It should be noted that the magnitude of SBP and pulse pressure changes observed in the BAT controlled trial are not trivial and carry potential implications for outcomes in heart failure. In the comparison of medical therapy, pacing, and defibrillation in heart failure trial, median changes in SBP from baseline to 3, 6, and 12 months in the two groups did not exceed 4 mm Hg.28 In the BAT trial treatment arm, the mean change in SBP was 8.5 ± 3.8 mmHg higher than that of the control arm (P = 0.03).
The data carry clinical relevance in view of the mechanistic studies demonstrating that the sympathovagal balance mediated by carotid baroreceptor activation is impaired even in mild heart failure, leading to increased sympathetic activity and decreased parasympathetic activity. This imbalance affects control of blood pressure (BP), peripheral vascular resistance, and the cardiopulmonary receptor's ability to modulate sympathetic activity. All this represents a primary mechanism of ventriculoarterial coupling loss and the consequent decline in heart function.29,30 Proof of this concept is evident from experiments in which intravenous infusions of phenylephrine restore sympathovagal balance and reinstate the basic ventriculoarterial coupling relation as expressed by heart rate decrease and BP increase.31
These studies support the hypothesis that restoration of BRS provided by BAT can lead to a more efficient ventriculoarterial coupling resulting in arterial BP amelioration. The trend toward declining pressure observed in the control arm of the BAT controlled trial27 likely mirrors a progression of heart failure worsening that, in this study, was prevented in the BAT treated arm.
The BP increase resulting from BAT also underscores its complementary value to medical therapy including β-blockade, which has been shown to provide benefit independently of BP.32 Indeed, although medical therapies address end-organ consequences of the hyperadrenergic state of heart failure, the added treatment benefit observed with BAT exploits additional therapeutic pathways.
On top of these positive cardiovascular actions, BAT has been successfully tested in refractory hypertensive patients, providing effective BP reduction in long-term follow-up.33 The highly significant decrease in BP translated to an 18% reduction of LV mass.34 The impressive physiological changes in hypertension, reinforced by confirmation of an impact on ventricular hypertrophy, suggest that BAT could be effective in the treatment of heart failure patients, as many peripheral mechanisms are common to hypertension and heart failure.
On the vagal stimulation side, heart failure studies have generated somewhat conflicting results (Table 2), with the recently published INOVATE-heart failure study results providing the most substantiated evidence.21 INOVATE-heart failure was a multicenter (involving 85 centers), randomized trial in patients with chronic heart failure, ejection fraction less than 40%, and NYHA class III symptoms that, for the first time in the neurostimulation field, challenged a combined endpoint including hospitalization for worsening heart failure and mortality. Patients were assigned to device implantation to provide VNS (active) or continued medical therapy (control) in a 3 : 2 ratio.
The mean stimulation current was 3.9 ± 1.0 mA at the 6-month follow-up visit [inferior only to the stimulation current in the CardioFit study (4.2 ± 1.2 mA)],3 with 73% of patients achieving the goal of more than 3.5 mA. The INOVATE-heart failure study primary endpoint was the composite of death from any cause or first event for worsening heart failure.
The study enrolled, randomized and followed 707 patients for a mean of 16 months. The primary efficacy outcome occurred in 132 of 436 patients in the VNS group, compared with 70 of 271 in the control group (30.3 vs. 25.8%; hazard ratio, 1.14; 95% confidence interval, 0.86–1.53; P = 0.37). Estimated annual mortality rates were 9.3 and 7.1%, respectively (P = 0.19) and LV end-systolic volume index were not different (P = 0.49) between the study groups. Similarly, hospitalization rate was identical in the two groups: 44/271 in the control group vs. 70/436 in the treatment arm (16% for both). Only quality of life, NYHA functional class and 6-min walking distance were favorably affected by VNS (P < 0.05).
Intriguing subgroup analyses [presented at the 2016 American College of Cardiology (ACC) meeting but not detailed in the INOVATE-heart failure manuscript] displayed some unexpected results. The study outcome was, at least partly, affected by the fact that women in the active arm had a significantly lower 6-min walking distance (P < 0.03) and LVEF (P < 0.01) at baseline in comparison with the control arm. Also, the female control arm had a better outcome in comparison with the global male population and to the female treated arm. Overall, these unexpected differences in the study populations might have negatively affected the trial outcome.
Also of interest is the fact that the subgroup without CRT, presenting with a QRS width less than 130 ms and the ability to walk at least 300 m, showed a better outcome with a nonstatistically significant 20% primary outcome event decrease in the active arm. Notably, the LV end-systolic and end-diastolic volumes also decreased, although the change was not statistically significant. These data (also not reported in the published manuscript, but presented at the 2016 ACC meeting) are similar to the results of the Barostim controlled trial post hoc analysis where only no-CRT patients displayed a significant increase of LVEF in the treated arm.35 On the other hand, the lack of efficacy of VNS and BAT in CRT nonresponders might suggest that this is a patient subset in which the disease severity has reached an irreversible stage.
Overall, neither VNS nor BAT are considered effective heart failure treatments in the European Society of Cardiology heart failure association guidelines. However, BAT efficacy is supported by a specific proof of concept study where MSNA decline after BAT in NYHA class III patients was coupled with a consistent drop in heart failure hospital admissions,25 and both effects were proven to persist throughout long-term follow-up.26 In the treated arm of the larger controlled study, reduction of hospital resource utilization was confirmed and associated with a decline in N-terminal probrain natriuretic peptide and an increase in SBP and pulse pressure,27 suggesting that the restraining action on sympathetic activity observed in the proof of concept study does translate to a significant clinical advantage.
Who can be a candidate for baroreflex activation therapy?
Defining the optimal patient population for BAT and, in general, for neuromodulation, is a challenging priority.36 Heart failure progression is characterized by relapsing and recurrent hospitalizations,8 coupled with progressive deterioration and increased mortality, despite optimal evidence-based, guideline-directed therapy. This negative progression is accompanied by persistent baroreflex impairment.37 Worsening heart failure is also detected by an increasing need to pharmacologically induce diuresis.9
The kidney is robustly innervated by both afferent and efferent sympathetic fibers, and their activity, as quantified by norepinephrine spillover, is a powerful predictor of survival in heart failure.38 Increased renal sympathetic tone enhances tubular sodium reuptake, thus decreasing natriuresis during daily physical activity and blunting the response to diuretics.39 These actions are key mechanisms underlying heart failure symptoms.
Therefore, escalating diuretic requirements or worsening renal function may be the pivotal marker of heart failure progression even if classical hemodynamic or symptomatic markers such as LVEF, NYHA class, or Seattle heart failure score40 may not provide meaningful information on the advancing of the clinical condition.
Recurrent heart failure hospitalizations are another critical clinical indicator which should lead physicians to consider novel therapies beyond guideline-based drug and device therapy and disease management.41 A useful tool for patient clinical profile assessment might be the North American Interagency Registry for Mechanically Assisted Circulatory Support scale, where patient profiles are classified by seven heart failure severity grades on the basis of functional capacity, clinical stability, and therapy needs.42 It is worth noting that patient profile 7 includes advanced heart failure patients that have achieved acceptable compensation with stable renal function after repeated heart failure hospitalizations. Patient profile 6 describes patients who are comfortable at rest but are significantly limited in daily activity because of high filling pressures generated by the persistence of fluid retention. Patient profile 5 addresses intolerance to exercise and profile 4 includes the presence of resting symptoms at home with oral therapy. The ‘frequent flyer’ definition is a common characteristic of the above detailed profiles and conveys the frequent need for hospital or emergency department admissions for worsening heart failure symptoms. The poor heart failure prognosis characterized by these heart failure profiles (Table 3) may identify candidates for baroreflex stimulation therapy.
The challenge of comorbidities in baroreflex activation therapy candidacy
Comorbidities are common in advanced heart failure 43 including diabetes,44 chronic kidney disease,45 respiratory sleep disorders,46 and chronic obstructive pulmonary diseases.47 Relevant to this is the evidence that obstructive sleep apnea independently induces sympathetic system activation which may contribute to heart failure progression.48
Among patients with many comorbidities, it may be difficult to judge which subgroup will have a net benefit from BAT. The extent of symptoms in such patients might relate more to the number of comorbidities than to heart failure itself. In such patient groups, a theoretical rationale might exist to quantify baroreflex impairment with a clinical test such as the phenylephrine test.
Many therapies may become less effective in highly diseased subpopulations, and BAT is not an exception. Patients with end-stage or unstable heart failure may be in an irreversible disease state such that BAT cannot contribute a beneficial treatment effect. Thus, patients with permanent NYHA class IV heart failure symptoms, with acute pulmonary edema or who need IV inotrope therapy are not ideal candidates for BAT. In addition, patients not yet on optimal drug and device therapy, and patients in the first few months after acute coronary syndrome or CRT where favorable remodeling may be occurring do not represent the target population at this moment but may become so in the future, once optimization of BAT is attained. Early use of BAT might indeed be superior to current therapies, because of its direct neural action in preventing negative LV remodeling during the progression of ischemic heart disease. Other groups who are not ideal candidates for BAT include those developing hypotensive intolerance to neurohormonal drugs such as β-blockers49 and those with accelerated renal impairment.50
These patients may have developed irreversible deterioration and may need advanced heart failure therapies (i.e. mechanical circulatory support or cardiac transplantation) rather than BAT.
Patients with baroreflex dysfunction or autonomic neuropathy may have little chance to benefit from BAT. Implantation may be complex in patients with prior surgery, radiation, or endovascular stent placement in the carotid sinus region, which may limit the ability to place the carotid sinus lead. The likelihood of benefit may be small when symptoms are driven by serious comorbidities, such as severe asthma, chronic lung disease, or active malignancy.
For effective vagal activation, BAT should be implemented after euvolemic status has been achieved because, while central venous pressure remains elevated, the venous backpressure raises renal intraparenchymal pressure that hydrostatically elevates tension in the glomerulus, which in turn, raises sympathetic tone51 at a point in the signaling pathway too distal for BAT to alleviate. A decision making chart for current eligibility for BAT is depicted in Fig. 3.
Future neurostimulation heart failure trials
The future of BAT and VNS is dependent on demonstrating solid clinical evidence of effectiveness in symptomatic NYHA class III heart failure with reduced ejection fraction (HFrEF) patients on appropriate heart failure guideline-directed therapy. The Barostim therapy for heart failure (BeAT-heart failure) trial is ongoing, randomizing patients in a 1 : 1 ratio to BAT or no BAT. The primary efficacy endpoint is cardiovascular mortality or worsening heart failure requiring hospitalization, a cardiac assist device, or a heart transplant.
The BeAT-heart failure trial began in April 2016 and is expected to close in 2021 (ClinicalTrials.Gov Identifier: NCT02627196). Should the BeAT-heart failure trial establish safety and efficacy of BAT in HFrEF, it will then be logical to study BAT in the HFpEF population in light of its efficacy in resistant hypertension.33,34
A conclusive take home message is that the current medical approach to heart failure has resulted in prolonged survival for patients by antagonizing the negative end-organ consequences of autonomic activation. Neural stimulation acting directly at the core of the autonomic storm might overcome the limits of currently available therapies, especially if initiated as early as possible. In this way, autonomic modulation may open new treatment opportunities for heart failure patients.
E.G., F.Z., C.H., and E.V. have received consulting fees and speaking honoraria from CVRx, Inc. IRCCS Multimedica has received a research grant from CVRx, Inc.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2017 Italian Federation of Cardiology. All rights reserved.
advanced heart failure with reduced ejection fraction; autonomic nervous system modulatory therapies; baroreflex activation; baroreflex activation therapy; chronic heart failure; modulatory therapies