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Background
Hypertension is an independent risk factor for cardiovascular disease. Treatment frequently includes administration of three or more drugs. Resistant hypertension is defined as blood pressure which remains above target levels despite use of the maximum tolerated dose of antihypertensive medications, consisting of at least three different classes of drugs, including a diuretic. Radiofrequency (RF) ablation of sympathetic nerve fibers around renal arteries has been proposed as a non-pharmacologic treatment to reduce blood pressure in drug resistant hypertension (Simonyi et al, 2013).
Selective renal sympathetic denervation interrupts the influence of the sympathetic nervous system on the kidney and systemic hemodynamics. The sympathetic innervation of the kidney is implicated in the pathogenesis of hypertension through effects on renin secretion, increased plasma renin activity that leads to sodium and water retention, and reduction of renal blood flow. Renal sympathetic ablation is a minimally invasive procedure utilizing a RF catheter inserted through the femoral artery and selectively engaging the renal artery (Papademitriou et al, 2011).
Krum et al (2009) performed a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (i.e., systolic blood pressure greater than or equal to 160 mm Hg on 3 or more anti-hypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness. The investigators enrolled 50 patients at 5 Australian and European centers; 5 patients were excluded for anatomical reasons (primarily due to dual renal artery systems). Patients received percutaneous RF catheter-based treatment between June 2007 and November 2008, with subsequent follow-up to 1 year. The effectiveness of renal sympathetic denervation with renal noradrenaline spillover was assessed in a subgroup of patients. Primary endpoints were office blood pressure and safety data before the procedure and at 1, 3, 6, 9, and 12 months after the procedure. Renal angiography was done before, immediately after, and 14 to 30 days after procedure, and magnetic resonance angiogram was assessed 6 months after procedure. Blood-pressure lowering effectiveness was analyzed using repeated measures ANOVA. In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean of 4.7 anti-hypertensive medications); estimated glomerular filtration rate was 81 ml/min/1.73m(2) (SD 23); and mean reduction in renal noradrenaline spillover was 47 % (95 % confidence interval [CI]: 28 % to 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 5 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 intra-procedural renal artery dissection occurred before RF energy delivery, without further sequelae. There were no other renovascular complications. The authors concluded that catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension. They also stated that prospective randomized clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.
A prioritizing summary of the Australia and New Zealand Horizon Scanning Network on renal sympathetic denervation for the treatment of resistant hypertension concluded that based on the low level of available evidence, it would appear that renal denervation may be a viable option for the treatment of resistant hypertension (Mundy & Hiller, 2010). Blood pressure was significantly lower after renal denervation than that measured at baseline; however, it is unclear whether this decrease is considered clinically significant. Final 12-month follow-up data were only reported for a small portion of the enrolled patients (22%) and in addition, six of the 45 patients were considered non-responders with non-significant reductions in blood pressure. The summary concluded that well conducted randomized controlled trial is needed to adequately investigate whether renal denervation is capable of producing a sustained lowering of blood pressure in hypertensive patients resistant to medication (Mundy & Hiller, 2010).
Voskuil et al (2011) described their first experience with a percutaneous treatment modality using renal artery RF ablation. Selected patients were resistant to at least 3 types of anti-hypertensive medical therapy (office systolic blood pressure greater than or equal to 160 mm Hg; n = 9) or who did not tolerate medication (n = 2). Between July and November 2010, a total of 11 patients received percutaneous RF treatment and were followed for 1 month after treatment. Urine and blood samples were taken to evaluate the effects on renal function and neurohumeral factors. No peri-procedural complications or adverse events during follow-up were noted. A reduction of mean office blood pressure was observed from 203/109 +/- 32/19 mmHg at baseline to 178/97 +/- 28/21 mm Hg at 1 month follow-up (mean difference 25 +/- 12 mm Hg, p < 0.01). The investigators also noted a significant decrease in aldosterone level (391 +/- 210 pmol/L versus 250 +/- 142 pmol/L; p = 0.03), but there was no decrease in plasma renin activity (190 +/- 134 fmol/L/s versus 195 +/- 163 fmol/L/s; p = 0.43). No change in renal function was noted. The authors concluded that catheter-based renal denervation seems an attractive novel minimally invasive treatment option in patients with resistant hypertension, with a low-risk of serious adverse events.
Mahfoud et al (2011) summarized the expert consensus and recommendations of the working group 'Herz und Niere' of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for anti-hypertensive treatment. Renal denervation was defined as a new, interventional approach to selectively denervate renal afferent and efferent sympathetic fibers. The authors noted that renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure greater than or equal to 160 mm Hg and greater than or equal to 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure. Exclusion of secondary hypertension causes and optimized anti-hypertensive drug treatment was described as mandatory in every patient with resistant hypertension. They also specified that 24-hour blood pressure measurements should be performed in order to exclude pseudo-resistance. Preserved renal function was an inclusion criterion in the Symplicity studies. Therefore, renal denervation should be only considered in patients with a glomerular filtration rate greater than 45 ml/min. Adequate center qualification in both treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety. The authors stated that long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.
Lobodzinski (2011) reviewed renal denervation system technology for treatment of drug resistant hypertension. These researchers described “an investigational device that is currently tested in an on-going clinical trial. The denervation device uses the RF thermal ablation catheter attached to the RF generator. The RF catheter is inserted into the renal artery and positioned in the vicinity of the efferent and afferent parasympathetic innervations. Renal denervation is a minimally invasive, localized procedure and the procedural and recovery times are very short. The entire procedure lasts about 40 minutes. In early clinical trials, the systolic blood pressure in 87 % of patients who underwent the denervation procedure resulted in an average blood pressure drop of greater than 10 mm Hg. The procedure has no systematic side effects, and appears to be beneficial in the management of hypertension in patients refractory to pharmacological therapy.”
Patel and White (2012) stated that renal artery intervention to treat hypertension is one of the frontiers of ongoing research in combating this epidemic. The investigators discussed recent data regarding renal artery angioplasty with stenting (PTRS) and catheter-based renal sympathetic denervation. They noted that despite progress in this field, large, multi-center, randomized trials that compare these treatment modalities with medical therapy for hypertension are lacking.
Tam et al (2012) stated that resistant hypertension, defined as the failure to achieve target blood pressure despite concurrent use of 3 anti-hypertensive agents of different classes, is estimated to affect 20 to 30 % of hypertensive patients. These patients are vulnerable to cardiovascular, cerebrovascular and renal complications. There is ample evidence that sympathetic nervous system hyperactivity contributes to the initiation, maintenance, and progression of hypertension. The renal sympathetic nervous system, in particular, has been identified as a major culprit for the development and progression of hypertension, heart failure and chronic kidney disease in both preclinical and human studies. Traditional surgical sympathectomy proposed in the 1940s was halted due to unacceptable operative risk and the emergence of anti-hypertensive medications. The authors report that recently, catheter-based renal sympathetic denervation by RF ablation has shown encouraging intermediate-term results with minimal complications in patients with resistant hypertension.
A May, 2012 National Institute for Health and Clinical Excellence guideline stated that “current evidence on percutaneous transluminal RF sympathetic denervation of the renal artery for resistant hypertension is from limited numbers of patients, but there is evidence of efficacy in the short and medium term. There is inadequate evidence on efficacy in the long term; this is particularly important for a procedure aimed at treating resistant hypertension. The limited evidence suggests a low incidence of serious periprocedural complications, but there is inadequate evidence on long-term safety. Therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research (NICE, 2012).”
Esler et al (2012) noted that renal sympathetic nerve activation contributes to the pathogenesis of hypertension. Symplicity HTN-2, a multicenter, randomized trial, demonstrated that catheter-based renal denervation produced significant blood pressure lowering in treatment-resistant patients 6 months after the procedure compared with controls, which were medication-only patients. The authors presented longer-term follow-up, including 6-month crossover results, is now presented. Eligible patients were on ≥3 antihypertensive drugs and had a baseline systolic blood pressure ≥160 mm Hg (≥150 mm Hg for type 2 diabetics). After the 6-month primary end point was met, renal denervation in control patients was permitted. Patients randomized to immediate renal denervation (n=47) were evaluated one year post-procedure and crossover patients were evaluated 6 months post-procedure. At 12 months after the procedure, the mean fall in office systolic blood pressure in the initial renal denervation group (-28.1 mm Hg; 95% confidence interval, -35.4 to -20.7; P<0.001) was similar to the 6-month fall (-31.7 mm Hg; 95% confidence interval, -38.3 to -25.0; P=0.16 versus 6-month change). The mean systolic blood pressure of the crossover group 6 months after the procedure was significantly lowered (from 190.0±19.6 to 166.3±24.7 mm Hg; change, -23.7±27.5; P<0.001). In the crossover group, there was 1 renal artery dissection during guide catheter insertion, before denervation, corrected by renal artery stenting, and 1 hypotensive episode, which resolved with medication adjustment. Control patients who crossed over to renal denervation with the Symplicity system had a significant drop in blood pressure similar to that observed in patients receiving immediate denervation. The authors concluded that renal denervation provided safe and sustained reduction of blood pressure to 1 year.
Geisler et al (2012) conducted a study to assess cost-effectiveness and long-term clinical benefits of renal denervation in resistant hypertensive patients. The authors noted that in the Symplicity HTN-2 randomized controlled trial, catheter-based renal denervation (RDN) lowered systolic blood pressure by 32 ± 23 mm Hg from 178 ± 18 mm Hg at baseline. A state-transition model was used to predict the effect of RDN and standard of care on 10-year and lifetime probabilities of stroke, myocardial infarction, all coronary heart disease, heart failure, end-stage renal disease, and median survival. The investigators adopted a societal perspective and estimated an incremental cost-effectiveness ratio in U.S. dollars per quality-adjusted life-year, both discounted at 3% per year. Robustness and uncertainty were evaluated using deterministic and probabilistic sensitivity analyses. Renal denervation substantially reduced event probabilities (10-year/lifetime relative risks: stroke 0.70/0.83; myocardial infarction 0.68/0.85; all coronary heart disease 0.78/0.90; heart failure 0.79/0.92; end-stage renal disease 0.72/0.81). Median survival was 18.4 years for RDN versus 17.1 years for standard of care. The discounted lifetime incremental cost-effectiveness ratio was $3,071 per quality-adjusted life-year. The investigators acknowledged that findings were relatively insensitive to variations in input parameters except for systolic blood pressure reduction, baseline systolic blood pressure, and effect duration. The 95% credible interval for incremental cost-effectiveness ratio was cost-saving to $31,460 per quality-adjusted life-year. The model suggests that catheter-based renal denervation, over a wide range of assumptions, is a cost-effective strategy for resistant hypertension that might result in lower cardiovascular morbidity and mortality.
The Symplicity HTN-3 Trial is currently in progress. Early clinical evaluation with catheter-based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is defined as the change in office-based systolic blood pressure from baseline to 6 months (Kandzari et al, 2012).
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