Felix Mahfoud

Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.

BACKGROUNDnActivation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension.nnnMETHODSnIn this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mmu2008Hg or more (≥150 mmu2008Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433.nnnFINDINGSn106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mmu2008Hg (SD 23/11, baseline of 178/96 mmu2008Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mmu2008Hg [21/10], baseline of 178/97 mmu2008Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mmu2008Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mmu2008Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment.nnnINTERPRETATIONnCatheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients.nnnFUNDINGnArdian.

Expert consensus document from the European Society of Cardiology on catheter-based renal denervation

Hypertension is highly prevalent and one of the most frequent chronic diseases worldwide.1 It has been suggested that over the next two decades up to 50% of the adult population will be diagnosed with hypertension, according to the standard guideline definitions.1 Despite the availability of many safe and effective antihypertensive drugs, control rates to target blood pressure remain low.2 Approximately 5–10% of all patients with high blood pressure are resistant to drug treatment defined as blood pressure >140/90 mmHg, >130–139/80–85 mmHg in diabetes mellitus or >130/80 mmHg in chronic kidney disease in the presence of three or more antihypertensives of different classes, including a diuretic, at maximal or the highest tolerated dose.3 Resistant hypertension is associated with an increased risk of cardiovascular events.4 Current non-invasive therapeutic strategies are mainly based on lifestyle interventions and pharmacological treatment, including mineralocorticoid receptor antagonists.3 Up until recently treatment options for patients with resistant hypertension were limited. Nowadays catheter-based renal denervation offers a new approach targeting the renal sympathetic nerves. Indeed, the technique has been shown to reduce sympathetic nerve activity,5 norepinephrine spillover6 as well as blood pressure7–9 in patients with resistant hypertension. Several national10–13 and international14 consensus documents from different societies have recently been published, with different degrees of involvement of interventionalists. This expert consensus document summarizes the view of an expert panel of the European Society of Cardiology and the European Association of Percutaneous Cardiovascular Interventions to provide guidance regarding …

Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial

AIMnThe aim of this study was to determine long-term results of renal artery denervation for treatment of treatment-resistant hypertension in the SYMPLICITY HTN-2 study.nnnMETHODSnSYMPLICITY HTN-2 randomized 106 subjects with treatment-resistant hypertension to renal denervation or medical therapy alone. At 6 months, 37 control subjects crossed over to renal denervation. Office blood pressure measurements, antihypertensive medication use, and safety events were followed every 6 months through 3 years.nnnRESULTSnFollow-up was available at 36 months in 40 of 52 subjects in the initial renal denervation group and at 30 months in 30 of 37 subjects who crossed over and received renal denervation at 6 months. Baseline blood pressure was 184 ± 19/99 ± 16 mmHg in all treated subjects. At 30-month post-procedure, systolic blood pressure decreased 34 mmHg (95% CI: -40, -27, P < 0.01) and diastolic blood pressure decreased 13 mmHg (95% CI: -16, -10, P < 0.01). The systolic and diastolic blood pressure reduction at 36 months for the initial renal denervation group was -33 mmHg (95% CI: -40, -25, P < 0.01) and -14 mmHg (95% CI: -17, -10, P < 0.01), respectively. Procedural complications included one haematoma, and one renal artery dissection before energy delivery that was treated successfully. Later complications included two cases of acute renal failure, which fully resolved, 15 hypertensive events requiring hospitalization, and three deaths.nnnCONCLUSIONnRenal denervation resulted in sustained lowering of blood pressure at 3 years in a selected population of subjects with severe, treatment-resistant hypertension without serious safety concerns.nnnCLINICAL TRIAL REGISTRATIONnNCT00888433.

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design

Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25nnWhatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

First Report of the Global SYMPLICITY Registry on the Effect of Renal Artery Denervation in Patients With Uncontrolled Hypertension

&NA;This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mmu2009Hg; 24-hour systolic pressure, ≥135 mmu2009Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mmu2009Hg for all patients and 179.3±16.5 mmu2009Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mmu2009Hg. At 6 months, the changes in office and 24-hour systolic BPs were −11.6±25.3 and −6.6±18.0 mmu2009Hg for all patients (P<0.001 for both) and −20.3±22.8 and −8.9±16.9 mmu2009Hg for those with severe hypertension (P<0.001 for both). Renal denervation was associated with low rates of adverse events. After the procedure through 6 months, there was 1 new renal artery stenosis >70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. Clinical Trial Registration—URL: www.clinicaltrials.gov. Unique identifier: NCT01534299

Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial

AIMSnSympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension.nnnMETHODS AND RESULTSnCardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m(1.7) vs. 43.0 ± 12.6 g/m(1.7), P < 0.001) without changes in the control group (41.9 ± 10.8 g/m(1.7) vs. 42.0 ± 9.7 g/m(1.7), P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (<50%) significantly increased after RDN (43% vs. 50%, P < 0.001). Left ventricular circumferential strain as a surrogate of diastolic function in the subgroup of patients with reduced strain at baseline increased by 21% only in the RDN group (-14.8 vs. -17.9; P = 0.001) and not in control patients (-15.5 vs. -16.4, P = 0.508).nnnCONCLUSIONSnCatheter-based RDN significantly reduced BP and LVMI and improved EF and circumferential strain in patients with resistant hypertension, occurring partly BP independently.

Rationale and design of a large registry on renal denervation: The Global SYMPLICITY registry

AIMSnHypertension is a global healthcare concern associated with a wide range of comorbidities. The recognition that elevated sympathetic drive plays an important role in the pathogenesis of hypertension led to the use of renal artery denervation to interrupt the efferent and afferent sympathetic nerves between the brain and kidneys to lower blood pressure. Clinical trials of the Symplicity™ renal denervation system have demonstrated that radiofrequency ablation of renal artery nerves is safe and significantly lowers blood pressure in patients with severe resistant (systolic BP >160 mmHg) hypertension. Smaller ancillary studies in hypertensive patients suggest a benefit from renal denervation in a variety of conditions such as chronic kidney disease, glucose intolerance, sleep apnoea and heart failure.nnnMETHODS AND RESULTSnThe Global SYMPLICITY registry, which incorporates the GREAT SYMPLICITY registry initiated in Germany, is being conducted worldwide to evaluate the safety and efficacy of treatment with the Symplicity renal denervation system in real-world uncontrolled hypertensive patients, looking first at subjects with severe resistant hypertension to confirm the results of prior clinical trials, but then also subjects with a wider range of baseline blood pressure and coexisting comorbidities.nnnCONCLUSIONSnThe rationale, design and first baseline data from the Global SYMPLICITY registry are presented.

Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials

BACKGROUNDnStudies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes.nnnMETHODSnIn this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2. These trials were registered with ClinicalTrials.gov, number NCT00153101.nnnFINDINGSnRecruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30u2008937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25u2008127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14u2008305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk.nnnINTERPRETATIONnMean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality.nnnFUNDINGnBoehringer Ingelheim.

Renal denervation: symply trapped by complexity?

This editorial refers to ‘Predictors of blood pressure response in the SYMPLICITY HTN-3 trial’[†][1], by D.E. Kandzari et al ., on page 219. nnSeven years after the first patient was treated with the Symplicity Arch catheter by Murray Esler and colleagues in Melbourne, Australia,1 our knowledge about the renal sympathetic nervous system and its modulation by catheter-based renal denervation has significantly evolved. This minimally invasive approach was developed to destroy the renal afferent and efferent sympathetic nerves in the vessel wall of the renal arteries by means of radiofrequency energy.2 First-in-man studies and open-label registries documented that this technique lowers sympathetic nerve activity and blood pressure in certain patients with resistant hypertension.3–6 The treatment was delivered safely with minimal procedural complications and with no detrimental effect on renal function.7,8 Long-term vascular safety, however, remains to be confirmed as concerns have been raised that the procedure might induce renal artery stenosis in some patients.9 Moreover, in preliminary studies, regression of left ventricular mass and improvements in diastolic function,10 as well as antiarrhythmic effects11 were observed following renal denervation. It was obvious that the results of previous published studies required validation in blinded, randomized, controlled clinical trials. While the first small randomized trial, Symplicity HTN-2 enrolling 106 patients to receive either renal nerve ablation or medical treatment alone without a sham procedure, confirmed the results obtained in registries, the blinded, sham-controlled Symplicity HTN-3 study randomizing 535 patients,8 again using Medtronics Symplicity device, did meet its primary safety endpoint, but disappointingly failed to reach its primary efficacy endpoint, defined as a statistically significant decrease …nn [1]: #fn-2

Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry

Aims Catheter-based renal artery denervation (RDN) has been shown to lower blood pressure (BP) in certain patients with uncontrolled hypertension. Isolated systolic hypertension (ISH) (systolic BP [SBP] ≥140 mmHg and diastolic BP <90 mmHg), characterized by increased vascular stiffness, is the predominant hypertensive phenotype in elderly patients. This study compared baseline characteristics and SBP change at 6 months between patients with ISH and combined systolic–diastolic hypertension (CH). Methods and results This study pooled data from 1103 patients from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. A total of 429 patients had ISH, and 674 had CH. Patients with ISH were significantly older than those with CH (66 vs. 55 years), had more type 2 diabetes mellitus (52.9 vs. 34.6%), and a lower estimated glomerular filtration rate (71.8 vs. 78.6 mL/min/1.73 m2); all P < 0.001. At 6 months, the SBP drop for CH patients was −18.7 ± 23.7 mmHg compared with a reduction of −10.9 ± 21.7 mmHg for ISH patients −7.8 mmHg, 95% confidence interval, CI, −10.5, −5.1, P < 0.001). The change in 24-h SBP at 6 months was −8.8 ± 16.2 mmHg in patients with CH vs. −5.8 ± 15.4 mmHg in ISH (−3.0 mmHg, 95% CI −5.4, −0.6, P = 0.015). Presence of ISH at baseline but not age was associated with less pronounced BP changes following the procedure. The strongest predictor of office SBP reduction at 6 months was CH, followed by aldosterone antagonist use and non-use of vasodilators. Conclusion The reduction in BP among patients with ISH following RDN was less pronounced than the reduction in patients with CH. Clinical.Trials.gov identifiers NCT01534299 and NCT01418261.