Hypertension remains an almost ubiquitous entity as a chronic disease around the world today. Its relevance lies in the fact that it is one of the most common risk factors responsible for cardiovascular morbidity and mortality. It is estimated that there are over 78 million adults in the United States who have hypertension, with African Americans having the highest prevalence of hypertension in the world. Despite the widespread availability of several classes of antihypertensive medications, many patients are not adequately controlled on a medication regimen. The importance of aggressive blood pressure control is well documented in reduction of adverse cardiovascular outcomes. The recently published SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated the reduction in fatal and nonfatal cardiovascular events from more intensive systolic blood pressure reduction in patients at higher cardiovascular risk.
Resistant hypertension is defined as the inability to reduce blood pressure to less than 140/90 mm Hg in patients who are taking maximally tolerated doses of at least three different classes of antihypertensive medications (including a diuretic). The prevalence of resistant hypertension in the hypertensive population varies from 8% to 12%. Furthermore, patients with resistant hypertension have higher rates of cardiovascular risk factors and those with higher ambulatory blood pressure monitoring (ABPM) blood pressures are at higher risk of cardiovascular morbidity and mortality ( Fig. 28.1 ). The promise of device-based therapy to treat resistant hypertension has emerged in the past several years with the goal of treating resistant hypertension where medical therapy has been inadequate.
The premise behind treatment of resistant hypertension with device therapy lies in observations that hypertension is mediated by central sympathetic activity. Higher levels of central sympathetic activity, as quantified by muscle sympathetic nerve activity (MSNA), were observed in patients with both essential and borderline hypertension. Furthermore, higher rates of noradrenaline spillover have been observed in hypertensive patients as compared with normotensive patients. Interventions designed to address neurovascular-mediated hypertension seek to interfere with the pathways involved in these processes.
Sympathetic innervation to the kidneys is via a network of efferent noradrenergic nerve fibers to the renal arteries, and afferent fibers from the renal arteries function to return signals to the central nervous system. Stimulation of the efferent fibers of the renal arteries results in renal artery vasoconstriction, increased salt and water uptake, and increased renin production, all of which serve to increase systemic blood pressure. The afferent fibers serve to provide sensory information to the central nervous system so as to help regulate the effects upon the efferent system ( Fig. 28.2 ). The importance of the central nervous system in mediating systemic blood pressure is not limited to the effects of renal innervation, as baroreceptor reflexes are also important in mediating acute blood pressure changes. Chronic elevations in blood pressure can lead to decreased baroreceptor reflex sensitivity. This has also been identified as a target for device based intervention for treatment of resistant hypertension.
Renal Artery Sympathetic Denervation
Increased levels of sympathetic activity have been clearly shown to be an underlying feature of many pathologic conditions such as hypertension, but also heart failure, chronic kidney disease, and disorders of blood glucose control. Both the afferent and efferent renal innervation has been shown to be important in the regulation of blood pressure. An abundance of preclinical and clinical data have demonstrated the effects of renal artery denervation upon systemic blood pressure. Early surgical experience demonstrated effective blood pressure reduction with surgical sympathectomy and lower associated mortality, although this was balanced, in part, with unpredictable blood pressure results, postoperative complications, prolonged hospital stays, and other serious side effects, such as severe orthostatic hypotension, erectile dysfunction, and incontinence. Translating this technique into a viable and safe percutaneous therapy to accomplish renal artery sympathetic denervation for the treatment of resistant hypertension and demonstrating efficacy has been a work in progress. Percutaneous renal artery denervation procedures have been hypothesized to reduce blood pressure while preserving renal homeostatic mechanisms for electrolyte and fluid balance and adrenaline-mediated stress responses.
The advantages of catheter-based techniques for renal denervation (RDN) over a surgical approach include ease of procedure, shorter procedure duration and recovery time, and minimally invasive approach. As such, much enthusiasm has followed the development and evaluation of catheter-based RDN procedures for the potential in treating a disease with enormous public health implications. The Ardian RDN catheter-based system (Medtronic, LLC, Minnesota) consists of a catheter-based delivery catheter and a radiofrequency (RF) generator. After femoral arterial access is obtained, the RDN catheter is delivered to the renal artery under fluoroscopic guidance. The tip of the catheter is placed against the renal artery wall and RF is delivered in four to six different locations throughout each renal artery ( Fig. 28.3 ). Because renal artery innervation is in the adventitial layer, the delivery of RF energy by the catheter tip is designed to ablate the afferent and efferent innervation to the renal artery, understanding that the afferent innervation does not seem to regenerate itself after ablative therapy.
The SYMPLICITY-HTN 1 study was a first in human safety and feasibility study of the Ardian catheter-based system in the treatment of resistant hypertension. A total of 45 patients with resistant hypertension were treated with renal sympathetic denervation and observed for reductions in office blood pressure and renal noradrenaline spillover. The primary study outcome was blood pressure lowering effectiveness and safety. Secondary endpoints included effects on renal function and renal noradrenaline spillover. Mean age of patients undergoing RDN was 58 years and the mean number of antihypertensive drugs they were taking was 4.7. There was a significant reduction of blood pressure postprocedure compared with preprocedure ( p = 0.026 for systolic and p = 0.027 for diastolic). A total of 10 patients from this group were studied to assess effectiveness of RDN using procedural changes in renal adrenaline spillover. In those 10 patients, a 47% mean reduction was noted and the corresponding blood pressure reduction at 6 months was 22/12 mm Hg.
The procedure itself was deemed to be safe. Of the 45 patients, one experienced a renal artery dissection, which was addressed with a renal artery stent and one patient had an access site complication. Short-term renal angiography in 18 patients did not demonstrate any adverse anatomic issues following the procedure. Interestingly, despite the impressive reduction in blood pressures observed, in 13% of the patients RDN had no discernable effect upon blood pressure. A longer-term follow-up on those original 45 patients and an additional 108 treated patients treated with RDN at 19 centers around the world has been published to assess long-term safety and efficacy. The 3-year outcomes on 153 treated patients also demonstrated significant reductions in both systolic and diastolic blood pressures. A 10 or more mm Hg drop in systolic blood pressure was observed in 93% of treated patients at 3 years. Of note, there was no information on medication related changes beyond 12 months in this follow-up study.
The SYMPLICITY HTN-2 study was a prospective randomized multicenter trial examining RDN in 106 patients with resistant hypertension with a primary efficacy endpoint of systolic blood pressure reduction by office-based measurement at 6 months follow-up. At 6 months, there was a significant decrease in systolic and diastolic blood pressure through office-based measurements in the renal denervation group with respect to baseline ( p < 0.0001). A total of 84% of patients who underwent RDN had a 10 or more mm Hg reduction versus 35% of controls ( p < 0.0001). There were no serious device or procedure-related complications. Furthermore, there were similar trends noted with both 6 months office-based blood pressure and 24-hour-ABPM in this study.
The SYMPLICITY HTN-3 study was a prospective, randomized, single blinded trial designed to help achieve regulatory approval. The trial sought to examine the safety and efficacy of RDN using the Ardian catheter-based denervation system (Medtronic, LLC) for the treatment of resistant hypertension. The primary endpoint was a change in office-based systolic blood pressure at 6 months and a secondary endpoint of change in average 24-hour ABPM over 6 months. A primary safety endpoint examined was a composite of all-cause mortality, end-stage renal disease, significant embolic events, new renal artery stenosis, renal artery perforation/dissection requiring intervention, vascular complications, or hospitalization secondary to hypertensive crises. Patients between the ages of 18 and 80 years with resistant hypertension who enrolled were randomized in a 2:1 fashion to either RDN versus a sham procedure. In comparison to all prior RDN trials, this trial was designed with a sham procedure, a larger study population, and 24-hour ABPM.
To be eligible for the study, participants had to have a systolic blood pressure (SBP) 160 or higher mm Hg and be on a stable antihypertensive regimen of maximally tolerated doses of at least three drugs, one of which was a diuretic. The patients were required to be stable on this regimen for at least 2 weeks and any postenrollment adjustments in antihypertensive medications would necessitate withdrawal and reenrollment after a 2-week period demonstrating a stable regimen. Specific protocols were established to obtain office-based blood pressures and 24-hour ABPM was performed to document an SBP of 135 or higher mm Hg. Exclusion criteria included hypertension from secondary causes, prior renal artery intervention, and several anatomic criteria for the renal artery.
A total of 535 patients were enrolled in the study across 88 sites in the United States with no differences in baseline characteristics between the randomized groups. For the primary endpoint, there was no significant difference at 6 months between the two groups with regard to office-based blood pressure measurement (−14.13 ± 23.93 mm Hg for RDN versus −11.74 ± 25.94 mm Hg for sham control, difference in change, −2.39 mm Hg; p = 0.26) ( Fig. 28.4 ). With regard to the secondary efficacy endpoint of change from baseline to 6 months in 24-hour average ABPM, there was no significant difference between the two groups (−6.75 ± 15.11 mm Hg for RDN versus −4.79 ± 17.25 mm Hg for sham control, difference in change, −1.96 mm Hg; p = 0.98). The rate of the primary safety endpoint in the trial was 1.4% in the RDN group and 0.6% in the sham-control group ( p = 0.67). These results were in direct contrast to the previously reported SYMPLICITY HTN-1 and SYMPLICITY HTN-2 trials. The reasons for the observed differences may have had to do more with the fact that SYMPLICITY HTN-3 was a well-conducted blinded, sham-controlled randomized study which accounted for several biases that prior studies did not.
Similar findings with no further ambulatory or office blood pressure (BP) reductions were observed at 1 year in the SYMPLICITY HTN-3 trial with follow-up data available for most of the denervation patients, non-crossover control subjects, and crossover control subjects. Beyond the trial design and conduct of the study, several other potential reasons for lack of observed response in blood pressure have been suggested. Multivariable analysis of the study population revealed that use of an aldosterone antagonist at baseline was a predictor of increasing 6-month change from baseline in office systolic blood pressure changes, whereas use of a vasodilator was a negative predictor for change in office systolic blood pressure. Furthermore, in the treatment arm, the total number of ablation attempts was a predictor for change in office systolic blood pressure at 6 months, as was the use of circumferential ablation patterns. This has potentially important implications for the understanding of the effects of RDN and future trial design. Our understanding of the anatomic and physiologic effects of RDN are likely very basic. The anatomy of the afferent and efferent innervation of the renal arteries appears more complex. The mean number of periarterial nerves appears greater in the proximal and midsegments of the renal artery, whereas the nerve distance to arterial lumen was largest in the more proximal segments. There is also a decrease in the amount of afferent fibers from proximal to distal artery and the density of innervation is lowest in the dorsal part of the artery. There may also be value in more distal ablation extending into branches of the main renal artery. This has potentially important implications when designing catheters and for study design. In the SYMPLICITY HTN-3 trial, there was a nonsignificant trend toward lower office and 24-hour ABPM in those patients who had four-quadrant ablations in one or both renal arteries as compared with no four-quadrant ablations. In the SYMPLICTY HTN-3 study, only 19 patients had four-quadrant ablations in both renal arteries, questioning the intensity of treatment in the RDN arm.
User experience may have also influenced the outcome of this study. Data from the Global SYMPLICTY Registry (GSR), an open-label multicenter registry of patients undergoing RDN for hypertension demonstrated a greater drop in both office-based and 24-hour ABPM in those patients from GSR versus SYMPLICTY HTN-3. One of the factors that may be at play is operator experience. The operators in the GSR had more experience in terms of prior cases and the average number of 120 second ablations was greater in the GSR than in SYMPLICTY HTN-3, suggesting that perhaps treatment intensity and operator experience may factor into outcomes.
In addition to procedural variables, classes of antihypertensive medications may have played a role in the outcomes of the study. Again, in a post hoc analysis of the SYMPLICTY HTN-3 data, the effect of vasodilator therapy on African Americans in the sham control in blood pressure reduction was greater than the effect seen on non-African Americans on vasodilator therapy, or on either African Americans or non-African Americans not on vasodilator therapy. Furthermore, there were more African Americans in the trial being prescribed vasodilators than non-African Americans (26.2% of the study population). There was an observed difference in office systolic blood pressure changes in the non-African American subgroup versus the African American subgroup after RDN, whereas no differences were observed in changes in 24-hour ABPM or home systolic blood pressure measurements. A separate analysis of the SYMPLICITY HTN-3 trial demonstrated that there was no differential effect of RDN based on race; however, the larger differences noted in the sham-control group, particularly in African Americans, was believed attributable to changes in medication adherence.
The SYMPLICTY HTN-3 trial serves to illustrate the challenges that persist in carrying out a trial of this magnitude and complexity. Despite the well conducted, sham-controlled, blinded nature of the study, there were still several issues that remain which could explain the lack of treatment effect observed. Furthermore, a standardized treatment algorithm for BP control and evidence of medication adherence among subjects may be needed to account for additional observed differences. Finally, the efficacy and intensity of treatment using RDN not being quantified was likely a weakness of the current study. Future trials need to address issues such as medication classes and adherence, procedural variability, and patient related factors to see if RDN remains a viable treatment option.
Interestingly, the renal denervation for hypertension (DENERHTN) trial used the SYMPLICITY RDN catheter in a prospective, open-label, randomized controlled trial with blinded endpoint evaluation in a multicenter fashion in patients with resistant hypertension. They compared RDN and a standardized stepped-care antihypertensive treatment (SSAHT) with SSAHT alone and found that in 207 patients, RDN and SSAHT decreased ambulatory blood pressure by a modest amount at 6 months, although office-based blood pressures were not significantly reduced. It is unclear as to what impact the sample size and open-label trial design had upon these findings.
The SPYRAL HTN trial (Medtronic) is currently enrolling and will evaluate patients with less severe hypertension than those enrolled in SYMPLICITY HTN-3 for the effectiveness of RDN using the novel SYMPLICITY SPYRAL multielectrode catheter. The trial will enroll 100 patients in each arm in patients with moderate to severe, not resistant, hypertension. In the SPYRAL HTN OFF MED ( NCT02439749 ) arm, the patients will stop antihypertensive medications whereas in the SPYRAL HTN ON MED ( NCT02439775 ) arm, they will continue with their antihypertensive regimen. It is anticipated that specific classes of medications will be used, without needing to achieve maximally tolerated dosages, and that medication adherence will be monitored. The primary efficacy endpoint will be change in 24-hour ABPM at 36 months versus baseline.
The REDUCE HTN:REINFORCE trial ( NCT02392351 ) is also currently enrolling patients with uncontrolled hypertension in a randomized fashion to assess whether or not RDN using the Vessix Reduce Catheter can reduce 24-hour ambulatory systolic blood pressure at 8 weeks in comparison to sham placebo. The EnligHTN Multi-Electrode Denervation System (St Jude Medical, St Paul, Minnesota) is currently under investigation in clinical studies. This device uses an expandable basket with four monopolar radiopaque electrodes and has a CE (Conformite Europeene) mark approval based on the results of EnligHTN-1. The EnligHTN-III trial ( NCT01836146 ) has recently completed enrollment looking to examine the safety and efficacy of the EnligHTN RDN system to treat uncontrolled drug resistant hypertension.
In addition to severe resistant hypertension, RDN has been examined in the context of mild resistant hypertension (SBP 135 to 149 mm Hg, and diastolic 90 to 94 mm Hg). A total of 71 patients were randomized to RDN with the SYMPLICITY catheter versus a sham-control procedure. RDN failed to result in a meaningful reduction in 24-hour systolic blood pressure in the prespecified intention to treat analysis; however, there was a statistically significant reduction in the per protocol analysis.
RDN has also been identified as a therapeutic adjunct in the treatment of heart failure, with the goal of addressing sympathetic overactivation as part of the neurohormonal response. The REACH-Pilot Study was a first-in-man safety study in seven patients using RDN to treat patients with chronic systolic heart failure with a bilateral denervation procedure. The procedure was well tolerated and safe with a resultant increase in 6-minute walk distance at 6 months. The Renal Artery Denervation in Chronic Heart Failure (REACH) Study ( NCT01639378 ) is a prospective, randomized, double-blinded trial examining the safety and efficacy of the SYMPLICITY RDN system in the patients with chronic systolic heart failure.
In addition to RF energy delivered through a catheter, other alternatives are in development for renal artery denervation. Ultrasound energy can be delivered for RDN using noninvasive techniques (Kona Medical, Bellevue, Washington) or intravascularly using a balloon catheter or a separate sound catheter. Guanethidine injections have been carried out using the Bullfrog Microinfusion catheter (Mercator MedSystems, Inc, San Leandro, California). Larger safety and feasibility studies will be ongoing to further evaluate these alternative approaches for RDN.
Although the initial enthusiasm for RDN has waned slightly after the SYMPLICTY HTN-3 trial results, it is clear that our understanding of RDN for the treatment of hypertension has improved. The initial positive results of both the SYMPLICTY HTN-1 and SYMPLICTY HTN-2 studies fueled the enthusiasm for this technology and its role in the management of resistant hypertension. Despite the well-conducted nature of the SYMPLICTY HTN-3 trial, we noted that there were several limitations and confounders that could have influenced the results of the study, including the technology and user experience. It may also be argued that our understanding of the anatomic and physiologic mechanisms behind resistant hypertension is not sophisticated enough. Despite the negative results of the primary trial, there is reason to think that RDN may still be a viable option. As newer devices and trials move forward, it will remain to be seen what role, if any, RDN has to play in the management of hypertensive disease.
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