Abstract
The rising incidence of hypertension and the increasing prevalence of treatment-resistant hypertension carry significant societal impact from a public health perspective. Nonpharmacologic adjuncts to the treatment of hypertension are a welcome addition to the management of hypertension and likely necessary for some patients. With the longitudinal success of the Rheos Pivotal Trial in sustained reduction in blood pressure and the early encouragement of a possibly safer procedural approach in the Barostim neo Trial, there is encouraging evidence that baroreceptor activation therapy may become a viable adjunct in the treatment of resistant hypertension and perhaps change the landscape of how we approach hypertension.
Heart failure (HF), the leading cause of hospitalization among adults >65 years of age in the United States, is intertwined with the very same physiological system baroreflex activation therapy (BAT) targets. The Barostim neo and its application in HF may hold the most immediate promise for mainstream use of BAT. The positive effects on functional status and improvement in quality of life for patients with New York Heart Association (NYHA) Class III HF already on guideline-directed medical therapy may make BAT a desirable treatment option for many patients living with a debilitating disease.
Keywords
Baroreflex activation therapy, Barostim HOPE4HF, Barostim neo, Blood pressure, Carotid baroreceptor stimulation, Heart failure, Hypertension, Resistant hypertension, Rheos, Sympathetic nervous system
Outline
Hypertension: Prevalence and Population Health 1293
The Pathophysiology of Hypertension 1294
Targeting the Sympathetic Nervous System With Modulatory Therapies 1295
Baroreflex Activation Therapy Trial Data 1295
Device-Based Therapy in Hypertension Trial 1295
Rheos Pivotal Trial 1297
Long-Term Rheos Pivotal Trial Patient Follow-Up 1298
Barostim Neo Trial 1298
Carotid Nitinol Device (MobiusHD) 1298
Heart Failure: Prevalence and Population Health 1299
Pathophysiology of Heart Failure 1299
Heart Failure and the Role of Baroreflex Activation Therapy 1301
The Barostim HOPE4HF (Hope for Heart Failure) Study 1302
Long-Term Chronic Baroreflex Activation in Heart Failure With Reduced Ejection Fraction 1302
Discussion and Future Directions 1302
Conclusions 1303
References 1303
Hypertension: Prevalence and Population Health
Hypertension is the leading cause of morbidity and mortality in the world with an incidence that continues to rise and currently affects 25% of the adult population, roughly 1 billion people, worldwide ( ). Long-standing, poorly controlled hypertension is associated with a higher incidence of stroke, myocardial infarction, cardiomyopathy, atherosclerotic disease, renal failure, and blindness. The SPRINT Trial found that even more intensive blood pressure (BP) control targets of <120/80 mm Hg compared to <140/90 mm Hg were associated with statistically significant reduction in the rates of fatal and nonfatal risk of major cardiovascular events or death ( ). The lifetime risk of heart failure for individuals with a BP > 160/90 is double that of individuals with a BP < 140/90 ( ).
Treatment-resistant hypertension (TRH) is defined as measured BP greater than 140/90 mmHg despite optimal doses of at least three antihypertensive agents including a diuretic ( ). Estimates of the prevalence of TRH range from 15% to 30% with observational studies like the National Health and Nutrition Examination Survey (NHANES) finding lower estimates and large prospective outcome studies, including the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) ( ), the Antihypertensive and Lipid-Lowering and Treatment to Prevent Heart Attack Trial (ALLHAT) ( ), and the Avoiding Cardiovascular Events in Patients Living with Systolic Hypertension (ACCOMPLISH) ( ), finding higher rates of uncontrolled hypertension despite at least three antihypertensive medications ( ). Analysis by Egan et al. of the NHANES data on hypertension in the United States from 1988 to 2008 found that the overall proportion of patients with untreated hypertension decreased when comparing the 1988–94 data to the 2005–08 data and the percentage of patients on two or fewer antihypertensive agents was unchanged, but there was an increase in the percentage of patient requiring ≥3 agents. Additionally, Dr. Egan and his colleagues found that in 2005–08 data, 28% of patients continued to have uncontrolled hypertension with systolic BP >140 mmHg or diastolic BP >90 mmHg despite treatment with three or more antihypertensive agents compared to 15% of patients 1988–94 date ( ). These findings demonstrate the increasing prevalence of TRH and at rates aligned with those found in ASCOT, ALLHAT, and ACCOMPLISH studies.
Pharmacologic medications are the mainstay of treatment for hypertension and are effective therapy for the majority of patients. Patients with TRH on optimal pharmacologic therapy may have increased sympathetic nervous system activation contributing to their resistant hypertension. The study of the role of sympathetic nervous system modulation and cardiovascular effects predates pharmacologic antihypertensive therapy with the first surgical sympathectomy, a surgical severing of the sympathetic ganglia, attempted during the 1930s in an effort to improve circulation and reduce vasoconstrictive effects in patients with peripheral vascular disease ( ). The technique was later applied to treatment of malignant hypertension in the 1940s and 1950s, though this application was short-lived given the considerable adverse side-effects associated with the procedure including severe orthostatic hypotension, impotence, and urinary or fecal incontinence ( ).
Advances in sympathetic modulation have shown promise in effectively reducing systemic hypertension without the morbidity associated with the early surgical predecessors. One of these new approaches being evaluated for long-term antihypertensive treatment is an implantable device, similar to a pacemaker, providing direct electrical stimulation to the baroreceptors of the carotid sinus to decrease sympathetic output and increase vagal tone to facilitate a centrally mediated decrease in systemic BP ( ).
The Pathophysiology of Hypertension
BP regulation is a dynamic and multifactorial process that requires integration of three main systems: the cardiovascular system, in which the heart provides the mechanical pump and forward pressure, and blood vessels provide systemic vascular resistance; the kidneys, which largely control intravascular volume regulation; and the adrenal system, which supplies the hormones that regulate and integrate these components. The Renin-Angiotensin-Aldosterone System (RAAS) plays a significant role in regulating arterial BP and cardiac output through its influence on intravascular volume status and systemic vascular resistance.
A low BP or a decrease in BP in the afferent arterioles within the kidneys causes a reduction in the glomerular filtration rate (GFR) and decreased sodium delivery to the distal tubule which in turn leads to the release of renin into the blood stream. Renin then cleaves angiotensinogen to form angiotensin (AT) I, which in turn is cleaved by angiotensin-converting enzyme (ACE) to form angiotensin II. Once released, angiotensin II acts on the adrenal cortex to release aldosterone and the posterior pituitary to release antidiuretic hormone (ADH) both of which facilitate increased sodium and fluid reabsorption in the renal tubules to increase intravascular blood volume. Additionally, Angiotensin II acts on AT1 receptors to constrict vasculature thereby increasing systemic vascular resistance and arterial BP, stimulates cardiac and vascular hypertrophy, and stimulates sympathetic adrenergic function through the release of norepinephrine.
Atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP) are released in response to atrial and ventricular stretch, respectively, and neurohumoral stimuli. Natriuretic peptides (NPs) serve as a counterregulatory measure on angiotensin II and the RAAS. NPs increase GFR and decrease renin release leading to increased natriuresis and diuresis, decreased conversion to angiotensin II and thus decreased aldosterone release. NPs also have vasodilatory effects that decrease central venous pressure and ventricular preload, thus reducing cardiac output as well as decreasing systemic vascular resistance and systemic arterial pressure.
The baroreceptor reflex is another mechanism that provides feedback to the cardiovascular system and arterial pressure. Baroreceptors are located in the aortic arch and the body of the carotid sinus. They respond to changes in arterial pressure by sensing stretch in the vessel wall. With increased arterial pressure, the vessel wall stretches and baroreceptors are stimulated sending increased signals to the medulla. This initiates a negative feedback loop that inhibits sympathetic nervous system outflow and stimulates the parasympathetic nervous system resulting in vasodilation, decreased peripheral vascular resistance, reduction in heart rate, and decreased cardiac output leading to an overall reduction in arterial pressure. The baseline level of stimulation tolerated by the baroreceptors is constantly recalibrating, meaning that over time the baroreceptors tolerate higher continuous arterial BPs without signaling a compensatory response. This means that chronic hypertension essentially leads to dysfunctional autoregulation of the baroreflex response and relative hyperactivity of the sympathetic nervous system continues unchecked, resulting in resistant hypertension.
Targeting the Sympathetic Nervous System With Modulatory Therapies
Pharmacologic antihypertensive treatments are aimed at targeting different components that drive hypertension with beta-blockers and alpha-blockers targeting sympathetic nervous system activity. Beta-blockers are used to reduce heart rate, myocardial contractility, and renin secretion to lower BP by reducing cardiac output. Alpha 2 -blockers act centrally to decrease sympathetic tone while alpha 1 -blockers act peripherally to relax vascular smooth muscle, resulting in decreased systemic vascular resistance and arterial pressure. Diuretics including thiazide, loop, and potassium sparing agents increase renal water losses, reducing intravascular blood volume and thus arterial pressure. ACE inhibitors and angiotensin II receptor blockers (ARB) target the RAAS system and aim to decrease circulating angiotensin II to allow for natriuresis and diuresis while lowering systemic vascular resistance. Finally, calcium channel blockers and peripheral vasodilators decrease peripheral vascular resistance to lower arterial BP.
There have been prior nonpharmacologic attempts to modify sympathetic nervous system activity in an attempt to reduce arterial BP with surgical sympathectomy. As discussed previously, these procedures did show promise in that they reduced BPs but they were associated with significant morbidity ( ). In the 1990s and 2000s, several studies examined unilateral and bilateral carotid stimulation and the impact on sympathetic nervous system activity and hemodynamics. found no difference in cardiac gains (measuring heart rate and mean arterial pressure) based on laterality with unilateral carotid sinus stimulation, though there was a possible inhibitory summative effect of bilateral carotid stimulation. and each conducted small studies of 12–30 young, normotensive subjects with application of external neck suction and found stimulation of the right carotid sinus baroreflex had equivocal results compared to bilateral stimulation in effecting systolic arterial pressure change, producing more significant changes when compared with stimulation of the left unilateral carotid sinus. Unfortunately, the collective findings of these studies were contradictory aside from the finding that carotid sinus stimulation can affect a notable inhibition of the sympathetic nervous system response as evidenced by decreased heart rate and mean arterial pressure. There were several limitations to the applicability of these studies including their small size, the variable method of stimulation with external neck suction, and application in normotensive, young subjects rather than in hypertensive subjects with dysfunctional carotid sympathetic autoregulation as occurs in resistant hypertension and heart failure ( ).
Advances in sympathetic neuromodulatory devices have led to two main therapies aimed specifically at baroreflex activation for treatment of resistant hypertension. The first is an implantable, pacemaker-like device with leads placed to provide electrical stimulation to baroreceptors in the carotid sinus rather than the heart, with the aim of decreasing sympathetic nervous system activity from the central nervous system ( ). The second is a nitinol carotid device that is specially designed to enhance carotid sinus stretch with each pulsation to effect increase baroreflex activation ( ).
Baroreflex Activation Therapy Trial Data
Stimulation of the carotid baroreceptors leads to increased vagal tone and decreased sympathetic outflow leading to a reduction in BP ( Fig. 107.1 ). Activation of carotid baroreceptors through local pulsatile electrical stimulation has been shown to be effective in achieving prolonged reduction in BP in animal models with dogs ( ). CVRx, Inc. in Minneapolis, MN, developed with first implantable device to be trialed in humans for long-term treatment of hypertension.
Device-Based Therapy in Hypertension Trial
Device-Based Therapy in Hypertension Trial (DEBuT-HT) ( ) was the first trial to evaluate baroreflex activation therapy (BAT) with a long-term implantable device in humans. The trial utilized the Rheos Baroreflex Hypertension Therapy device (CVRx, Inc., Minneapolis, MN) to examine the feasibility and safety of using BAT therapy for ongoing hypertensive treatment in humans. The device consisted of an electrical-pulse generator that was implanted subcutaneously under the pectoral muscle, similar to a pacemaker placement, and two leads tunneled from the generator to the bilateral carotid bulbs. Projections at the ends of the leads wrapped around the carotid bulbs and required open surgical placement ( Fig. 107.2 ). DEBuT-HT was nonplacebo-controlled trial with a primary end-point of testing device safety with a secondary end-point of efficacy.
Forty-five patients with TRH, defined as BP >160/90 mm Hg despite three antihypertensive medications including a diuretic, were enrolled in the study and had a device placed. Study participants were followed every 3 months and then annually for 2 years. The mean reduction in the BPs was 21/12 mm Hg at 3-month, 30/20 mm Hg at 1-year and sustained reduction of 33/22 mm Hg at 2-years. The study investigators also reported a finding of immediacy of BP lowering effect and prolonged therapeutic value of the device reporting that at each visit the device was turned off and BPs returned to preimplantation levels. Once the device was turned on again, BPs decreased showing the sustained antihypertensive effect of the device; that is, no tolerance to the antihypertensive effect of BAT was noted with prolonged therapy.
Rheos Pivotal Trial
Following the success of DEBuT-HT, the first large-scale, double-blinded, randomized, placebo-controlled trial was undertaken: the Rheos Pivotal Trial. The Rheos Pivotal Trial utilized the same CVRx Rheos device and enrolled 265 patients with TRH, which was defined as BP >160/80 mm Hg despite three antihypertensive agents, including a diuretic, and an ambulatory systolic blood pressure >135 when averaged over a 24-h period ( ). The criterion was evaluated by a core laboratory and excluded patients who had orthostatic hypotension. All patients received implantation of the Rheos device (CVRx, Inc., Minneapolis, MN) at the start of the trial. At 1 month, the 265 patients were then randomized into one of two groups in a 2:1 (181:84) ratio: an immediate treatment arm, in which they received BAT starting 1 month after implantation for the first 6 months, and a delayed treatment arm, in which the Rheos device was not turned on and thus BAT was not initiated until after the 6-month visit. Once the device was activated, BAT was increased in a protocol-driven fashion with aim for optimal therapy at month 5 of active therapy (6 months from implantation for the active treatment arm).
There were five prespecified primary endpoints evaluated during the study including two efficacy endpoints, both sustained and acute, and three safety endpoints (procedural, BAT, and device safety). The trial did not meet acute efficacy or procedural safety endpoints though it did meet the endpoints of device and BAT safety as well as sustained efficacy. It also showed improvement in predefined secondary endpoints of reduced mean office-based systolic blood pressure and a comparison of immediate versus delayed BAT outcomes.
The acute efficacy end-point was defined as the proportion of patients in the immediate active therapy arm who demonstrated a reduction in systolic blood pressure (SBP) ≥10 mm Hg at 6 months compared to the control (delayed BAT) group. The active BAT found a 54% reduction of SBP ≥10 mm Hg compared to a 46% reduction in the control group ( P = .97), which was not a statistically significant difference. The procedural safety end-point was defined based on pacemaker/automatic implantable cardioverter-defibrillator (AICD) literature as 82% of patients with a 30-day period postimplantation without serious procedure-related events. The event-free rate was 74.8%, which did not meet the predefined event-free goal. Procedure-related events included general surgical complications (4.8%), long-term nerve injury (4.8%), transient nerve injury (4.4%), and wound complications (2.6%). The implantation of the device requires open exposure of the carotid bulb and bilateral lead placement. At optimal therapy, 75% of patients had a Rheos device programmed for unilateral BAT, which may mean bilateral lead placement is an unnecessary risk for most patients. In addition, estimating the procedure risk to be akin to that of a pacemaker or defibrillator placement is a gross underestimate of risk for this device since an open neck dissection is required. The open approach is similar to the approach of an open-carotid endarterectomy but without breaching the vessel wall. In actuality, the adverse event profile of the Rheos device implantation compares favorably with trials involving carotid endarterectomy ( ). Establishing such a disparate comparator for a procedural events end-point highlights the shortcomings of the trial design which ultimately led to the inability to reach statistical significance on two of the five prespecified primary endpoints.
The experimental design required certain assumptions that could not be verified from prior studies given the novelty of the device and the unique patient population studied. One example is the previously mentioned safety end-point, where the prespecified event-free objective performance criterion was based on historic implant safety of implantable cardioverter-defibrillators (ICD). Unconsidered was the fact that ICD devices do not require a neck dissection, which is the highest risk portion of the procedure, which would have been the more appropriate procedural safety target.
Failure to meet the acute efficacy end-point may have been secondary to the inability to take into account multiple confounders associated with excess variability, Hawthorne effect, and placebo effect. The unanticipated BP differences from preimplant to randomization (1 month after implantation) were likely due to the variability in timing of the BP measurements, limits in the number of BP measurements during the screening period and following device implantation, as well as the lack of restriction on medication adjustments from enrollment to trial initiation. The identification of such shortcomings post hoc provided the basis for improvement for future studies.
During the trial period there were seven deaths, which were not related to the procedure, device, or BAT. Hypertensive disease was a likely contributing factor in many of the deaths including three intracerebral hemorrhages, two cardiac arrests, and a ruptured aortic aneurysm. The last death was related to a drug overdose.
Overall, the trial was most encouraging in that the patients who did demonstrate initial reduction in BP were able to maintain it throughout the 12-month follow-up period. The sustained efficacy end-point was therefore met by maintaining at least half the initial 6-month reduction in SBP out to 12 months (88% of responders, P < .001). The BAT safety end-point was also met with a 91.7% therapy-related event-free rate in the 1-month activation group and 89.3% in the delayed to 6-month activation group ( P < .001). The device safety end-point also reached the established end-point with an 87.2% event-free rate (lower CI of 83.8%) measured against a predefined objective performance criterion of 72% ( P < .001). Of the 54% of patients with SBP ≥10 mm Hg reduction at 6 months, 88% continued to have a reduction of at least 50% of their 6-month reduction level at 1-year ( P < .001) ( ).
An interesting finding of the secondary endpoints was the lack of a statistically significant difference in SBP reduction at either 6 months or 1 year in the active versus delayed BAT groups. At 6 months, the active BAT group has a mean reduction in SBP of 16 ± 29 mm Hg that was not statistically different compared to the control (delayed BAT) group with an SBP reduction of 9 ± 29 mm Hg. At 1 year, both the immediate and delayed BAT groups had mean SBP reduction of 25 mm Hg. It is unclear as to why the delayed therapy group experienced reduction prior to initiating BAT and achieved reductions more quickly with treatment. Explanations include more engagement in health care, medical follow-up, and perhaps better adherence to existing medications after enrollment in the study. There may be an initial muting of baroreceptor response following the trauma of implantation and healing that may take longer than the initial 1 month to recover. Meaning that with activation of BAT at 1 month postoperatively, perhaps there is not a robust response of the baroreflex, leading to a slower therapeutic effect.
Long-Term Rheos Pivotal Trial Patient Follow-Up
After 12 months of BAT therapy, 88% (244) of the patients from the original Rheos Pivotal Trial were found to be responders with reductions in SBP < 140 mm Hg (<130 mm Hg with diabetes mellitus or renal disease) or had a clinically significant increase in SBP with deactivation of the device, which was defined as an increased in SBP > 20 mm Hg or a hypertensive crisis requiring hospitalization with SBP > 220 mm Hg ( ).
Responders were followed longitudinally for 22–53 months and demonstrated continued reductions in SBP > 30 mm Hg. Additionally, longitudinal responders experienced a reduction in the average number of antihypertensive medications from 5.3 ± 1.9 to 4.7 ± 2.1 ( P < .001). During the longitudinal follow-up trial, 40% of patients used more advanced programming settings than were utilized in the device program protocol for the original Rheos Pivotal Trial.
Five years after starting the initial Rheos Pivotal Trial, 216 patients continue to receive active BAT. At the last report, 40 patients have received at least 5 years of follow up and 207 receiving at least 3 years of follow-up. Patients in this long-term follow-up group had mean sustained reductions in SBP >30 mm Hg and mean reductions in diastolic BP >16 mm Hg ( ).
The longitudinal follow-up data of the Rheos Pivotal Trial demonstrates sustainable reductions in both systolic and diastolic BP and tangible improvements in patient quality of life with statistically significant reductions in the mean number of antihypertensive medications required.
Barostim Neo Trial
The Barostim neo device is a second-generation BAT device by CVRx, Inc. that is smaller in size and features a single-button electrode. The goal of this new generation of device is to reduce the procedural risk involved in the implantation of the device by reducing the number and extent of surgical neck dissections required to implant the device. Procedural safety was an important primary aim of this study particularly given the failure of the original Rheos Pivotal Trial to meet its predetermined procedural safety measure in the initial Pivotal trial.
Barostim neo trial was a single-arm, open-label study that enrolled 30 patients using the new Barostim neo device ( ). Participants were required to have stable medical therapy of 4 weeks prior to implantation and a baseline BP was determined by averaging two readings at least 24-h apart. This second-generation device has only a unilateral lead extending from the finding during the Rheos Pivotal Trial that 75% of patients had unilateral BAT for optimal therapy ( Fig. 107.2 ). The single-button lead is sutured to a single site on the carotid sinus and does not require exposure of the external carotid artery or as extensive an incision or dissection in the neck ( Fig. 107.3 ). There was a 2-week delay after implantation before the device was activated. BAT was individually titrated for optimal response as opposed to the protocol-driven titration used in the original Rheos Pivotal Trial.
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