Renal sympathetic denervation for treatment of resistant hypertension

Abstracts

INTRODUÇÃO: A hipertensão arterial sistêmica afeta mais de 1,2 milhão de pessoas no mundo. Apenas 35% dos pacientes hipertensos têm valores de pressão arterial controlados. Recentemente a denervação simpática renal (DSR) tem demonstrado diminuir significativamente os valores de pressão arterial nos pacientes com hipertensão arterial sistêmica resistente. MÉTODOS: Estudo prospectivo, de braço único, observacional, multicêntrico, incluindo pacientes consecutivos submetidos a DSR. O objetivo primário foi avaliar os níveis da pressão arterial sistólica aos 30 dias de seguimento. O objetivo secundário foi determinar a ocorrência de qualquer evento adverso relacionado com o procedimento. RESULTADOS: Foram incluídos os primeiros 20 pacientes submetidos a DSR. A média de pressão arterial antes do procedimento foi de 171,6/93,2 ± 15,5/11,3 mmHg, com média de uso de 4,1 ± 1,5 fármacos anti-hipertensivos por paciente. A taxa de sucesso foi de 95%, tendo sido aplicadas 11,1 ± 1,9 ablações por paciente. Foi observada diminuição média de 29 ± 21 mmHg (P = 0,009) na pressão arterial sistólica 30 dias após o procedimento. Não houve complicação associada ao procedimento. CONCLUSÕES: A DSR por cateter em pacientes da prática clínica diária diminuiu significativamente os valores de pressão arterial. Em nossa experiência, a DSR demonstrou ser factível e segura.

Hipertensão; Rins; Simpatectomia; Cateteres

ORIGINAL ARTICLE

^IInterventionist Cardiologist Physician, Director of Cardiovascular Research Center Caracas. Caracas, Venezuela

^IIInterventionist Cardiologist Physician, Director of Cardiovascular Research Center Caracas. Caracas, Venezuela

^IIIInterventionist Cardiologist Physician at the Invasive Cardiology Service of Instituto Médico La Floresta. Caracas, Venezuela

^IVInterventionist Cardiologist Physician at the Invasive Cardiology Service of Centro Médico de Caracas. Caracas, Venezuela

^VInterventionist Cardiologist Physician at the Invasive Cardiology Service of Instituto Médico La Floresta. Caracas, Venezuela

^VIMédica cardiologista da Clínica El Ávila. Caracas, Venezuela

^VIIInterventionist Cardiologist Physician at the Invasive Cardiology Service of Instituto Médico La Floresta. Caracas, Venezuela

^VIIICardologist Physician at Clínica El Ávila. Caracas, Venezuela

^IXCardologist Physician at Instituto Médico La Floresta. Caracas, Venezuela

^XCardologist Physician at Clínica El Ávila. Caracas, Venezuela

^XICardologist Physician at Instituto Médico La Floresta. Caracas, Venezuela

^XIIInterventionist Cardiologist Physician, Resident in Structural Interventions at Universidade de Catânia. Catânia, Italy

^XIIIInterventionist Cardiologist Physician, Director of the Invasive Cardiology Service of Clínica El Ávila. Caracas, Venezuela

^XIVInterventionist Cardiologist Physician, Director of the Invasive Cardiology Service of Instituto Médico La Floresta. Caracas, Venezuela

Correspondence

ABSTRACT

BACKGROUND: Systemic arterial hypertension affects over 1.2 million people worldwide. Only 35% of hypertensive patients have controlled blood pressure levels. Renal sympathetic denervation (RSD) has shown to significantly decrease blood pressure levels in patients with resistant systemic hypertension.

METHODS: Prospective, single arm, observational, multicenter study including consecutive patients undergoing RSD. The primary endpoint was to assess systolic blood pressure levels at the 30-day follow-up. The secondary endpoint was to determine the presence of procedure-related adverse events.

RESULTS: The first 20 patients undergoing RSD were included. The average blood pressure prior the procedure was 171.6/93.2 ± 15.5/11.3 mmHg, with the use of 4.1 ± 1.5 antihypertensive drugs per patient. Success rate was 95%, and 11.1 ± 1.9 ablations were performed per patient. A systolic blood pressure decrease of 29 ± 21 mmHg (P = 0.009) was observed 30 days after the procedure. There were no procedure-related complications.

CONCLUSIONS: Catheter-based RSD in daily clinical practice patients significantly decreased blood pressure levels. In our experience, RSD proved to be feasible and safe.

Descriptors: Hypertension. Kidney. Sympathectomy. Catheters.

Systemic arterial hypertension (SAH) affects over 1.2 million people worldwide, with a prevalence of 28% in the adult population.^1,2 The consequences and progressive damage of SAH on target organs reduce patient survival, accounting for half of coronary and cerebrovascular events.^3,4

Adequate control of SAH reduces the occurrence of adverse events. A 5 mmHg reduction in the systolic blood pressure is associated with a 10% decrease in relative risk of death from cerebrovascular causes and acute coronary syndrome. Conversely, a 20 mmHg increase in systolic blood pressure doubles the risk of mortality from cardiovascular causes.⁵ However, only 35% of hypertensive patients have blood pressure values within the targets proposed by the guidelines,⁵ in most cases due to poor adherence to prescribed treatment, suboptimal treatment, or secondary causes of SAH. However, approximately 10% of patients with appropriate use of three or more antihypertensive drugs do not manage to control their blood pressure levels; this group of patients, known as resistant hypertensive patients, have a high risk for the occurrence of adverse cardiovascular events.⁶

In the resistant hypertensive population, studies using microneurography and measurement of blood catecholamines demonstrated the participation of the sympathetic nervous system in the genesis and maintenance of SAH.⁷⁹ Surgical sympathectomy was shown to be effective in reducing blood pressure in patients with resistant SAH; however, this technique was abandoned due to high rates of complications.^10-12 More recently, a less invasive approach with percutaneous renal sympathetic denervation performed by applying radiofrequency to the renal artery wall was shown to decrease adrenergic tone, release of norepinephrine, and blood pressure.¹³ Catheter-guided (Symplicity^®, Ardian Medtronic - Minneapolis, USA) renal sympathetic denervation was tested in the clinical trials Symplicity HTN-1-first-in-man and Symplicity HTN-2, presenting a significant and sustained decrease in systolic blood pressure.^13,14 Recently, this system was made available for clinical use in Venezuela, initiating the authors' experience with this procedure.

This study aimed to describe the characteristics of patients undergoing renal sympathetic denervation, as well as to evaluate the efficacy and safety of the procedure in daily clinical practice.

METHODS

Renal sympathetic denervation system

The components of the renal sympathetic denervation system are the Symplicity^® catheter and radiofrequency generator. The generator consists of two parts: the console and the pedal (Figure 1). The generator produces energy through radiofrequency, following a predetermined algorithm. During the radiofrequency application, voltage, temperature, and impedance of the application point on the renal artery are continuously monitored and controlled. The maximum voltage is 8 W, and the system generates energy with impedances between 20 ohms and 500 ohms. The Symplicity^® catheter, compatible with 6 Fr, applies radiofrequency energy to the renal artery wall. It comprises the handle lever and a flexible portion, 108 cm long, with a platinum monopolar electrode at the tip, with two radiopaque marks 5 mm apart from each other. By manipulating the handle lever, the catheter tip can be flexed and/or rotated to reach the correct position for the application of radiofrequency (Figure 2).

Procedure

An abdominal aortography was performed by femoral approach to assess the renal arteries and the technical feasibility of the procedure. Subsequently, the renal arteries were selectively catheterized, and the Symplicity^® catheter was advanced within the vessel. Four to eight ablations were applied from the distal to the proximal portion, 5 mm apart, with duration of 120 seconds in both renal arteries (Figure 3). Each radiofrequency application has a maximum of 8 W and increases in impedance and temperature are controlled by the system in order to avoid tissue injury due to overheating. All patients were anticoagulated with unfractionated heparin (70 U/kg until an activated clotting time > 250 s was attained) during the procedure, and analgesia with benzodiazepines and opioids was used for pain control.

Study Design

This was a prospective, single-arm, observational multicenter study that included consecutive patients undergoing renal sympathetic denervation between March and December 2012 at three centers in Venezuela. The primary outcome was the decrease of systolic blood pressure at 30 days of follow-up. The secondary outcome was the occurrence of any procedure-related adverse event.

The criteria for patient inclusion were: age > 18 years with resistant SAH, defined as systolic blood pressure > 160 mmHg despite adequate use of three or more antihypertensive agents (at least one diuretic), or patients taking > four antihypertensive medications. The assessment of renal artery anatomy was recommended before the procedure using renal artery Doppler and/or imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) or aortography.

Patients with glomerular filtration rate 45 ml/ min/1.73 m² (calculated by the Cockcroft-Gault formula),¹⁵ renal artery < 4 mm in diameter, < 20 mm in length, previous interventions in renal arteries, renal artery stenosis, and acute coronary syndrome or stroke < six months were excluded. Procedural success was defined as attaining the procedure in both renal arteries without procedure-related complications.

Patient follow-up was performed by their respective attending physicians, who were instructed not to modify the antihypertensive treatment, if clinically possible, within the first 30 days after the procedure, and to report an average of three blood pressure measurements obtained at the office at 30 days of follow-up, according to the recommended guidelines.⁵

This study was performed in accordance with the Declaration of Helsinki and the principles of good clinical practice. All patients signed an informed consent before the procedure.

Statistical analysis

Quantitative variables are shown as means and standard deviations, and qualitative variables are shown as percentages. Student's t-test was used to compare quantitative variables. A P-value < 0.05 was considered significant. Statistical analysis was performed with SPSS software, version 16.0 (SPSS Inc., Chicago, USA).

RESULTS

This analysis included the first 20 patients undergoing renal sympathetic denervation. The mean age was 56 ± 12.1 years, 55% were females, and 55% were whites. Blood pressure (BP) before the procedure was 171.6/93.2 ± 15.5/11.3 mmHg, using 4.1 ± 1.5 antihypertensive drugs per patient (Table 1).

Regarding the characteristics of the procedure, success rate was 95%; 11.1 ± 1.9 ablations were applied per patient, 5.7 ± 1.3 in the right renal artery and 5.5 ± 2.8 in the left renal artery, and the mean decrease in impedance was 15.2 ± 1.9 ohms (Table 2).

Regarding the primary outcome, a decrease of 29 ± 21 mmHg (P = 0.009) was observed in the systolic blood pressure 30 days after the procedure (Figure 4). Regarding the secondary safety outcome, there were no complications related to the procedure or the adverse events after 30 days of follow-up. Among the studied population, 80% had a decrease of at least 10 mmHg in systolic blood pressure, and 68% of patients had blood pressure values within the targets proposed by the guidelines.⁵

DISCUSSION

In the initial experience with the percutaneous renal sympathetic denervation system for the control of resistant hypertension, the authors observed a significant decrease in systolic blood pressure after 30 days. There were no complications related to the procedure.

Symplicity HTN-1, a single-arm trial that included 45 patients undergoing renal sympathetic denervation, observed a decrease of 14 mmHg and 22 mmHg at 30 days and six months of follow-up, respectively.¹³ Subsequently, the Symplicity HTN-2 trial randomized 106 patients with resistant SAH, in which the group allocated for renal sympathetic denervation had a BP of 178/96 mmHg with the use of 5.2 antihypertensive medications. Six months after the procedure, a significant decrease of 32 mmHg was observed in the group submitted to renal sympathetic denervation, when compared with the clinical treatment group.¹⁴ In the scenario of real-world clinical practice, the Venezuelan Symplicity registry presented a decrease of 34 mmHg at 30 days of follow-up.¹⁶ In the present group, the decrease in BP at 30 days was 29 ± 21 mmHg, consistent with in the results of the Symplicity HTN-1 and HTN-2 trials and the Venezuelan Symplicity registry.^13,14,16

Regarding safety, the complication rates during the procedure are low, mainly due the guide-catheter handling during renal artery catheterization. In the Symplicity HTN-1 trial, among the 45 treated patients, one had renal artery dissection during catheterization with no need for additional treatment.¹³ In the Symplicity HTN-2 trial, there were no major adverse events and only one patient had lower back pain, which resolved spontaneously after 30 days, and 13% of the cases had bradycardia during the procedure, which was successfully reversed using atropine.¹⁴ It is important to emphasize that, although this is the initial phase of the learning curve with the study device, procedure-related adverse events were not observed. Except for one case in which it was not possible to catheterize the renal artery due to extreme aortic tortuosity, all other cases were successful.

Renal sympathetic denervation has been shown an additional benefit besides the lowering of blood pressure. Brandt et al.¹⁷ demonstrated a significant reduction in left ventricular mass and improved diastolic function in patients undergoing renal sympathetic denervation. It is noteworthy that such findings were independent from the reduction in blood pressure.

Mahfoud et al.¹⁸ evaluated the effect of renal sympathetic denervation in diabetic patients, finding, at the three-month follow-up, a decrease in fasting glucose levels, from 118 ± 3.4 ± mg/dL to 108 ± 3.8 mg/dL (P = 0.039); insulin levels, from 20.8 ± 3 IU/ mL to 9.3 ± 2.5 IU/mL (P = 0.006); and C peptide, from 5.3 ± 0.6 ng/mL to 3 ± 0.9 ng/mL (P = 0.002). These findings suggest that renal sympathetic denervation, in addition to lowering blood pressure, improves glucose metabolism and insulin sensitivity. Currently, new renal sympathetic denervation effects are being tested on heart failure, sleep apnoea, atrial fibrillation, and pulmonary hypertension.

Study limitations

The main limitations of this study were the small sample size and the fact that it was an observational study; therefore, it is necessary to confirm its findings in larger populations and, preferably, in a randomized fashion. However, the results were similar to those observed in the largest recently published studies,^13,14 which confers reliability to the present findings. Clinical follow-up of patients was performed by their attending physicians, who, despite strictly instructed not to modify the antihypertensive treatment within 30 days and to report any complaint or adverse effect, may have failed to follow such recommendations. Follow-up was conducted through mean blood pressure measured at the office, instead of 24-hour ambulatory blood pressure monitoring, a method that presents a better correlation with target-organ damage.¹⁹ Finally, although the results related to the decrease in BP values are promising, late follow-up is essential to verify the maintenance of these acquired benefits.

CONCLUSIONS

In this observational study, renal sympathetic denervation guided by Symplicity^® catheter promoted decrease in systolic blood pressure in patients with resistant hypertension. This initial experience was shown to be safe, with no intraprocedure-related adverse events and at the 30-day follow-up.

CONFLICTS OF INTEREST

Carlos Adolfo Collet is a proctor and speaker for Medtronic (Minneapolis, USA). Guilherme F. Attizzani is a consultant for St. Jude Medical (St. Paul, United States). The remaining authors declare to have no conflicts of interest.

REFERENCES

• 1. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009; 119(3):480-6.
• 2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217-23.
• 3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-13.
• 4. Vasan RS, Larson MG, Leip EP, Evans JC, O'Donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18):1291-7.
• 5. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52.
• 6. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25): e510-26.
• 7. DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens. 2002;11(2):197-200.
• 8. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77(1):75-197.
• 9. Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11(1):3-20.
• 10. Morrissey DM, Brookes VS, Cooke WT. Sympathectomy in the treatment of hypertension: review of 122 cases. Lancet. 1953;1(6757):403-8.
• 11. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. J Am Med Assoc. 1953; 152(16):1501-4.
• 12. Evelyn KA, Singh MM, Chapman WP, Perera GA, Thaler H. Effect of thoracolumbar sympathectomy on the clinical course of primary (essential) hypertension. A ten-year study of 100 sympathectomized patients compared with individually matched, symptomatically treated control subjects. Am J Med. 1960; 28:188-221.
• 13. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671): 1275-81.
• 14. Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA; Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-9.
• 15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
• 16. Casal H, Collet C, Burger B, Beer N, Bellera V, Leon C, et al. Renal sympathetic denervation for resistant hypertension in the real world clinical practice: preliminary results of the Symplicity Venezuela Registry. J Am Coll Cardiol. 2013; 61(10 Suppl):E2055.
• 17. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59(10):901-9.
• 18. Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123(18):1940-6.
• 19. Franklin SS, Gustin W, Wong ND, Larson MG, Weber MA, Kannel WB, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96(1):308-15.

Renal sympathetic denervation for treatment of resistant hypertension

Carlos Adolfo Collet^I; Juan Simon Muñoz^II; Oscar Sanchez^III; Roberto Correa^IV; Pedro Aguiar^V; Rosalin Vasquez^VI; Alejandro Sanchez^VII; Hector Marcano^VIII; Olga Azuaje^IX; Maritza Duran^X; Julio Guerrero^XI; Guilherme F. Attizzani^XII; Carlos Dávila^XIII; Francisco Tortoledo^XIV

Publication Dates

• Publication in this collection
  01 July 2013
• Date of issue
  June 2013

History

• Received
  01 Mar 2013
• Accepted
  12 May 2013