN-3 is the most recent trial to report the effects of this technique on resistant hypertension. This review discusses this study and its surprising neutral results before ending with an overview of key lessons learned

Di Mario, C

Hayward, C

Patel, HC

Global Cardiology Science and Practice

PubMed

Patel, Hitesh C

Hayward, Carl

Di Mario, Carlo

Florence Research

OPEN ACCESS Lessons from the trialsSYMPLICITY HTN 3: The death knellfor renal denervation inhypertension?Hitesh C Patel*, Carl Hayward, Carlo Di MarioABSTRACTResistant hypertension is, by definition, a challenge to most physicians treating hypertension. Renalsympathetic denervation has shown promising early results in treating this condition. The SYMPLICITYHTN-3 is the most recent trial to report the effects of this technique on resistant hypertension. Thisreview discusses this study and its surprising neutral results before ending with an overview of keylessons learned.Keywords: Renal denervation, resistant hypertension, trial designCite this article as: Patel HC, Hayward C, Di Mario C. SYMPLICITY HTN 3: The death knell for renaldenervation in hypertension? Global Cardiology Science and Practice 2014:15http://dx.doi.org/10.5339/gcsp.2014.15http://dx.doi.org/10.5339/gcsp.2014.15Submitted: 23 April 2014Accepted: 30 April 2014ª 2014 Patel, Hayward, Di Mario,licensee Bloomsbury QatarFoundation Journals. This is an openaccess article distributed under theterms of the Creative CommonsAttribution license CC BY 4.0, whichpermits unrestricted use,distribution and reproduction in anymedium, provided the original workis properly cited.National Institute of Health Research(NIHR), Cardiovascular BiomedicalResearch Unit, Royal BromptonHospital, Sydney Street, London SW36NP, United Kingdom*Email: h.patel3@rbht.nhs.ukINTRODUCTIONSYMPLICITY HTN-11 and SYMPLICITY HTN-22 demonstrated that renal denervation (RDN) could achievea significant reduction in office blood pressure in patients with resistant hypertension. At 36 months,88 patients in SYMPLICITY HTN-1, a proof-of-concept first-in-man registry, achieved a 32/14mmHgreduction in blood pressure from baseline. The more robust randomised SYMPLICITY HTN-2 trialshowed a 33/11mmHg drop in blood pressure against control. These positive results, supported bypublished data on thousands of other patients, added to the enthusiasm for this procedure.3 Therewere few who doubted that RDN deserved a place in the hypertension specialist’s armoury andthousands of procedures had already been performed mainly in Europe when SYMPLICITY HTN-3 waslaunched as a prerequisite for registration of renal denervation in the United States (US) according tothe stringent standards of the Food and Drug Administration.SYMPLICITY HTN-3SYMPLICITY HTN-3 was designed as a prospective, randomised, single-blind, sham-controlled trial. Itcompared the effect of RDN using the Symplicitye catheter (Medtronic, Minneapolis, MN-USA) againsta sham procedure (renal angiography) in 535 patients.4 There was unequal randomisation, 2:1(RDN:control). The study was conducted across 88 centres in the United States between October 2011and May 2013.The inclusion and exclusion criteria are illustrated in Table 1. In contrast to SYMPLICITY HTN-2,patients not only had initial evidence of a persistently elevated systolic blood pressure $160mmHgin an office measurement but also had an elevated 24hr ambulatory systolic blood pressure($135mmHg) two weeks later.The primary efficacy endpoint was defined as a change in office systolic blood pressure at 6 months.A primary safety composite endpoint consisting of mortality, end-stage renal failure and need for renalartery intervention amongst others was included. Change in 24hr ambulatory systolic blood pressurewas a secondary endpoint. The study was powered to show a superiority margin of 5mmHg or greaterin office systolic blood pressure and 2mmHg or greater in ambulatory systolic blood pressure.At baseline, patients were on an average of five anti-hypertensive medications with four of thesebeing at maximally tolerated doses and these proportions did not change significantly at the 6 monthfollow-up. Blinding was considered to be adequate with an index score .0.5.RESULTSThere was no difference between the two groups in the change in office systolic blood pressure at6 months:214.13^ 23.93mmHg (RDN group) vs211.74^ 25.94mmHg (sham-procedure) representinga between group change of 22.39mmHg (p ¼ 0.26). There was also no difference with respect toambulatory systolic blood pressure (26.75^ 15.11mmHg vs 24.79^ 17.25mmHg, p ¼ 0.98).Subgroup analysis showed RDN may have been better at lowering blood pressure in non-blackindividuals and those less than 65 years of age. However, these changes were not found to besignificant after adjusting for multiple comparisons.Table 1. Key inclusion and exclusion criteria of the SYMPLICITY HTN-3 trial.Inclusion Criteria Exclusion CriteriaOffice SBP $160mmHg on two clinicvisits two weeks apartIneligible renal artery anatomy (main renal artery ,4mm orwith ,20mm treatable length; multiple renal arteries;renal artery stenosis (.50%), previous renal artery intervention)On stable maximally tolerated doses of3 or more antihypertensivemedications including a diureticeGFR , 45ml/min/1.73m224hr ABPM SBP ,135mmHgSymptomatic postural hypotensionOther conditions (including primarypulmonary hypertension, type 1 diabetes, severe valve stenosis,acute coronary syndrome or stroke in last 6 months)SBP – systolic blood pressure; eGFR – estimated glomerular filtration rate; ABPM – ambulatory blood pressure monitor.Page 2 of 5Patel et al. Global Cardiology Science and Practice 2014:15The study did achieve its primary safety endpoint (composite of death, end-stage renal disease,embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at1 month or new renal-artery stenosis of more than 70% at 6 months), showing no difference betweenthe groups (1.4% vs 0.6%; p ¼ 0.67).DISCUSSIONSYMPLICITY HTN-3 was the best designed and largest randomised trial of RDN in resistant hypertensionto date and demonstrated that RDN achieved a reduction of blood pressure in patients with resistanthypertension that was large in absolute terms but rendered non-significant when compared to theequally large drop of blood pressure in the sham group.Before we ring the death knell on RDN we must first consider the explanations for this surprisingoutcome. These explanations fall in to two main camps: the detractors’ camp who argues that RDN istruly ineffective at lowering blood pressure and we have been misled by earlier trials in to believing thisnovel therapy could eradicate resistant hypertension. For the supporters’ camp, the argument is thatRDN is in principle an effective treatment but that there were factors in this trial which erroneously ledto a negative conclusion.To address the first camp we need to consider the differences between SYMPLICITY HTN-3 and thefirst two SYMPLICITY HTN trials. SYMPLICITY HTN-3 required that resistant hypertension be confirmed onambulatory blood pressure monitoring. The value of ambulatory blood pressure monitoring cannotbe over-emphasized. In a cohort of 8295 patients classified as having resistant hypertension basedon office readings alone, a staggering 37.5% of subjects were reclassified as having white coathypertension after ambulatory monitoring.5 SYMPLICITY HTN-2 did not require ambulatorymeasurements and hence may have recruited individuals with white coat hypertension. The secondimportant difference is that SYMPLICITY HTN-3 included a single-blinded sham procedure where theearlier SYMPLICITY HTN trials did not. Unblinded patients and blood pressure assessors can introduceimportant biases. Health care professionals assessing office blood pressure may alter the manner inwhich they measure and record blood pressure to be more optimistic after their patient has undergoneRDN and on the patient’s part, they may become more compliant with standard medical therapy.3,6 Thecombination of these two factors and the recruitment of some white coat hypertensives may have ledto such a large drop in blood pressure in SYMPLICITY HTN-2 which would have not have been seen hadthere been a blinded sham procedure and ambulatory blood pressure monitoring at recruitment.3The supporters’ camp emphasises the factors in SYMPLICITY HTN-3 which could have falsely lead to anegative result. After all it is not only the earlier SYMPLICITY HTN studies which provided support for thisstrategy but also the preclinical data showing the role of the renal sympathetic nerves both inhypertension7 and heart failure.8 One factor which may have led to a falsely negative study is theuncertainty whether the ablations were technically successful. All three SYMPLICITY HTN trials used thesame catheter: the single electrode Medtronic Symplicitye system (Figure 1). The single electrodesystem requires manipulation to apply energy in a helical pattern to the superior, inferior and lateral(anterior and posterior) walls of the renal artery (Figure 1). Technically, this can be difficult to achieve,not least because there is no intra-procedure marker of success and it is difficult to distinguish betweenan anterior and posterior position on fluoroscopy.9It is possible that the SYMPLICITY HTN-2 trialists (non-US) who had better experience of usingthe device were able to perform more effective renal denervation than the US operators in SYMPLICITYHTN-3. Only 26 interventionists out of 111 in SYMPLICITY HTN-3 had performed 5 or more denervations.This could explain some of the 19mmHg discrepancy in the fall of systolic blood pressure in thedenervation arms between SYMPLICITY HTN-2 and 3.The final contribution to the failure of SYMPLICITY HTN-3 is the large drop in blood pressure seen inthe sham arm. The SYMPLICITY HTN-2 control arm actually showed an increase in systolic bloodpressure of 1 ^ 21mmHg (Figure 2). Thus if it had not been for the large drop in blood pressure in thesham group (211.7 ^ 25.9mmHg), SYMPLICITY HTN-3 would have demonstrated the predicteddifference of 10mmHg. However, we cannot attribute the failure of SYMPLICITY HTN-3 to an “aberrant”drop in blood pressure in the sham arm because although uncommon, such a large decrease in bloodpressure in the control arm of a trial is not unique to SYMPLICITY HTN-3. The ASPIRANT study was arandomised, multi-centre, double-blind, placebo controlled trial of spironolactone in patients withresistant hypertension (n ¼ 117).10 Though it recruited patients whose average blood pressure waslower than that of the SYMPLICITY HTN-3 cohort, it too demonstrated a large placebo effect ofPage 3 of 5Patel et al. Global Cardiology Science and Practice 2014:1528.1 ^ 14.8mmHg (Figure 2) but unlike SYMPLICITY HTN-3 it showed that spironolactone significantlylowered systolic blood pressure beyond this placebo effect. Placebo effects do abate with time andconversely RDN effects on blood pressure have been shown to increase with time.11 SYMPLICITY HTN-3reported only blood pressure changes at 6 months. It would be of interest to review the 12-monthfindings. Patient selection is also extremely important. Expecting RDN to be a panacea for patients of allage, race and sex was probably too simplistic and a consequence of our incomplete understanding ofthe mechanism of the antihypertensive effect of RDN therapy. If black patients were excluded fromanalysis, the difference in systolic ambulatory blood pressure was greater than 6mmHg and we knowthat black patients have a worse response than white hypertensives to beta blockers andACE-inhibitors and better response to diuretics and vasodilators.SYMPLICITY HTN-3 ASPIRANTSpironolactonen=55Placebon=56RDNn=52RDNn=364Controln=54Shamn=171SYMPLICITY HTN-2Office SBP at baseline(mean±SD)Difference between groups178±18 178±16 180±16 180±17 155±10 154±12p<0.0001 p=0.26 p=0.001Change in office SBP(mean±SD)0mmHg–8±15–15±16–12±26–14±24+1±23–32±230mmHgFigure 2. A graph summarising the effect sizes of active and comparator in three contemporary trials of resistanthypertension.Treat distal to proximal≥5 mmspacingFigure 1. Renal Denervation. The Symplicitye Catheter is abutted to the renal artery wall using fluoroscopicguidance. Ablations are applied as shown in a helical pattern including at least one of each anterior, posterior,superior and inferior positions.Page 4 of 5Patel et al. Global Cardiology Science and Practice 2014:15Determining which of these camps is correct is important not only for the future of RDN inhypertension but also in its application to other conditions such as heart failure. If the problem istechnical (incomplete denervation) then more effective technology using multi-electrode catheters inexperienced hands should lead to better outcomes in future trials of RDN. Another problem may bepatient selection; none of the SYMPLICITY HTN trials used evidence of a raised sympathetic tone as aninclusion criterion.WHAT HAVE WE LEARNED?Despite SYMPLICITY HTN-3 being a well-designed study, a number of uncertainties have arisen whichprevent us from asserting that denervation is definitely ineffective at treating resistant hypertension.We can learn some lessons from the design of the earlier SYMPLICITY HTN trials which both promotedthe use of RDN but have now left us with some uncertainty. The first simple lesson is the importance ofusing ambulatory blood pressure to accurately diagnose resistant hypertension and exclude those withwhite coat hypertension. Another lesson learned is the importance of blinding and a sham procedureeven if this carries risk to those in the sham arm because the small risk in a small number of patientsearly in development can be justified by limiting exposure of a larger number of patients to theprocedure later in development if it ultimately fails to show a benefit.A final comment is on the need to develop a method to confirm incomplete or ineffective renaldenervation. This is a critical uncertainty which is essential to determine whether it is the therapy whichis ineffective or the technique of achieving denervation is ineffective. Catheters have now beendeveloped with multiple electrodes, balloon mounting and irrigation. If it is ultimately shown thatincomplete denervation was the downfall of SYMPLICITY HTN-3 then these new technologies may bethe saviour of RDN.FUNDING SOURCESHP and CH are funded by the NIHR Cardiovascular BRU at the Royal Brompton Hospital, London, UK.AUTHORS’ CONTRIBUTIONSAll authors have read and approved the final manuscript.REFERENCES[1] Krum H, Schlaich M, Whitbourn R, Sobotka P, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S,Abraham W, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safetyand proof-of-principle cohort study. Lancet. 2009;373:1275–1281.[2] Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renalsympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomisedcontrolled trial. Lancet. 2010;376:1903–1909.[3] Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with a focus on trial design: the CONVERGE report. Heart.2013;99:1579–1587.[4] Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA,Oparil S, Rocha-Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN-3 Investigators. A controlled trial of renaldenervation for resistant hypertension. N Engl J Med. 2014;370:1393–1401.[5] De la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical featuresof 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring.Hypertension. 2011;57:898–902.[6] Howard JP, Cole GD, Sievert H, Bhatt DL, Papademetriou V, Kandzari DE, Davies JE, Francis DP. Unintentionaloverestimation of an expected antihypertensive effect in drug and device trials: mechanisms and solutions. Int JCardiol. 2014;172:29–35.[7] Patel HC, di Mario C. Renal denervation for hypertension: where are we now? Br J Cardiol. 2013;20:142–147.[8] Patel H, Rosen S, Lindsay A, Hayward C, Lyon A, di Mario C. Targeting the autonomic nervous system: measuringautonomic function and novel devices for heart failure management. Int J Cardiol. 2013;170:107–117.[9] Patel H, Dhillon P, Mahfoud F, Lindsay A, Hayward C, Ersnt S, Lyon A, Rosen S, di Mario C. The biophysics of renalsympathetic denervation using radiofrequency energy. Clin Res Cardiol. 2013;103:337–344.[10] Vaclavik J, Sedlak R, Plachy M, Navratil K, Plasek J, Jarovsky J, Vaclavik T, Husar R, Kocianova E, Taborsky M. Addition ofspironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double blind, placebo-controlled trial. Hypertension. 2011;57:1069–1075.[11] Krum H, Schlaich M, Sobotka P, Bohm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler M. Percutaneous renaldenervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet.2014;383:622–629.Page 5 of 5Patel et al. Global Cardiology Science and Practice 2014:15

English

SYMPLICITY HTN 3: The death knell for renal denervation in hypertension?

Spiral - Imperial College Digital Repository

OPEN ACCESS Lessons from the trialsSYMPLICITY HTN 3: The death knellfor renal denervation inhypertension?Hitesh C Patel*, Carl Hayward, Carlo Di MarioABSTRACTResistant hypertension is, by definition, a challenge to most physicians treating hypertension. Renalsympathetic denervation has shown promising early results in treating this condition. The SYMPLICITYHTN-3 is the most recent trial to report the effects of this technique on resistant hypertension. Thisreview discusses this study and its surprising neutral results before ending with an overview of keylessons learned.Keywords: Renal denervation, resistant hypertension, trial designCite this article as: Patel HC, Hayward C, Di Mario C. SYMPLICITY HTN 3: The death knell for renaldenervation in hypertension? Global Cardiology Science and Practice 2014:15http://dx.doi.org/10.5339/gcsp.2014.15http://dx.doi.org/10.5339/gcsp.2014.15Submitted: 23 April 2014Accepted: 30 April 2014ª 2014 Patel, Hayward, Di Mario,licensee Bloomsbury QatarFoundation Journals. This is an openaccess article distributed under theterms of the Creative CommonsAttribution license CC BY 4.0, whichpermits unrestricted use,distribution and reproduction in anymedium, provided the original workis properly cited.National Institute of Health Research(NIHR), Cardiovascular BiomedicalResearch Unit, Royal BromptonHospital, Sydney Street, London SW36NP, United Kingdom*Email: h.patel3@rbht.nhs.ukINTRODUCTIONSYMPLICITY HTN-11 and SYMPLICITY HTN-22 demonstrated that renal denervation (RDN) could achievea significant reduction in office blood pressure in patients with resistant hypertension. At 36 months,88 patients in SYMPLICITY HTN-1, a proof-of-concept first-in-man registry, achieved a 32/14mmHgreduction in blood pressure from baseline. The more robust randomised SYMPLICITY HTN-2 trialshowed a 33/11mmHg drop in blood pressure against control. These positive results, supported bypublished data on thousands of other patients, added to the enthusiasm for this procedure.3 Therewere few who doubted that RDN deserved a place in the hypertension specialist’s armoury andthousands of procedures had already been performed mainly in Europe when SYMPLICITY HTN-3 waslaunched as a prerequisite for registration of renal denervation in the United States (US) according tothe stringent standards of the Food and Drug Administration.SYMPLICITY HTN-3SYMPLICITY HTN-3 was designed as a prospective, randomised, single-blind, sham-controlled trial. Itcompared the effect of RDN using the Symplicitye catheter (Medtronic, Minneapolis, MN-USA) againsta sham procedure (renal angiography) in 535 patients.4 There was unequal randomisation, 2:1(RDN:control). The study was conducted across 88 centres in the United States between October 2011and May 2013.The inclusion and exclusion criteria are illustrated in Table 1. In contrast to SYMPLICITY HTN-2,patients not only had initial evidence of a persistently elevated systolic blood pressure $160mmHgin an office measurement but also had an elevated 24hr ambulatory systolic blood pressure($135mmHg) two weeks later.The primary efficacy endpoint was defined as a change in office systolic blood pressure at 6 months.A primary safety composite endpoint consisting of mortality, end-stage renal failure and need for renalartery intervention amongst others was included. Change in 24hr ambulatory systolic blood pressurewas a secondary endpoint. The study was powered to show a superiority margin of 5mmHg or greaterin office systolic blood pressure and 2mmHg or greater in ambulatory systolic blood pressure.At baseline, patients were on an average of five anti-hypertensive medications with four of thesebeing at maximally tolerated doses and these proportions did not change significantly at the 6 monthfollow-up. Blinding was considered to be adequate with an index score .0.5.RESULTSThere was no difference between the two groups in the change in office systolic blood pressure at6 months:214.13^ 23.93mmHg (RDN group) vs211.74^ 25.94mmHg (sham-procedure) representinga between group change of 22.39mmHg (p ¼ 0.26). There was also no difference with respect toambulatory systolic blood pressure (26.75^ 15.11mmHg vs 24.79^ 17.25mmHg, p ¼ 0.98).Subgroup analysis showed RDN may have been better at lowering blood pressure in non-blackindividuals and those less than 65 years of age. However, these changes were not found to besignificant after adjusting for multiple comparisons.Table 1. Key inclusion and exclusion criteria of the SYMPLICITY HTN-3 trial.Inclusion Criteria Exclusion CriteriaOffice SBP $160mmHg on two clinicvisits two weeks apartIneligible renal artery anatomy (main renal artery ,4mm orwith ,20mm treatable length; multiple renal arteries;renal artery stenosis (.50%), previous renal artery intervention)On stable maximally tolerated doses of3 or more antihypertensivemedications including a diureticeGFR , 45ml/min/1.73m224hr ABPM SBP ,135mmHgSymptomatic postural hypotensionOther conditions (including primarypulmonary hypertension, type 1 diabetes, severe valve stenosis,acute coronary syndrome or stroke in last 6 months)SBP – systolic blood pressure; eGFR – estimated glomerular filtration rate; ABPM – ambulatory blood pressure monitor.Page 95 of 98Patel et al. Global Cardiology Science and Practice 2014:15The study did achieve its primary safety endpoint (composite of death, end-stage renal disease,embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at1 month or new renal-artery stenosis of more than 70% at 6 months), showing no difference betweenthe groups (1.4% vs 0.6%; p ¼ 0.67).DISCUSSIONSYMPLICITY HTN-3 was the best designed and largest randomised trial of RDN in resistant hypertensionto date and demonstrated that RDN achieved a reduction of blood pressure in patients with resistanthypertension that was large in absolute terms but rendered non-significant when compared to theequally large drop of blood pressure in the sham group.Before we ring the death knell on RDN we must first consider the explanations for this surprisingoutcome. These explanations fall in to two main camps: the detractors’ camp who argues that RDN istruly ineffective at lowering blood pressure and we have been misled by earlier trials in to believing thisnovel therapy could eradicate resistant hypertension. For the supporters’ camp, the argument is thatRDN is in principle an effective treatment but that there were factors in this trial which erroneously ledto a negative conclusion.To address the first camp we need to consider the differences between SYMPLICITY HTN-3 and thefirst two SYMPLICITY HTN trials. SYMPLICITY HTN-3 required that resistant hypertension be confirmed onambulatory blood pressure monitoring. The value of ambulatory blood pressure monitoring cannotbe over-emphasized. In a cohort of 8295 patients classified as having resistant hypertension basedon office readings alone, a staggering 37.5% of subjects were reclassified as having white coathypertension after ambulatory monitoring.5 SYMPLICITY HTN-2 did not require ambulatorymeasurements and hence may have recruited individuals with white coat hypertension. The secondimportant difference is that SYMPLICITY HTN-3 included a single-blinded sham procedure where theearlier SYMPLICITY HTN trials did not. Unblinded patients and blood pressure assessors can introduceimportant biases. Health care professionals assessing office blood pressure may alter the manner inwhich they measure and record blood pressure to be more optimistic after their patient has undergoneRDN and on the patient’s part, they may become more compliant with standard medical therapy.3,6 Thecombination of these two factors and the recruitment of some white coat hypertensives may have ledto such a large drop in blood pressure in SYMPLICITY HTN-2 which would have not have been seen hadthere been a blinded sham procedure and ambulatory blood pressure monitoring at recruitment.3The supporters’ camp emphasises the factors in SYMPLICITY HTN-3 which could have falsely lead to anegative result. After all it is not only the earlier SYMPLICITY HTN studies which provided support for thisstrategy but also the preclinical data showing the role of the renal sympathetic nerves both inhypertension7 and heart failure.8 One factor which may have led to a falsely negative study is theuncertainty whether the ablations were technically successful. All three SYMPLICITY HTN trials used thesame catheter: the single electrode Medtronic Symplicitye system (Figure 1). The single electrodesystem requires manipulation to apply energy in a helical pattern to the superior, inferior and lateral(anterior and posterior) walls of the renal artery (Figure 1). Technically, this can be difficult to achieve,not least because there is no intra-procedure marker of success and it is difficult to distinguish betweenan anterior and posterior position on fluoroscopy.9It is possible that the SYMPLICITY HTN-2 trialists (non-US) who had better experience of usingthe device were able to perform more effective renal denervation than the US operators in SYMPLICITYHTN-3. Only 26 interventionists out of 111 in SYMPLICITY HTN-3 had performed 5 or more denervations.This could explain some of the 19mmHg discrepancy in the fall of systolic blood pressure in thedenervation arms between SYMPLICITY HTN-2 and 3.The final contribution to the failure of SYMPLICITY HTN-3 is the large drop in blood pressure seen inthe sham arm. The SYMPLICITY HTN-2 control arm actually showed an increase in systolic bloodpressure of 1 ^ 21mmHg (Figure 2). Thus if it had not been for the large drop in blood pressure in thesham group (211.7 ^ 25.9mmHg), SYMPLICITY HTN-3 would have demonstrated the predicteddifference of 10mmHg. However, we cannot attribute the failure of SYMPLICITY HTN-3 to an “aberrant”drop in blood pressure in the sham arm because although uncommon, such a large decrease in bloodpressure in the control arm of a trial is not unique to SYMPLICITY HTN-3. The ASPIRANT study was arandomised, multi-centre, double-blind, placebo controlled trial of spironolactone in patients withresistant hypertension (n ¼ 117).10 Though it recruited patients whose average blood pressure waslower than that of the SYMPLICITY HTN-3 cohort, it too demonstrated a large placebo effect ofPage 96 of 98Patel et al. Global Cardiology Science and Practice 2014:1528.1 ^ 14.8mmHg (Figure 2) but unlike SYMPLICITY HTN-3 it showed that spironolactone significantlylowered systolic blood pressure beyond this placebo effect. Placebo effects do abate with time andconversely RDN effects on blood pressure have been shown to increase with time.11 SYMPLICITY HTN-3reported only blood pressure changes at 6 months. It would be of interest to review the 12-monthfindings. Patient selection is also extremely important. Expecting RDN to be a panacea for patients of allage, race and sex was probably too simplistic and a consequence of our incomplete understanding ofthe mechanism of the antihypertensive effect of RDN therapy. If black patients were excluded fromanalysis, the difference in systolic ambulatory blood pressure was greater than 6mmHg and we knowthat black patients have a worse response than white hypertensives to beta blockers andACE-inhibitors and better response to diuretics and vasodilators.SYMPLICITY HTN-3 ASPIRANTSpironolactonen=55Placebon=56RDNn=52RDNn=364Controln=54Shamn=171SYMPLICITY HTN-2Office SBP at baseline(mean±SD)Difference between groups178±18 178±16 180±16 180±17 155±10 154±12p<0.0001 p=0.26 p=0.001Change in office SBP(mean±SD)0mmHg–8±15–15±16–12±26–14±24+1±23–32±230mmHgFigure 2. A graph summarising the effect sizes of active and comparator in three contemporary trials of resistanthypertension.Treat distal to proximal≥5 mmspacingFigure 1. Renal Denervation. The Symplicitye Catheter is abutted to the renal artery wall using fluoroscopicguidance. Ablations are applied as shown in a helical pattern including at least one of each anterior, posterior,superior and inferior positions.Page 97 of 98Patel et al. Global Cardiology Science and Practice 2014:15Determining which of these camps is correct is important not only for the future of RDN inhypertension but also in its application to other conditions such as heart failure. If the problem istechnical (incomplete denervation) then more effective technology using multi-electrode catheters inexperienced hands should lead to better outcomes in future trials of RDN. Another problem may bepatient selection; none of the SYMPLICITY HTN trials used evidence of a raised sympathetic tone as aninclusion criterion.WHAT HAVE WE LEARNED?Despite SYMPLICITY HTN-3 being a well-designed study, a number of uncertainties have arisen whichprevent us from asserting that denervation is definitely ineffective at treating resistant hypertension.We can learn some lessons from the design of the earlier SYMPLICITY HTN trials which both promotedthe use of RDN but have now left us with some uncertainty. The first simple lesson is the importance ofusing ambulatory blood pressure to accurately diagnose resistant hypertension and exclude those withwhite coat hypertension. Another lesson learned is the importance of blinding and a sham procedureeven if this carries risk to those in the sham arm because the small risk in a small number of patientsearly in development can be justified by limiting exposure of a larger number of patients to theprocedure later in development if it ultimately fails to show a benefit.A final comment is on the need to develop a method to confirm incomplete or ineffective renaldenervation. This is a critical uncertainty which is essential to determine whether it is the therapy whichis ineffective or the technique of achieving denervation is ineffective. Catheters have now beendeveloped with multiple electrodes, balloon mounting and irrigation. If it is ultimately shown thatincomplete denervation was the downfall of SYMPLICITY HTN-3 then these new technologies may bethe saviour of RDN.FUNDING SOURCESHP and CH are funded by the NIHR Cardiovascular BRU at the Royal Brompton Hospital, London, UK.AUTHORS’ CONTRIBUTIONSAll authors have read and approved the final manuscript.REFERENCES[1] Krum H, Schlaich M, Whitbourn R, Sobotka P, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S,Abraham W, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safetyand proof-of-principle cohort study. Lancet. 2009;373:1275–1281.[2] Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renalsympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomisedcontrolled trial. Lancet. 2010;376:1903–1909.[3] Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with a focus on trial design: the CONVERGE report. Heart.2013;99:1579–1587.[4] Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA,Oparil S, Rocha-Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN-3 Investigators. A controlled trial of renaldenervation for resistant hypertension. N Engl J Med. 2014;370:1393–1401.[5] De la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical featuresof 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring.Hypertension. 2011;57:898–902.[6] Howard JP, Cole GD, Sievert H, Bhatt DL, Papademetriou V, Kandzari DE, Davies JE, Francis DP. Unintentionaloverestimation of an expected antihypertensive effect in drug and device trials: mechanisms and solutions. 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SYMPLICITY HTN 3: The death knell for renal denervation in hypertension?

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