Elsevier

The Lancet

Volume 373, Issue 9671, 11–17 April 2009, Pages 1275-1281
The Lancet

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Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study

https://doi.org/10.1016/S0140-6736(09)60566-3Get rights and content

Summary

Background

Renal sympathetic hyperactivity is associated with hypertension and its progression, chronic kidney disease, and heart failure. We did a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (ie, systolic blood pressure ≥160 mm Hg on three or more antihypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness.

Methods

We enrolled 50 patients at five Australian and European centres; 5 patients were excluded for anatomical reasons (mainly on the basis of dual renal artery systems). Patients received percutaneous radiofrequency catheter-based treatment between June, 2007, and November, 2008, with subsequent follow-up to 1 year. We assessed the effectiveness of renal sympathetic denervation with renal noradrenaline spillover in a subgroup of patients. Primary endpoints were office blood pressure and safety data before and at 1, 3, 6, 9, and 12 months after procedure. Renal angiography was done before, immediately after, and 14–30 days after procedure, and magnetic resonance angiogram 6 months after procedure. We assessed blood-pressure lowering effectiveness by repeated measures ANOVA. This study is registered in Australia and Europe with ClinicalTrials.gov, numbers NCT 00483808 and NCT 00664638.

Findings

In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean 4·7 antihypertensive medications); estimated glomerular filtration rate was 81 mL/min/1·73m2 (SD 23); and mean reduction in renal noradrenaline spillover was 47% (95% CI 28–65%). Office blood pressures after procedure were reduced by −14/−10, −21/−10, −22/−11, −24/−11, and −27/−17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five non-treated patients, mean rise in office blood pressure was +3/−2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae. There were no other renovascular complications.

Interpretation

Catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension. Prospective randomised clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.

Funding

Ardian Inc.

Introduction

Hypertension is a major global public health concern. An estimated 30–40% of the adult population in the developed world suffer from this condition. Furthermore, its prevalence is expected to increase, especially in developing countries.1, 2 Diagnosis and treatment of hypertension remain suboptimal, even in developed countries. Despite the availability of numerous safe and effective pharmacological therapies, including fixed-drug combinations, the percentage of patients achieving adequate blood-pressure control to guideline target values remains low.3, 4 Much failure of the pharmacological strategy to attain adequate blood-pressure control is attributed to both physician inertia and patient non-compliance and non-adherence to a lifelong pharmacological therapy for a mainly asymptomatic disease. Thus, the development of new approaches for the management of hypertension, especially those that could help overcome these issues, is a priority. All these considerations are especially relevant to patients with so-called resistant hypertension5 (ie, those unable to achieve target blood-pressure values despite multiple drug therapies at the highest tolerated dose). Such patients are at high risk of major cardiovascular events.5

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal artery, are crucial for initiation and maintenance of systemic hypertension.6, 7, 8, 9 Indeed, sympathetic nerve modulation as a therapeutic strategy in hypertension had been considered long before the advent of modern pharmacological therapies. Radical surgical methods for thoracic, abdominal, or pelvic sympathetic denervation had been successful in lowering blood pressure in patients with so-called malignant hypertension. However, these methods were associated with high perioperative morbidity and mortality and long-term complications, including bowel, bladder, and erectile dysfunction, in addition to severe postural hypotension.10, 11, 12 Nevertheless, selective renal sympathetic denervation is still an intriguing therapeutic target.

In this context, a percutaneous, catheter-based approach has been developed to disrupt renal sympathetic nerves without affecting other abdominal, pelvic, or lower extremity innervation. Renal sympathetic denervation is achieved percutaneously via the lumen of the main renal artery with a catheter connected to a radiofrequency generator. Preclinical juvenile swine studies (Ardian Inc, unpublished) have confirmed that the procedure reduces noradrenaline content in the kidney by more than 85%, which is comparable to direct surgical renal denervation via artery transection and re-anastomosis. The catheter-based procedure resulted in no severe vascular or renal injury, which was evaluated 6 months after procedure.

Our aim was to assess the safety and blood-pressure lowering effectiveness of therapeutic renal denervation with a percutaneous treatment in patients who are resistant to current standard antihypertensive therapies.

Section snippets

Study setting

This study was approved by the ethical review committees at all five participating centres in Australia and Europe. Patients were treated with the renal denervation procedure between June, 2007, and November, 2008, with subsequent follow-up to 1 year. Assessment included physical examination, and blood-pressure and renal-function measurements. An independent data safety and monitoring committee reviewed angiograms and serious adverse events. Written informed consent was obtained from all

Results

50 patients underwent renal angiogram in preparation for renal denervation (figure 1). Five patients were excluded from the procedure for anatomical reasons (mainly on the basis of dual renal artery systems). The remaining 45 patients underwent renal denervation.

Treated patients were similar to those reported with resistant hypertension, being 58 years of age (SD 9; range 37–76 years) and 44% (n=20) female (table). Treated patients had numerous concomitant illnesses, including type 2 diabetes,

Discussion

We present clinical findings of renal denervation using a catheter-based approach for the treatment of patients with resistant hypertension. We showed an excellent safety profile of this brief, catheter-based therapy. No long-term adverse events resulted from the procedure. Specifically, we did not see cases of renal artery aneurysm or stenosis despite repeated scrutiny, including renal angiograms done 14–30 days after the procedure and magnetic resonance angiogram at 6 months. Furthermore,

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